Journal of Gerontology: MEDICAL SCIENCES
2003, Vol. 58A, No. 4, 331–353
Review Article
Management of Alzheimer’s Disease
George T. Grossberg and Abhilash K. Desai
Department of Psychiatry, Division of Geriatric Psychiatry, Saint Louis University School of Medicine, St. Louis, Missouri.
A LZHEIMER’S disease (AD) is a devastating and
debilitating neurodegenerative condition and the most
common cause of dementia in the elderly. AD may not be
a single disease but rather a group of diseases with over-
lapping pathogenetic mechanisms and clinical manifesta-
tions. The condition accounts for an estimated 60–70% of
all dementing disorders in the elderly (1). Between 5% and
10% of the population aged 65 years and older, and up to
50% of those older than 85 years of age, are estimated to
suffer from AD (2). One hundred thousand deaths per year
are attributed to AD in the United States. In the last 50
years, AD has grown from relative obscurity to becoming
a defining characteristic of industrialized society. In 1950, at
the most 200,000 people in the United States suffered from
the ailment. The total stands at 4 million today (3). By 2050,
barring a cure, the number of U.S. sufferers is expected
to reach 16 million, out of a total of 80 million sufferers
worldwide (4).
Despite consensus on both clinical (5) and neuropatho-
logic (6) definitions of AD, only limited information is
known about its etiology and pathogenesis. It is probably
caused by several mechanisms that include both genetic
and environmental influences (7). The disease manifests as
a relentless decline in a broad range of intellectual and func-
tional abilities, followed eventually by death. In addition,
as many as 90% of people with AD demonstrate clinically
significant behavioral and psychological symptoms at some
point in the course of the illness, causing severe emotional
suffering. Caring for patients with AD imposes an immense
burden on caregivers (8).
Although most patients with AD develop the disease after
the age of 65, 5–10% develop the disease at a younger age
(early-onset AD). Less than 10% of patients with AD,
almost all being early-onset AD, have a familial AD with an
autosomal dominant pattern of inheritance. Abnormal genes
on chromosomes 21, 14, and 1 appear to account for the vast
majority of cases of the early-onset familial AD (9–11). All
these genes are almost fully penetrant.
There are 3 stages of AD—mild, moderate, and severe—
with cognitive and functional decline stretching over 5–8
years on an average (range 2–20 years) (Table 1) (12). A
recent study indicates that people with AD often die within
about 3 years of diagnosis, especially those above the age of
85—a far grimmer prognosis than was previously thought to
exist (13). Without treatment, the initial, mild stage usually
lasts 2–3 years, during which time patients show short-term
memory impairment, often accompanied by symptoms of
Copyright 2003 by The Gerontological Society of America
Downloaded from biomedgerontology.oxfordjournals.org at The Australian National University on March 23, 2011
anxiety and depression. During the moderate stage these
symptoms appear to abate, as neuropsychiatric manifesta-
tions such as visual hallucinations, delusions, and reversal
of sleep patterns emerge. The severe and final stage is char-
acterized by motor signs such as motor rigidity and prom-
inent cognitive decline. Cognitive and functional decline
tend to be linear throughout the 3 stages of the disease,
whereas caregiver burden is high in severe AD, since at this
point patients require almost total care; the physical care
burden is the greatest, although the neuropsychiatric care
burden can also be considerable.
MANAGEMENT oF AD
Although the focus of many physicians is the management
of AD with cholinesterase inhibitors (ChEI), it is crucial that
physicians develop a global management strategy for their
patients with AD and their caregivers. Global management
includes early accurate diagnosis and providing counseling
and pharmacological treatment to the patient and the family/
caregiver (Table 2). The patient and family must agree with
the physician on the treatment ultimately selected for use;
this decision must include duration and cost considerations.
Both the patient’s premorbid functioning and potential im-
pact on their quality of life must be taken into account when
making any treatment decisions for AD patients. A thorough
evaluation of comorbid medical and psychiatric disorders
and a review of current medications (including discontinu-
ation of unnecessary or harmful medications) are important.
As over-the-counter products are popular, physicians are en-
couraged to ask about their use and to provide appropriate
counsel regarding their safety and efficacy. During the eval-
uation phase, emphasis must be placed on establishing a
good rapport with the patients and their families. Regularly
scheduled visits, every 1–2 months initially and then every 3
months, for health maintenance and routine patient assess-
ment will assist in maximizing independence and functioning
and will minimize behavioral disturbances associated with
the progression of the disease. Families with early-onset fa-
milial AD may be encouraged to enroll in a research database
for potential future curative therapies.
Naming the Disease
The management of AD begins with naming the disease
and evaluating its severity. The clinical diagnosis of AD can
be accurate 90% of the time. Recent data indicates that AD
can be accurately diagnosed even in very mildly impaired
individuals (14). A definitive diagnosis of AD still can be
331
332 GROSSBERG AND DESAI
Table 1. Measures of Global and Cognitive Dysfunction Associated
With the 3 Stages of Alzheimer’s Disease
Measure
Global Mini-Mental
Duration Deterioration State Exam Global
Stage (years) Scale (score)* (score)y Autonomy
Mild 2–3 3–4 26–18 Independent living
Moderate 2 5 17–10 Supervision required
Severe 2–3 6–7 9–0 Total dependence
* Scale measures progressive need for assistance in daily activities (e.g.,
choosing clothes, dressing); scores range from 1–2 (normal) through 6–7 (severe
dysfunction (219).
y nonpharmacological and, if necessary, pharmacological interventions
This 22-item scale measures cognitive function; scores range from 30 (ex-
cellent function) to 0 (severe dysfunction) (220).
Note: Reprinted with permission of Dr. S. Gauthier and Can Med Assoc J.
made only by histopathologic examination of brain tissue
after the patient’s death (15). Early and accurate diagnosis
affords the patient, family, and physician the time to plan
the best way to manage the disease. If diagnosis is made in
the early stages of AD, the patient can assume a significant
role in planning financial, legal, and care issues as well as
housing arrangements for the future. At the time of di-
agnosis, physicians need to reinforce with caregivers that
the condition is a brain disorder, and they need to clear up
any misconceptions that the family may have.
Role of the Primary Care Physician
The primary care physician will manage a growing num-
ber of persons with AD and their family members or other
caregivers upon whom these patients depend. In addition to
the diagnostic and pharmacological treatment components
of managing AD, the physician will be called upon to assist
with the behavioral, social, economic, legal, and living-
environment problems facing the patient and her or his fam-
ily. A team approach to managing these complex problems
of AD is a practical and effective management strategy. In
addition to nurses and physician assistants, the team may
include those with expertise in neurology, geriatric psychi-
atry, social work, clinical psychology, and elder law. The
neurologist assists in the differential diagnosis of patients
with atypical dementia presentation and in the management
of later stage neurologic features of AD, such as seizures. The
geriatric psychiatrist assists in the differential diagnosis of
complex cases and in the recognition and psychopharma-
cologic management of behavioral problems such as agita-
tion, psychosis, and depression. The social worker assists
in maintaining the integrity of the patient’s family unit and
in identifying and mobilizing community care resources and
may provide psychotherapy for patients and caregivers. The
clinical psychologist assists in the diagnosis of early-stage or
questionable dementia and provides expertise in behavioral
approaches to such problems as depression. The elder law
attorney assists in addressing issues such as guardianship
and health-care financial planning. Experts from other disci-
plines such as pharmacy, nutrition, physical therapy, and
occupational therapy can also make important contributions
to management. For patients with early-onset familial AD,
Table 2. Goals of Management of Alzheimer’s Disease (AD)
Patient care goals
Educating the patient regarding the disease
Symptomatic treatment with a cholinesterase inhibitor (ChEI)
Reducing excess disability
Addressing safety concerns (driving, firearms, wandering, poisonous
substances, etc.)
Addressing ability to make medical and financial decisions and capacity to
live independently
Screening for abuse and neglect
Treating medical comorbidity with intensity appropriate to the stage of the
disease and patient/family wishes
Downloaded from biomedgerontology.oxfordjournals.org at The Australian National University on March 23, 2011
Treating psychiatric comorbidity (depression, psychosis, agitation) with
Addressing end-of-life-issues
Counseling regarding research options
Family care goals
Increasing effectiveness of care and coping strategies
Increasing satisfaction with the family member’s preferred level of
involvement—often, no matter how much an individual is doing for his
or her family member with AD, he or she harbors feelings that it is
not enough
Decreasing negative consequences on the family
Minimizing family conflicts
referral to a geneticist or a genetic counselor for the whole
family and the patient is recommended.
Educating the Patient and Caregiver
During the workup and in disclosing the diagnosis to
the patient and the family, the clinician begins to educate
about AD. This discussion should include a frank, honest,
balanced view of what is known about the disease process
and available treatment options. Education regarding the
recognition of current symptoms and the symptoms likely
to occur with progression of the disease will assist in
formulating plans for safety and health maintenance. Addi-
tional sources of education should be provided. These may
include material written for the lay person, such as The
36-Hour Day (16) and Forget Me Not (17). The 3 ‘‘R’s’’—
repeat, reassure, and redirect—can help caregivers reduce
escalating behaviors and limit the need for pharmacologic
management. Caregivers should be counseled to help pa-
tients with AD maintain social and intellectual activities as
tolerated, especially important family events.
Referrals to local and national groups, such as the
Alzheimer’s Association, that are dedicated to the education
and support of patients with AD is strongly recommended.
Information about agencies such as the Administration on
Aging (202-619-1006), the Alzheimer’s Association (800-
272-3900, www.alz.org), the Alzheimer Research Forum
(www.alzforum.org), and the Alzheimer’s Disease Educa-
tion and Referral Center (800-438-4380, www.alzheimers.
org) should be provided. An additional resource may be the
American Bar Association Commission on Legal Problems
of the Elderly (202-662-8690). Other community services,
such as the local chapters of the Agency on Aging, Meals
on Wheels, and organizations providing transportation, may
all be important as a means of reducing the burden of care-
 MANAGEMENT OF ALZHEIMER’S DISEASE
giving. The physician is the critical conduit for providing
this information to the caregiver.
Genetic Testing
Testing for the apolipoprotein E-4 (APOE-4) gene, one
form of a gene on chromosome 19 that is more common
in individuals with AD than in age-matched individuals
without dementia, is not currently recommended for use in
diagnosis because it is found in many undemented elderly
and is not found in many patients with AD (18,19). Em-
pirical data on the benefits and potential harm of genetic
susceptibility testing with APOE-4 are currently being col-
lected and studied in the multicenter REVEAL study (Risk
Evaluation and Education for Alzheimer’s Disease) (20).
Patients with early-onset familial AD should be referred to
Alzheimer Disease Research Centers for counseling regard-
ing the potential benefits of genetic testing. An impersonal
relationship or an encounter created solely for the purpose
of risk assessment would seem more vulnerable to mis-
communication than would an encounter discussing risk
assessment that is embedded in a long-term clinical re-
lationship (20).
Caring for the Caregiver
Caring for the caregiver is an essential element of
managing the patient with AD. The majority of patients with
AD are cared for by family members or other caregivers
in their own homes. They frequently continue to devote
a substantial amount of time to caring for a patient after
admission to a nursing home. Caregivers are responsible
for administering medication prescribed by the physician.
The burden of caregiving exacts a heavy toll: it is estimated
that about half of all caregivers of people with dementia
suffer severe emotional distress, and dementia caregivers
have significantly higher rates of depression, physical illness,
and other health-related problems (21,22). Almost 90% of
caregivers interviewed in one study reported fatigue, anger,
and depression directly linked to caring for a demented
family member (23). Fatigue is probably the most under-
estimated reaction. Caregiving is also associated with a
greater use of sedative hypnotics and a higher mortality
rate among caregivers. Caregivers must be warned of the
dangers of emotionally, physically, and financially deplet-
ing themselves, and regular assessments must be made to
screen for psychiatric disorders in the caregivers. Spouses
of patients with AD should be also screened for a dement-
ing illness if, during the patient’s evaluation, the physician
learns about cognitive impairment in the spouse. Caregivers
often do not recognize that their guilty feelings lead them
to make unrealistic demands. It also is not uncommon for
spouses or children to feel that they would be betraying their
relatives by sending them to a nursing home.
Many caregivers are reluctant to ask for help. It is im-
portant that health care providers ask the caregivers if they
need assistance and validate their feelings. Clinicians must
be prepared to help the caregivers deal with anger, denial,
anxiety, guilt, grief, and clinical depression as they adjust to
the progression of the disease. The grief and adjustment
process for a caregiver is complex and cyclical, potentially
reactivated by the additional impairments at each new stage
333
of the illness. Family and caregiver interventions will help
not only the caregivers but also the patients with AD by pre-
venting premature institutionalization (24,25). Educational
program, training program, support, and respite services
directed toward caregivers of dementia patients may improve
their coping skills and reduce stress (26–29).
Reducing Excess Disability/Functional Impairment
Many factors contribute to functional impairment in pa-
tients with AD. They include social issues, cultural expec-
tations, environmental factors, sensory deficits (hearing
Downloaded from biomedgerontology.oxfordjournals.org at The Australian National University on March 23, 2011
and vision), pain, coexisting disease states (e.g., over- or
undercorrection of hypothyroidism, vitamin B12 deficiency,
etc.), fear of falling, and lack of motivation. Treatment of
medical comorbidity can improve function (30) and can
be important in delaying the progression of frailty (31).
For patients who need them, the value of new eyeglasses
or a hearing aid cannot be overemphasized. Such devices
facilitate patients’ understanding of and participation in
the choices surrounding care at the end of their lives. Ad-
dressing these issues can greatly improve AD patients’ func-
tional and even cognitive abilities. In addition, nursing
care and care by caregivers that creates dependency is a sig-
nificant factor in causing excess functional impairment.
Teaching the caregivers (at home as well as in long-term
care facilities [LTCFs]) to implement a restorative philos-
ophy of care is recommended. Restorative care focuses on
the restoration and/or maintenance of physical function and
helps AD patients to compensate for functional impairment
so that the highest level of function is obtained.
COUNSELING REGARDING SPECIFIC ISSUES
Should the Patients Be Told of Their Diagnosis?
In sharing the diagnosis of dementia, one needs to
consider each patient individually (32). Generally speaking,
patients in their early stages need to know the nature and
prognosis of their disease once the diagnosis is clear to the
treating physician. Physicians must not allow their own dis-
comfort—or the misguided requests of family members—to
subvert the honesty with which they relate to patients. It is
also important to ensure that the patient’s ability to com-
prehend is at its highest possible level. Disclosure may also
assist in persuading the patient to accept help and in man-
aging social needs (33). It also enables the issue of driving
safety to be addressed. With the development of new drug
treatments, disclosure allows patients to consent to partic-
ipation in clinical trials when they still have the capacity to
consent. Currently most research relies on relatives to give
proxy consent, although this has been challenged as legally
unacceptable (34). This said, there are circumstances in which
it may be ill-advised to tell a patient that he/she has AD
during the first few visits. For example, if the patient has
no support system, there is a potential that such a disclosure
may undermine his will to live. In such situations, it may
be prudent to first assist the patient in establishing support
networks and relevant services and then sensitively dis-
close the diagnosis.
In the late stages of disease the truth may neither benefit
nor harm the patient (33). Of course, there exists a greater
334 GROSSBERG AND DESAI
dilemma in the cases in which some patient understanding
remains. With sensitivity, flexibility, and discretion, such bad
news may still be delivered. Disclosure of diagnosis should
not be a one-office-visit event and must be seen as an on-
going, dynamic process and a fundamental part of the care
of a patient with dementia.
Discussion of Future Financial,
Health Care, and End-of-Life Issues
Physicians should help both the family and patient to
establish medical and legal advance directives for patients
with AD and should recommend updating the patient’s
will early in the course of treatment (35). Open discussions
regarding role and responsibility changes within the family
system should be encouraged. Assignment of health care
proxy, durable power of attorney, and discussion of end-
of-life issues, including living wills, should be addressed
while the patient is competent to make informed decisions
regarding these concerns. It is important to introduce the
topic of advance directives sooner rather than later. The un-
predictability of serious events such as hip fracture, pneu-
monia, etc., drive home the point that the discussion should
take place before the crisis occurs. Discussions about ad-
vance planning do not have to be lengthy or conclusive.
But the topic should be an agenda item in encounters with
patients with dementia, much like nutrition and safety are.
Safety Issues
Clinicians should counsel the caregivers regarding vari-
ous safety issues in the home. Caregivers need to be told when
the patient will start needing 24-hour care and supervision.
Driving.—Many elderly patients with AD may continue
to drive despite having impaired abilities (36–38). Physi-
cians often fail to identify signs of impaired mental perfor-
mance in their older patients, further compounding this issue.
A history of getting lost, misjudging distances, inappropri-
ate speed, missing signs or signals, moving violations, motor
vehicular accidents or near misses, passenger panic, etc.,
should be documented (39,40). A substantial proportion of
even mildly demented people are not safe drivers when di-
rectly observed. A substantial proportion of mildly demented
people can pass performance tests. For patients with very
mild AD, formal, serial performance evaluations are recom-
mended. Patients with more advanced AD should be recom-
mended to discontinue driving. All patients with AD should
be systematically evaluated regarding their driving abilities.
Presence of firearms.—Many elderly in the United States
have firearms in their households, most of which are stored
loaded (41). Each patient and his or her family/caregiver
must be specifically asked about access to firearms. The
physician must advocate for the safe storage or removal of
these firearms. Any firearms in the patient’s house should be
disabled in order to prevent accidental gunshot wounds or
deaths.
Wandering.—Families should be warned of the hazards of
wandering. Supervised walks and using door locks or elec-
tronic guards to prevent wandering are recommended. Regis-
tration with the Safe Return Program through the Alzheimer’s
Association should be encouraged. Ethical considerations
should be kept in mind when using electronic tagging de-
vices in patients with AD who have a tendency to wander
(42). When used, particularly in mild AD patients, these
devices are often demoralizing and dehumanizing.
Poisonous or harmful substances.—Families and care-
givers need to be counseled to keep such substances out of
the reach of patients with AD.
Downloaded from biomedgerontology.oxfordjournals.org at The Australian National University on March 23, 2011
Other safety concerns.—Families and caregivers should
be counseled to modify the place of living in order to reduce
objects and hurdles that might increase the risk of falls.
Sharp objects should be kept out of the patient’s reach, and
appliances and power tools should be kept unplugged and
out of sight. Smoke alarms should be kept in working order.
A home visit for safety assessment and guidance by a social
worker may be helpful.
Counseling Regarding Long-Term Care Placement
As many as 90% of patients with AD reportedly become
institutionalized before death (43). However, most patients
with AD continue to live in the community until family
caregivers are no longer able to care for them. Patient char-
acteristics (e.g., high cognitive impairment, one or more
dependencies in ADL, difficult behaviors) and caregiver
characteristics (e.g., high caregiver burden) are both impor-
tant determinants of long-term care placement for patients
with dementia (44). Planned admissions to a LTCF may
be better than unplanned admissions (45). Numerous local,
state, and federal agencies monitor nursing homes, but vigi-
lant, assertive family members may be most helpful in as-
suring quality care. High-quality LTCFs encourage family
participation. Before choosing a LTCF, consumers should
examine reports of the deficiencies found in state inspec-
tions. These can be accessed at the website www.medicare.
gov. Family members should also contact their state Depart-
ment of Health with concerns about general conditions or
care in nursing homes; the ombudsman in their local aging
department about problems with finances, property, or other
consumer concerns; and local police or their aging depart-
ment’s office of protective services with any concerns about
abuse.
OTHER IMPORTANT ISSUES
Abuse and Neglect
Patients with AD are certainly at high risk of abuse and
neglect (46). Estimates of the prevalence of abuse of older
adults suffering from dementia range from 5.4% to 11.9%
(46). They far exceed the 1–4% prevalence rates typically
cited for all older adults, cognitively intact as well as de-
mented (47). The physician must acknowledge that not only
will some family members have conflicts with AD patients,
but a small number will actually neglect or abuse their AD
relatives. This also applies to nonfamily members or profes-
sional caregivers. Physicians must be able to identify the
 MANAGEMENT OF ALZHEIMER’S DISEASE
potential for emotional, physical, sexual, and financial abuse
or neglect, detect its occurrence, and deal with situations in
which abuse is present. Financial abuse by telemarketers
and other people (including those on television) who make
patients with AD easy victims of solicitation should also
be suspected and reported to the state’s attorney general
office. A prior history of abuse is associated with a greater
likelihood of abusiveness once dementia occurs. Malnutri-
tion, noncompliance with medications, bruises, decubitii,
poor personal hygiene, and other evidence of trauma are
some of the signs that should alert physicians that abuse
or neglect may be an issue. Physicians need to learn their
state’s law on reporting of suspected elder abuse. Interven-
tions such as supportive counseling, individual or family
psychotherapy for caregivers, respite or in-home care ser-
vices for patients, and alternative living situations for all
parties concerned may be helpful.
End-of-Life Care
Dementia severity and other patient characteristics are
important for informed end-of-life decision making and
for assessing effectiveness of interventions in severely de-
mented patients in order to prevent an unfavorable outcome
of medical comorbidity, such as pneumonia or hip fracture
(48). Patients with advanced dementia commonly develop
difficulty eating, often when they become bedridden and
dependent in all activities of daily living (49–51). They may
resist or be indifferent to food or fail to manage the food
bolus properly once it is in the mouth (oral phase dys-
phagia). In moderately demented patients, prevention of
aspiration and weight loss, if possible, may improve mid-
term outcome (52). Enteral tube feeding is intended to
prevent aspiration pneumonia, to forestall malnutrition and
its sequelae, including death by starvation, and to provide
comfort. There is no evidence to indicate that tube feeding
improves any of these clinically important outcomes, and
some data seem to indicate that it does not (53,54). Indeed,
tube feeding may increase the risk of aspiration. In addition,
the risks of this treatment are substantial. Nasogastric tubes
may promote sinus and middle ear infections, and gastro-
stomy tubes may cause cellulitis, abscesses, necrotizing
fasciitis, and myositis. Many patients are put in physical
restraints to prevent tube removal. For severely demented
patients, the practice of tube feeding should be discouraged
on clinical grounds, but this decision needs to be made in
the context of the patients’ and families’ moral and religious
belief systems. There are no published studies that compare
tube feeding to oral feeding.
It is possible to convert tube feeding to hand feeding and,
in some cases, patients may be able to feed themselves again
(55). Withdrawing sedatives and psychotropic medications
should be considered in AD patients with swallowing prob-
lems, because these medications may reduce consciousness
and thus predispose the patient to aspiration pneumonia.
Improving oral care is recommended to reduce oropharyn-
geal colonization by pathogens. Inadequate staffing and lack
of supervision at mealtime may contribute to weight loss in
nursing homes. If fed quickly, AD patients may cough or
choke or aspirate. Adequate staffing and allowing patients
with AD to take their time to eat is thus very important.
335
In the presence of dementia, successful cardiopulmonary
resuscitation (CPR) is 3 times less likely to succeed, as
compared to CPR in patients with metastatic cancer (56). In
addition, in the demented population, most cardiac arrests
occur in long-term care institutions, not acute-care hospitals.
The success rate of CPR is only 1% in demented LTCF
residents. The benefits of successful CPR are further dimin-
ished because of injuries, such as broken ribs, associated
with CPR and because of the need for mechanical venti-
lation. Families should be counseled about these outcomes
and whether the patient and family would like ‘‘do not
Downloaded from biomedgerontology.oxfordjournals.org at The Australian National University on March 23, 2011
resuscitate’’ directives instituted. These discussions should
ideally occur when the patient is in the early stages of AD
and thus can be an active participant.
Antibiotic therapy may be withheld in some frail AD
patients who are expected to die soon (such as patients in
their severe to terminal stages of AD). Most severely de-
mented AD patients are indeed frail and at high risk of dying
from pneumonia or sepsis, in spite of antibiotic treatment
(54). Palliative management of symptoms such as pain, dys-
pnea, etc., in patients with severe to end-stage AD should be
similar to that used in patients who are dying from cancer.
An agreed-upon, documented goal and treatment approach
for all health-care team members is an essential component
of end-of-life care for AD patients. Management should
involve vigilance to ensure good symptom management,
support to families of patients with AD in their end-stages of
dementia, communication with other health team members,
and objective documentation. Palliative care is an appro-
priate treatment strategy for the management of patients with
advanced AD. Palliative care should never mean that the
patient with AD receives less care. Rather, palliative care
replaces aggressive intervention, with care oriented toward
comfort. Hospice care may be appropriate for patients with
AD in the terminal stages of the disease (57).
PHARMACOTHERAPY oF AD
ChEI Therapy
This class of drugs is presently regarded as the standard
treatment of AD. Four ChEIs have been approved by the
U.S. Food and Drug Administration (FDA) for the treatment
of mild to moderate AD. They are tacrine, donepezil, rivas-
tigmine, and galantamine. These compounds increase the
concentration of acetylcholine and the duration of its action
in synapses by inhibiting the degradation of acetylcholine.
These compounds provide symptomatic treatments and may
also have disease-modifying effects. They have been shown
in several large, multicenter, randomized, double-blind,
placebo-controlled trials (of 3–6 months’ duration) to im-
prove cognitive function, global outcome, and activities of
daily living (58–61). There is also accumulating evidence
that ChEIs may improve behavioral and psychological symp-
toms of AD, such as psychosis and apathy (62). Treat-
ment with ChEIs may also help caregivers by reducing the
burden of caregiving (63). The mean effect of drug over
placebo represents an improvement in cognition roughly
equivalent to stemming 6–12 months of natural decline in
untreated patients. There is preliminary evidence from a retro-
336 GROSSBERG AND DESAI
spective return drop-out data indicating that the effects of
rivastigmine on cognition may be sustained in rivastig-
mine-treated patients and indicating that rivastigmine may
affect disease progression (64). Evidence with the ChEIs
also suggests that the effect is extremely variable, with large
improvements in some patients and none in others. At the
moment we have no reliable way of distinguishing potential
responders from nonresponders. When response occurs, it
does so relatively quickly (12 weeks). The only certain way
of proceeding is therefore to use a ChEI for at least 12 weeks
at the proper dose and to observe the results systematically.
The physician should seek evidence of changes in all 3
domains (cognition, ability to perform ADL, and behavior)
to determine if the patient has benefited from the ChEI.
Group means hide a marked heterogeneity of response, as
40–50% of patients show a definite clinical improvement
(
4 points on the AD assessment scale–cognitive subscale
[ADAS-cog], equivalent to stemming half a year or more
of natural cognitive decline), whereas 20% show a stronger
response (
7 points on the ADAS-cog, equivalent to stem-
ming a year or more of natural cognitive decline). Respon-
ders are maintained close to baseline for 12–18 months on
both cognitive and noncognitive measures. No reliable pre-
dictors of response have emerged, and in each patient,
careful assessment of benefit needs to be undertaken after
2–4 months of treatment.
Tacrine.—Tacrine was the first ChEI to be approved
specifically for the symptomatic treatment of patients with
mild to moderate AD. The starting dose for tacrine is 10 mg
4 times daily, and this dose is increased by 40 mg/day no
more frequently than every 4 weeks (according to tole-
rance), to a maximum daily dose of 160 mg (40 mg 4 times
daily). Tacrine has been associated with hepatotoxicity (65)
and thus requires baseline and multiple follow-up liver
enzyme determinations. This along with the need for mul-
tiple daily dosing makes it unsuitable as a ChEI of first
choice. We recommend that its use be restricted to patients
who do not tolerate or respond to ChEIs. Tacrine is exten-
sively metabolized by the liver via the cytochrome P450
1A2 isoenzyme system; therefore, it has the potential to
interact with other medications metabolized by this isoen-
zyme, such as theophylline, fluvoxamine, and cimetidine.
Tacrine should be avoided in patients with liver disease.
Donepezil.—Donepezil was the second ChEI approved by
the FDA for symptomatic treatment of mild to moderate AD
in the United States. Two placebo-controlled clinical trials
of donepezil have been reported in which efficacy was
demonstrated for 1 year in mild-to-moderate AD based on
cognitive (66) and functional (67) measures. Donepezil is
largely metabolized by the liver, although some of the dose
is recovered in the urine as unchanged drug (11–17%) (68).
It is metabolized by the cytochrome P450 isoenzymes 2D6
and 3A4. Clinically relevant drug interactions with other
drugs have not been studied. Interaction with paroxetine
(patient developing increased confusion and agitation) has
been reported (69). Caution should be exercised in using
donepezil in patients with severe hepatic or renal disease.
The recommended starting dose is 5 mg daily, which is
increased to 10 mg daily after 4–6 weeks. Morning dosing
of donepezil may be preferable in some patients who ex-
perience nightmares or insomnia. It may be taken without
regard to meals unless gastrointestinal side effects occur, in
which case it should be taken with meals. Although there is
1 case report of fulminant hepatitis with the concomitant use
of donepezil and sertraline (70), laboratory monitoring of
liver enzymes is not required.
Rivastigmine.—This was the third ChEI approved by the
Downloaded from biomedgerontology.oxfordjournals.org at The Australian National University on March 23, 2011
FDA for symptomatic treatment of mild to moderate AD in
the United States. Rivastigmine should be titrated every 4
weeks, as opposed to every 2 weeks, as recommended when
the drug was first made available. Slower titration and
taking rivastigmine with a full meal significantly improves
tolerability, especially with regard to gastrointestinal side
effects. One unique feature of rivastigmine that distingui-
shes it from other ChEIs is the very low risk of drug inter-
actions in AD patients receiving multiple medications for
‘‘real-world’’ comorbidities (71). This is because the meta-
bolism of rivastigmine occurs primarily via enzymatic
cleavage (hydrolysis) by cholinesterases at the site of action
and does not require the cytochrome P450 enzyme system.
The starting dose is 1.5 mg twice a day with meals (break-
fast and supper), and this dose is increased by 3 mg/day, not
faster than every 4 weeks (as tolerated), to a therapeutic dose
of 6–12 mg/day. The highest tolerated dose is recommen-
ded, as there is some evidence that higher doses may pro-
vide greater benefits. A more rapid progression of AD while
receiving placebo treatment was predictive of a significantly
stronger patient response to rivastigmine therapy on various
measures (72). Laboratory monitoring is not required.
Galantamine.—This was the fourth ChEI approved by the
FDA for symptomatic treatment of mild to moderate AD in
the United States. Metabolism is hepatic via glucuronidation
and the cytochrome P450 isoenzymes 2D6 and 3A4; inter-
actions with other drugs that are metabolized through this
pathway are therefore possible. Caution should be used in
patients with liver disease. The starting dose is 4 mg twice
a day, and this dose is increased every 4 weeks. The thera-
peutic dose is 16–24 mg/day. A 6-month study showed no
additional benefit and a higher rate of side effects with a dose
of 32 mg/day (73). Laboratory monitoring is not required.
Role of Butyrylcholinesterase and Nicotinic Modulation
Humans have 2 types of cholinesterase: acetyl and buty-
ryl. The physiological role of butyrylcholinesterase is being
investigated, but levels of this enzyme have been shown to
increase as AD progresses, whereas levels of acetylcholin-
esterase decrease (74). Both enzymes are found in neuritic
plaques, and their inhibition with ChEIs may modify the
deposition of beta-amyloid, a key component of the patho-
physiology of AD as we currently understand it. The clinical
significance of this action, if any, in terms of slowing pro-
gression of the disease or better symptomatic efficacy in
later stages has yet to be fully established. Of the currently
available ChEIs, only tacrine and rivastigmine have the
ability to inhibit butyrylcholinesterase. Of the currently avail-
 MANAGEMENT OF ALZHEIMER’S DISEASE
Table 3. Characteristics of Commonly Used Cholinesterase Inhibitors (ChEIs)
Donepezil
1. Elimination half-life (hr) 70–80
2. Metabolism Liver
3. Protein binding 96%
4. Food interaction No
5. Dosing Once daily
6. Pricing 2 Level
7. BuChE inhibition No
8. Nicotinic modulation No
9. Specific AchE subtype inhibition No
10. Titration 1 Step
* Enzyme inhibition significantly outlasts elimination half-life.
Note: BuChE ¼ butyrylcholinesterase; AchE ¼ acetylcholinesterase.
Reprinted (with modification) by permission of Dr. R. Bullock and Br J Psychiatr. 2002;180:135–139.
able ChEIs, only galantamine has the property of allosteric
modulation of the presynaptic nicotinic receptors. The
potential significance of this effect is additional increase in
cholinergic neurotransmission. Whether this provides any
additional clinical benefit over other ChEI has not been
proved at the present time.
Which ChEI Should Be the First Choice?
Only direct comparisons between various currently avai-
lable ChEIs will provide definitive data that can be used
to maximize patient outcome. In general, these agents all
have similar degrees of efficacy. However, there are some
important differences (refer to Table 3). Certain patients may
benefit more from one particular agent over the others. For
AD patients living alone who do not have close daily super-
vision over their medications, donepezil may be preferable
because of its once-a-day dosing. For patients with AD who
also have hepatic disease or who are on numerous other
medications metabolized by cytochrome P450 2D6 and 3A4
enzymes, rivastigmine may be preferable because of its lack
of cytochrome P450 metabolism. Patients with AD who ex-
perience impaired sleep or excessive dreaming with done-
pezil may benefit more from rivastigmine or galantamine.
Switching From One ChEI to Another
There is some preliminary evidence that if a patient
does not respond to one ChEI, switching to another may
be beneficial (75,76). Switches can also be performed to
cope with side effects (75,77). In general it is not difficult
to switch from one drug to another among the 3 ChEIs
(donepezil, rivastigmine, and galantamine). Combination of
ChEI is not recommended. Standard dose escalation using
monthly titration is recommended. Preliminary data indicate
that for patients experiencing no safety/tolerability problems
on a ChEI, another ChEI can be administered the follow-
ing day with no washout period (78,79). If the patient is
experiencing safety/tolerability problems with a ChEI, a
washout period of 7 days, or until symptoms resolve, is rec-
ommended before switching to another ChEI (78,79). As
yet, no guidelines for switching from one ChEI to another
have been published.
337
Rivastigmine Galantamine Clinical Relevance
0.6–2* 7–8 Easier to switch from drug with shorter half-life
By AchE Liver Liver metabolism involves P450 system: potential for drug
interaction
40% 8% Potential for interaction with drugs having high protein
binding
Yes No Need to take the drug with meals if food interaction
Twice daily Twice daily Compliance issues
Flat rate 3 Level Cost implications
Yes No Unknown
Downloaded from biomedgerontology.oxfordjournals.org at The Australian National University on March 23, 2011
No Yes Unknown
Yes No Unknown
2–4 Steps 2–3 Steps Complex titration may influence decisions in busy
practices
Importance of Starting ChEI Early
Patients with AD who begin treatment with a ChEI later
do not do as well as those who began treatment early
(73,80,81). In a 1-year study, in which the double-blind,
placebo-controlled phase lasted for 26 weeks, all subjects—
whether started on rivastigmine or placebo—were switched
to open-label rivastigmine and followed for an additional 26
weeks (81). Patients who were initially placed on placebo
and later started on rivastigmine seemed to respond to the
ChEI and had a significant increase in cognitive function,
but then they started to decline. They never caught up to
the group that started on rivastigmine initially. Similar find-
ings were seen with galantamine and donepezil (73,80). An
open-label extension study found that the group that was
started on donepezil (10 mg/day) and continued on this
dosage functioned better for 18 to possibly 24 months
longer than persons who were initially on placebo and then
started on donepezil (10 mg) (80). These findings indicate
the importance of starting ChEI as early as possible in AD.
Early institution of ChEI may also delay the emergence of
neuropsychiatric symptoms in patients with mild to mod-
erate AD, as shown in a 5-month placebo-controlled study
with galantamine (82).
More Advanced AD and ChEI Therapy
There is preliminary evidence that the beneficial effects of
ChEIs may extend to more advanced (moderate to severe
AD) stages and that effects may even be more robust than
seen in mild to moderate AD (83). In this 24-week, random-
ized, double-blind placebo-controlled study, the donepezil
group showed significant improvement in the neuropsychia-
tric inventory (NPI) scores, whereas the placebo group
worsened slightly. The donepezil group was better than the
placebo group for all individual items in the NPI, with sta-
tistically significant differences seen for depression, anxiety,
and apathy (83).
Treatment of AD With ChEIs
in the Nursing Home Setting
Very little controlled data is available for the potential
benefits of ChEIs in patients with AD in the LTCF setting.
338 GROSSBERG AND DESAI
Donepezil was found to be beneficial in the domain of cog-
nition and overall dementia severity compared to placebo in
a 6-month treatment period of AD patients in the nursing
home setting (84). Unfortunately, no significant differences
were obtained in the noncognitive domains of behavioral
disturbances and ADL in this study. An open-label, 52-
week study of rivastigmine in nursing home patients with
AD demonstrated improvement in many of the behavioral
and psychiatric symptoms, such as irritability, anxiety, de-
lusions, hallucinations, disinhibition, aberrant motor activ-
ity, nighttime behavior, and appetite (85). In addition, about
40% of patients who were on neuroleptic medications for
these symptoms were able to reduce or discontinue these
medications over the course of the study. Patients with AD
in the nursing home are generally older, exhibit greater se-
verity of dementia, and have more comorbid illness than
do AD patients in the community.
Use of ChEIs in Non-Alzheimer’s Dementias
ChEIs are approved for use in mild to moderate AD only,
and use of these agents to treat other dementing disorders is
an off-label use. There is initial evidence from randomized,
double-blind, placebo-controlled studies that ChEIs may
also benefit cognition, daily functioning and behavioral
symptoms in vascular dementia (VaD) and Lewy body
disease/dementia (LBD) (86–88). Both of these dementing
disorders have been found to have an associated cholinergic
deficit. Preliminary data indicates that early and widespread
cholinergic losses may help differentiate LBD from AD
(89), suggesting that cholinergic replacement therapy may
be even more effective in LBD than in AD, especially in
mild-stage disease. We recommend a trial of ChEIs for
patients with VaD and LBD. Other disorders associated with
cholinergic deficit include but are not limited to Parkinson’s
disease with dementia and Down’s syndrome with pro-
gressive cognitive decline. These disorders may also benefit
from a trial with ChEI, although large controlled studies are
lacking. The only double-blind, placebo-controlled 24-week
pilot study in patients with Down’s syndrome
and AD showed that improvement in the donepezil group
was not significantly better than improvement with placebo.
Surprisingly, noncognitive symptoms showed less improve-
ment than they did in the placebo group (90). The biological
basis of these findings is not yet certain. No therapeutic
benefit is anticipated in dementia syndromes without a
cholinergic deficit, such as frontotemporal dementia or
Huntington’s dementia. Nonprogressive dementias, such as
those secondary to traumatic brain injury or anoxic enceph-
alopathy, may also not respond to ChEIs.
Patient Selection, Management of Adverse Effects,
and Therapeutic Outcome
All pivotal studies have investigated patients with mild to
moderate AD. How early in the course of AD ChEIs should
be initiated and for how long they are of use have not been
elucidated fully. Although most studies have been done
in patients with mild to moderate AD (Mini-Mental State
Exam [MMSE] scores between 10 and 26), clinicians are
recommended to consider ChEI even in patients with AD
and scores of more than 26 or less than 10. We recommend
that patients should continue on these medications until
they no longer have meaningful interactions with other indi-
viduals, because ChEIs may still help alleviate behavior
problems even when cognition is severely impaired. Several
factors influence medication prescribing for most older pa-
tients with AD, resulting in considerable variability and the
need to individualize treatments. Elderly patients often take
multiple medications, so the clinician must be aware of
potential drug interactions. Patients with symptomatic bra-
dyarrhythmia, active peptic ulcer disease, and acute exacer-
bation of chronic obstructive pulmonary disease and asthma
Downloaded from biomedgerontology.oxfordjournals.org at The Australian National University on March 23, 2011
may experience worsening of their problems because of the
mild peripheral cholinergic effects of ChEIs. Generally,
ChEIs can be safely instituted once these conditions are
stabilized. Adverse effects are similar for all ChEIs and
typically are gastrointestinal (nausea, vomiting, diarrhea,
anorexia, and weight loss) in nature. They are usually seen
during dose escalation. Other adverse effects such as abdom-
inal pain, dizziness, syncope, and headache have been also
described but are less common. Adverse effects are usually
mild to moderate in severity and resolve spontaneously or
after dosage reduction. The frequency of adverse effects
dramatically increases when the dose of a ChEI is increased
too rapidly (in 1–2 weeks). Their frequency is very low dur-
ing the maintenance phase. Potential for prolonging the
effects of the muscle relaxant succinylcholine, used during
anesthesia, exists with all ChEIs but does not seem to be
clinically significant, although the anesthetist should be
informed of the possibility. We do not recommend discon-
tinuing these drugs a few days prior to surgery because of
the risk of cognitive deterioration. If for any reason a ChEI
is discontinued for a significant period and need to be re-
instituted, it should be done by again starting at the lowest
dose and gradually titrating upward to the highest tolerated
therapeutic dose. These drugs have not been well studied
in patients with severe hepatic or renal impairment. Hence,
caution should be exercised when using a ChEI in this pa-
tient population.
Dose titration should be as slow as necessary to prevent
the development of gastrointestinal or other side effects. The
risk of nausea can be reduced by administering the medi-
cation on a full stomach, and intermittent antiemetics can
be used if necessary. Patients should be titrated up to the
highest therapeutic dose they can tolerate (for donepezil it is
10 mg/day, for rivastigmine it is 12 mg/day, and for galan-
tamine it is 24 mg/day). Once therapy with ChEI is begun
and the therapeutic dosage reached, patients should be eval-
uated every 3 months to monitor response to treatment in 3
domains, cognitive, functional, and behavioral. If unaccept-
able side effects occur at higher doses, the dose should be
decreased as long as it is in the therapeutic range. If side
effects develop with dose escalation, we recommend going
back to the tolerated dose and then increasing the interval
of dosage escalation. ChEI should be discontinued if side
effects persist at the lowest therapeutic dose, if the patient
shows accelerated decline after a 6-month trial, or if a
medical condition develops that significantly increases the
risk benefit ratio. The lowest therapeutic dose is 5 mg/day
for donepezil, 6 mg/day for rivastigmine, and 16 mg/day for
galantamine. If patients with AD are not able to tolerate
 MANAGEMENT OF ALZHEIMER’S DISEASE
more than donepezil 5 mg/day, rivastigmine 3 mg/day, or
galantamine 8 mg/day, another agent should be considered.
Patients who have been on one ChEI and failed to benefit
(due to intolerable side effects or accelerated decline) should
be considered for a trial with another ChEI. Incontinence
and increased behavioral disturbances (irritability) have been
described with donepezil use and may be seen with other
ChEIs as well.
The course of AD tends to be slowly progressive, with
a loss of 3–5 points per year on a standard assessment in-
strument such as the MMSE. Caregivers and patients must
have realistic expectations (Table 4); these drugs’ effects are
modest, and sometimes no symptomatic improvement is
noted. In fact, a report of Ôno change’ means that these drugs
are helping, because without ChEI treatment, one would
have seen a decline in functioning.
If a ChEI is stopped, rapid deterioration can occur in
some patients. Also, reintroducing the drug after the AD pa-
tient has been taken completely off a ChEI may not yield the
same benefit. By tapering the dosage slowly, we can detect
early those patients who are going to lose function or show
cognitive deterioration. If they do, then there exists a good
reason not to take them off the drug. Only very early in the
disease will the patient be able to self-report improvement
or benefit. Many of the patients, by the time they are diag-
nosed, have already lost insight and are unable to appreciate
the benefits of ChEIs.
Other Agents for Treatment of AD
Metrifonate.—Metrifonate is another ChEI that has been
investigated for the treatment of mild to moderate AD.
Metrifonate was found to be beneficial in areas of cognition,
global functioning, and ADLs, compared to placebo in
patients with mild to moderate AD, in a meta-analysis of
4 randomized, double-blind, placebo-controlled trials (91).
Unfortunately, development of this agent was halted re-
cently secondary to problems with muscle weakness and
respiratory paralysis.
Memantine.—Memantine, a noncompetitive, highly volt-
age-dependent NMDA antagonist, has been approved for
use in the treatment of dementia in Germany for over 10
years and recently was approved for use in the treatment of
AD in the European Union. It has been found to be useful
in more advanced (moderate to severe) cases of AD (92).
Patients with AD in the United States may import the drug
or consider participating in double-blind, placebo-controlled
studies currently underway at numerous sites all over the
country. The FDA is currently reviewing the data for ap-
proval of its use in the United States.
Ginkgo biloba extract.—Oken and colleagues reviewed
the published literature on efficacy of Ginkgo biloba for AD
(93). They identified 4 well-designed, randomized, placebo-
controlled studies that met their inclusion criteria. They
concluded that treatment with Ginkgo biloba extract (120 to
240 mg/day for 3–6 months) had a small but significant
effect on objective measures of cognitive function in AD.
We need further research to determine whether there is im-
339
Table 4. Clinical Expectations From Cholinesterase Inhibitor
Therapy
Primary benefits
Maintain current level of daily functioning or slow the decline in current
level of functioning
Maintain current level of cognition or slow the cognitive decline associated
with Alzheimer’s disease (AD)
Decrease emergence of behavioral and psychological disturbances
associated with AD
Secondary benefits
Decrease caregiver burden and distress
Downloaded from biomedgerontology.oxfordjournals.org at The Australian National University on March 23, 2011
Decrease overall health-care cost
Delay institutionalization
Caregiver and physician expectations
‘‘No change’’ means cholinesterase therapy is helping
provement in noncognitive behavioral or ADL functions
with Ginkgo biloba extract, since this is critical in eval-
uating the use of treatment in AD. Also, there is no data
regarding the safety of the use of Ginkgo biloba extract
along with ChEIs.
Antioxidants (vitamin E and selegiline).—In a double-
blind, randomized, placebo-controlled study (94), fewer
participants (58%) in group taking vitamin E (2000 IU/
day) and selegiline (5 mg bid) reached 1 of the 4 endpoints
(death, institutionalization, loss of 2 out of 3 basic ADL,
or severe dementia), compared to 74% with a placebo.
However, more participants taking vitamin E suffered a fall
compared to patients receiving a placebo. It was not possible
to interpret the reported results for specific endpoints (95).
There was no difference between the vitamin E group and
the selegiline group. There appeared to be no additive bene-
fit to treatment with both agents. The principal concerns
with high-dose (2000 IU) vitamin E are gastrointestinal
upset and prolonged clotting time, with easy bruisability or
bleeding. A lower dose (400 iu bid) of vitamin E is recom-
mended by many experts for patients with AD and may be
associated with lowered risk of adverse effects without
compromising the beneficial effects. In patients with AD,
selegiline leads to small short-term improvement in cogni-
tion and activities of daily living. Selegiline does not improve
emotional state or global response (96). For patients with
AD who can tolerate vitamin E, there is no reason to take
selegiline.
Estrogen.—Clinical trials indicate that oral conjugated
equine estrogen is not an effective treatment for AD in
postmenopausal women (97,98). Hence, estrogen is not rec-
ommended for the treatment of cognitive or functional
deficits attributable to AD. Preliminary data indicate that
short-term estrogen therapy may safely decrease the fre-
quency and severity of behavioral disturbances of dementia
in elderly patients (99,100). Larger randomized, controlled
studies are needed to further explore the potential benefits of
estrogen in the treatment of behavioral disturbances (aggres-
sion, sexual disinhibition) in patients with AD. There is in-
creasing evidence that estrogen may decrease the risk for or
340 GROSSBERG AND DESAI

Table 5. Common Behavioral Disturbances in Dementia

Aggression Affect mood
Verbal Anxiety
Screaming Depressive symptoms
Cursing Apathy
Irritability
Physical
Anger outbursts
Hitting
Biting Thought and perception
Kicking Delusions
Scratching Hallucinations
Grubbing Illusions

Downloaded from biomedgerontology.oxfordjournals.org at The Australian National University on March 23, 2011
Misperceptions
Nonaggressive behavioral
Verbal Vegetative symptoms
Repetitive questioning Sleep disturbances
Complaining Insomnia
Increased daytime napping
Physical
Sundowning
Wandering
Pacing Sexual
Hoarding Hyposexuality
Rummaging Hypersexuality
Hiding Sexual disinhibition
Taking other people’s belongings Appetite
Voiding in inappropriates places Poor food intake
Shadowing Hyperphagia
Resistance to care
Intrusiveness
Fatigability
Mannerisms

delay the onset of AD in postmenopausal women (101,102).

However, this has not been universal (103,104), and a num-
ber of methodological shortcomings in these studies have
been identified (105). These potential benefits have to be
weighed against the known risks of estrogen, such as in-
creased risk of thromboembolism and gynecological cancers.

Figure 1. An algorithm for the management of behavioral disturbances in

TREATMENT oF BEHAVIORAL AND PSYCHOLOGICAL
SYMPTOMS oF AD
The most challenging aspect of AD care is management
of behavioral and psychological signs and symptoms of
dementia (BPSD) (106,107). BPSD are common, serious
problems that affect the quality of life of both patient and
caregiver and that frequently result in premature institu-
tionalization. The majority of BPSD in AD are of clinical
significance based on their severity and because of co-occur-
rence of multiple symptoms (108). BPSD are associated with
more rapid rates of cognitive and functional decline. BPSD
include agitation, aggression, delusions, hallucinations, de-
pression, apathy, sleep disturbances, and sexually inappro-
priate behaviors (Table 5). These difficulties occur in 90%
of patients at some point in the course of the disease and
have been described in all dementing illnesses. Many clinical
practice guidelines (109,110) have addressed the treatment
of these disturbances, noting that even modest improvement
in these behaviors can markedly improve quality of life for
both patient and caregiver. Practice guidelines frequently
recommend starting with behavioral and environmental
approaches, followed by a wide variety of pharmacologic
interventions, including antipsychotics, antidepressants, and
patients with Alzheimer’s disease (AD).
anticonvulsants. For a comprehensive review of manage-
ment of BPSD in patients with AD, the reader is referred
to the review article on recognition and management of
behavioral disturbances in dementia by the authors (107).
Figure 1 provides an algorithm for the management of
behavioral disturbances in patients with dementia. Before
any behavioral symptoms are ascribed to AD, the possibility
that the symptom is produced by environmental influences
or by intercurrent medical problems needs to be eliminated.
Environmental influences that may affect behavior include
temperature extremes, excessive noise, and physical re-
straints. In addition, many medical conditions, including
cardiovascular disease, chronic obstructive pulmonary
disease, infection, anemia, and metabolic disorders, may
produce behavioral symptoms. One of the more common
conditions that may elicit behavioral disturbances in patients
with AD is unrecognized pain. Because AD individuals fre-
quently are unable to express pain verbally, any patient exhib-
iting new or increased behavioral symptomatology should
be carefully evaluated for the presence of pain.
 MANAGEMENT OF ALZHEIMER’S DISEASE
After environmental or physical reasons for behavioral
symptoms are eliminated, it is essential to determine which
psychiatric syndrome of dementia is producing agitation.
Treatment of depression, psychotic symptoms, and anxiety
symptoms is more effective than treating several individual
peripheral symptoms such as insomnia, aggression, weight
loss, etc. Psychotropic medications play a critical role in the
management of behavioral disturbances of patients with AD.
Table 8 lists the principles of using pharmacotherapy to
manage behavioral disturbances in patients with demen-
tia. Although improved quality of life for AD patients and
caregivers can be achieved in many cases with appropriate
pharmacotherapy, there is currently no FDA-approved medi-
cation for the treatment of behavioral symptoms of AD. For
the treatment of mild behavioral problems, ChEIs are an
effective treatment option, although in some patients they
may exacerbate BPSD (111).
NONPHARMACOLOGICAL INTERVENTIONS
Nonpharmacological interventions are the key to man-
agement of BPSD. The majority of AD patients are calmer
and better adjusted when treated with low-tech, nondrug
approaches that help to decrease problem behaviors and
promote independence (Table 6). The foundation of non-
pharmacologic management is recognizing that the person
with dementia is no longer able to adapt and that instead
the environment must be adapted to the patient’s specific
needs. Caregivers should be counseled to learn to change
what can be changed through information gathering and di-
rect action. They must also train themselves to cope with
their reactions to what cannot be changed (and ‘‘intrapsy-
chic’’ tricks or reframing perspectives—‘‘tomorrow will be
better,’’ ‘‘my husband is difficult but he could be worse’’).
Positive outcomes derived from support groups include
not only increased knowledge of the illness and services
available as well as decreased feelings of isolation but also
creative and practical suggestions for dealing with BPSD
using nonpharmacological interventions. Adult day services
are often an effective method for managing demented pa-
tients and postponing the need for institutionalization.
Caring for loved ones with AD is psychologically and physi-
cally challenging but also provides the family with oppor-
tunities for personal growth and deepening of relationships
with the patient and other family members. Behavioral
disturbances are often provoked through interaction with
caregivers. The manner in which caregivers approach the
patient with AD is critical, because most episodes of aggres-
sive behavior occur during contact with caregivers. Effective
strategies include leaving the patient and returning later or
having one caregiver distract the patient while another is
providing care. As ADL dependence on others increases,
patients are at risk of invalidism, social isolation, lower self-
esteem, depression, and a loss of control over their destiny,
which may in turn generate a sense of helplessness and hope-
lessness. Inactivity also increases the risk of pressure sores,
falls, loss of range of motion, and muscle wasting. Structured
and unstructured activities improve subjective well-being,
help maintain function, and decrease BPSD. People with AD
are still people, with the same emotional needs as all people.
They need to know they are loved and they need to feel good
341
Table 6. Nonpharmacological Interventions for the Treatment
of Alzheimer’s Disease (AD)
Interventions with the patient
Specific nonpharmacological interventions
Behavior-oriented approaches
Behavioral treatment (increasing pleasant events): especially useful for
treatment of depression in moderate stages of AD
Describe the problem behavior, assess specific antecedents and
consequences and implement specific strategies suggested by
the first 2 steps
Emotion-oriented approaches
Downloaded from biomedgerontology.oxfordjournals.org at The Australian National University on March 23, 2011
Supportive psychotherapy: especially in early stages of AD
Reminiscence therapy: in mild to moderate stages of AD
Validation therapy: in mild to moderate stages of AD
Simulated presence therapy: in moderate to severe stages, especially for
patients in long-term care facilities
Cognition-oriented approaches
Cognitive therapy: especially for treating depression in early stages of
AD
Stimulation-oriented approaches
Recreational therapies (crafts, games, pets)
Art therapies (music, dance, art)
Nonspecific nonpharmacological interventions
Reassurance
Distraction
Bright-light therapy
Touch therapy: hand massages, back rubs
One-to-one therapy
Gardening
Aromatherapy
Light exercise
Interventions with the family member/caregivers
Interventions to benefit the patient
Problem-solving therapy for the caregivers: especially for treating
depression in moderate stages of AD
Skills training for the caregivers: to improve personal care skills
Structured educational programs to decrease use of inappropriate
medications and psychotherapeutic agents for behavioral and
psychological symptoms of AD (BPSD)
Interventions to benefit the family member/caregivers
Family therapy: especially to address conflicts, abuse
Support groups: to decrease loneliness, increase knowledge of illness
and services available, and learn creative and practical
nonpharmacological interventions
Psychoeducational groups
Self-help groups
Respite care
Cognitive behavioral approaches: especially for treatment of
depression in the caregiver
about themselves, to be respected, to have the approval of
others who are important to them, to be stimulated in body,
mind, and spirit, to feel secure, to be included (not alienated
and marginalized), and to be needed. Every effort must be
made by the health-care providers to assist the caregivers in
meeting these needs of patients with AD. Some more-specific
nonpharmacological interventions are as follows:
1. People with very early or mild AD who have been told
their diagnosis and prognosis are faced with psycho-
logical problems that may be helped by regular counsel-
ing or psychological support.
342 GROSSBERG AND DESAI
2. In the early stages of AD, patients can use diary and
dictaphone to help them remember events and con-
versations. Patients should try and concentrate on doing
things they are good at, rather than pursuing tasks they
cannot manage.
3. The desire to ‘‘go home’’ is common in people who have
AD, even when they’re still residing in the homes in
which they have lived independently for years. The care-
giver should avoid correcting the patients or reassuring
them that they are in their homes. It is better to inquire
where home is and who the patients might be worried
about there.
4. Often people with dementia report being worried about
their young children—even though they’re now grown—
or about their parents—even if they’re deceased. We
recommend reassuring these persons that everyone at
home is OK and that those at home know that the pa-
tients are OK. Asking what the patients like best about
‘‘home’’ and helping patients with AD to reminisce
about the good times in the home are also beneficial.
5. People with AD may curse or use language that the
family finds shocking. This may be a sign that the per-
son has lost inhibition and impulse control and now says
the first thing that enters his or her mind. It’s important
to remind the caregivers that this isn’t intentional and
should not be taken personally.
6. The caregivers should listen attentively and watch for
nonverbal clues that might indicate hunger or thirst,
implied meanings, and expressed feelings.
7. Caregivers need to adjust their expectations regarding
a loved one with AD throughout the course of the ill-
ness. Activities such as folding and stacking items gives
the person with AD a sense of purpose and accom-
plishment. Maintaining a routine of meaningful activ-
ities that promote success is important for people with
AD, whose days are filled with frustration and failure.
8. Religious worship is a safe and soothing activity for
many persons with AD. It enables them to respond to
their faith and spiritual needs through long-remembered
rituals that connect past and present. For persons living
alone, members of the congregation may be the first to
notice the early signs of AD.
9. Although a recent randomized, controlled trial did not
find walking and or talking to provide any benefits in
communication, ambulation, and functional status in resi-
dents with AD (112), exercise has been documented to
improve muscle strength (thereby reducing frailty, func-
tional decline, and injuries), even in frail residents in
nursing homes (113,114). In addition, walking and other
forms of light exercise may decrease problem behaviors.
10. Meaningful activities may improve depression and di-
minish agitation, apathy, insomnia, and repetitive vocal-
ization.
11. Graded assistance, practice, and positive reinforcement
should be used to increase functional independence.
12. Patients with AD may experience decreased problem
behaviors with music, particularly during meals and
bathing.
13. Use of therapeutic touch, including massage, may de-
crease agitation/irritability (115).
Specific Therapies/Approaches and Their Efficacy
Whatever the intervention, it is critical to match the level
of demand on the patient with his or her current capacities,
avoiding both infantilization and frustration, and to modify
the environment insofar as possible to compensate for defi-
cits and to capitalize on the patient’s strengths.
Behavior-oriented approaches.—Behavioral approaches
can be effective in lessening or abolishing problem behav-
iors. The steps involve careful description of the problem
behavior, assessment of specific antecedents and conse-
Downloaded from biomedgerontology.oxfordjournals.org at The Australian National University on March 23, 2011
quences, and implementing specific strategies that are often
suggested from the first 2 steps (116).
Emotion-oriented approaches.—These interventions in-
clude but are not limited to supportive psychotherapy, remi-
niscence therapy, validation therapy, sensory integration,
and simulated presence therapy (116–120). These interven-
tions have been shown to improve mood and behavior.
Cognition-oriented approaches.—These techniques in-
clude reality orientation and skills training (121,122). These
interventions have shown slight transient improvement in
cognition, but there have also been reports of anger and
frustration. The slight improvements observed with some of
these treatments have not lasted beyond the treatment ses-
sions and thus do not appear to warrant the risk of adverse
effects.
Stimulation-oriented approaches.—These treatments in-
clude activities (structured and unstructured) or recreational
therapies (e.g., crafts, games, pets) and art therapies (e.g.,
music, dance, art). There is some evidence that, while they
are in use, these interventions decrease behavioral problems
and improve mood (123–125).
Interventions for Families and Caregivers
Practical and creative problem solving, prayer, humor, the
dependable support of family and friends, expressive outlets,
the ability to forgive others and one’s self, and learning
how to economize the personal and family ‘‘energy’’ that is
available, for example, can all be effective coping strategies
that families and caregivers should be encouraged to use. For
families who are struggling with various aspects of the issues
that arise while caring for a patient with AD, sessions of
family therapy have proven beneficial (126). For alleviating
caregiver and family distress, a broad array of psychosocial
interventions was assessed in a meta-analysis of 18 studies
(127). The interventions included psychoeducation, support,
cognitive-behavioral techniques, self-help, and respite care.
Exercise has been shown to improve caregiver outcomes (128).
Individual and respite programs were found moderately
effective at reducing caregiver burden and dysphoria, but
group interventions were only marginally effective.
Subsequent research buttressed the utility of adult day care
in reducing caregiver’s stress and depression and in en-
hancing their well-being (129). Targeted behavioral techni-
ques also improved the quality of caregivers’ sleep (130),
whereas psychoeducation and family support appeared to
 MANAGEMENT OF ALZHEIMER’S DISEASE
promote better patient management. A range of behavioral
interventions for nursing home staff have been shown to be
effective in improving behavioral symptoms of AD, such as
incontinence (131,132), dressing problems (133), and verbal
agitation (134,135). A major problem is that interventions are
not maintained or implemented correctly by nursing home
staff (136). Additional patient and caregiver benefits may
be obtained by the use of computer networks to provide
education and support to the caregivers.
Depression
Population studies have shown that major depression
occurs in 12% of demented patients, while higher per-
centages have been reported in clinical samples. Depressive
symptoms are much more common in AD than major
depression and afflict more than 30% of these patients (137).
Depressed mood and anhedonia have been identified in
49% of AD patients; these symptoms do not correlate with
either vegetative symptoms or cognitive symptoms of de-
pression. Family history of depressive disorders increases
the probability of developing depression during the course
of AD. Common depressive symptoms and signs in AD in
those who do not meet criteria for major depression include
loss of interest, lack of energy, thinking and concentration
difficulties, and psychomotor disturbances. Depressive symp-
toms as a rule do not coexist with apathy in demented
patients (138). Apathy appears to be a syndrome distinct
from depression, and its prevalence increases as the cogni-
tive impairment in AD increases (138). Depressive symp-
toms add to functional impairment of AD patients and are
associated with increased psychopathology in their care-
givers. If left untreated, depressive symptoms or syndromes
persist or subside to some extent and then recur. As AD
progresses, depressive symptoms become less prominent
and often are overshadowed by other behavioral abnormal-
ities, including delusions, aggressive behavior, and agita-
tion. Depression of AD involves fewer required symptoms
than a major depressive episode, and less emphasis is
placed on verbally weighted items. Provisional diagnostic
criteria for depression of AD have been proposed (139).
Health-care providers need to be aware that suicide
attempts are not rare in AD patients (140). Thus, all AD
patients with depression should be carefully evaluated for
suicide potential. Treatment is likely to be of value, with
reported response rates of up to 85% (141).
There is some evidence that it is possible to modify
cognitive-behavioral therapies for depression to allow them
to be administered to patients with mild dementia and to
modify behavioral therapies to allow them to be provided for
those with moderate to severe dementia (142,143). Cognitive
therapy, seen as more promising in the early stages of
dementia, strives to help patients cope with depression by
reducing cognitive distortions and by fostering more adap-
tive perceptions (142). Behavioral therapy, seen as more
promising for more moderately or severely affected adults
with dementia, targets family caregivers directly—and pa-
tients indirectly—by helping caregivers identify, plan, and
increase pleasant activities for the patient, such as taking a
walk, designed to improve their mood (130). Further affir-
mation for behavioral therapy for depression of patients
343
with AD was provided by a controlled clinical trial (144). In
this randomized clinical trial, researchers compared 2
behavioral therapies with a typical care condition, in which
family caregivers were given information, advice, and sup-
port in their efforts to manage patient problems, and a wait
list control in 72 individuals who had major depression and
AD (145). One type of behavioral treatment consisted of
teaching caregivers to focus on increasing pleasant events for
the patient, while the other focused on improving the
caregivers’ approach to problem solving. Those in the 2
behavior therapy conditions and those in typical care received
Downloaded from biomedgerontology.oxfordjournals.org at The Australian National University on March 23, 2011
the intervention in the form of 9 weekly, 60-minute sessions.
The study provided strong support for the efficacy of specific
psychosocial treatments; the 2 behavior therapy conditions
were equally beneficial in reducing depressive symptoms and
were superior to both the typical care and wait list conditions.
Outcomes were similar for the typical care and wait list
conditions, suggesting that, in the absence of a structured
approach to treatment, professional contact alone is not
effective. Depressed mood may also respond to improve-
ments in living situation or stimulation-oriented treatments.
Somatic treatments for depression can be used in
demented patients to improve mood, functional status, and
quality of life. These treatments should be considered even
for patients with depressed mood who do not meet the
diagnostic criteria for major depression (132). Patients with
severe or persistent depression should be treated with anti-
depressants. The choice among agents is based on the side
effect profile and the characteristics of a given patient.
Selective serotonin reuptake inhibitors (e.g., citalopram, ser-
traline, paroxetine) are probably the first-line treatments and
are supported by many RCTs, although other agents such
as mirtazapine and venlafaxine may be more appropriate for
some patients (146–150). Electroconvulsive therapy (ECT)
is effective in the treatment of depression in dementia pa-
tients (151). ECT may be beneficial for patients with severe
major depression who are ineligible for, cannot tolerate, or
do not respond to antidepressants (152). Individuals whose
cognitive symptoms recover fully with treatment of depres-
sion are considered not to have been demented but rather
to have a condition called dementia syndrome of depression;
however, about half of such persons may develop dementia
in 5 years (153). The management of depression has been
reviewed in detail in a recent issue of the Journal (154).
Psychotic Symptoms
It is estimated that approximately 30–50% of patients
with AD develop delusions and hallucinations at some point
during the course of AD (155). Psychosis with AD may run
in families (156). The psychotic symptoms consist of non-
elaborate persecutory delusions (e.g., accusations of some-
one stealing the patient’s possessions) and simple visual
or, less commonly, auditory hallucinations. Psychotic symp-
toms often cause severe agitation and aggression as well as
emotional distress and may precipitate institutionalization or
hospitalization.
Mild psychotic symptoms associated with AD are best
managed with nonpharmacological interventions and cho-
linesterase inhibitors. If antipsychotics are used, the goals
should be modest (reduction of emotional distress and
344 GROSSBERG AND DESAI
behavioral disturbances) and should not be resolution of
psychotic symptoms. A dose decrease or discontinuation is
recommended periodically for all patients with psychoses
associated with AD who receive antipsychotic medications
(157). The major predictors of relapse, if antipsychotics
are discontinued, are agitation and aggressive features. Al-
though conventional or typical antipsychotics (e.g., Halo-
peridol, thioridazine, chlorpromazine, perphenazine,
fluphenazine, etc.) are somewhat better than placebo for
psychosis of AD (158,159), the effect is modest, and the
high risk of toxicity (especially extrapyramidal syndrome
[EPS] and tardive dyskinesia [TD]) usually makes them
inappropriate. Despite this, conventional antipsychotics
continue to be chosen over atypical antipsychotics for psy-
chotic symptoms and aggression in patients with demen-
tia, even in industrialized countries (160). Even low-potency
conventional antipsychotics (e.g., Thioridazine, chlorprom-
azine) are associated with high frequency of EPS in patients
with AD. Risperidone has the largest body of currently
available published evidence amongst the atypical anti-
psychotics for the treatment of psychoses associated with
AD. Two 12-week, randomized, double-blind, placebo-
controlled trials of risperidone included nearly 1000 test
subjects who were suffering from dementia with psychosis
and agitation (AD, VaD, and related disorders) (161,162).
They found that 1 mg was the optimal dose. Doses of
0.5–1.5 mg daily do not produce a significantly increased
incidence of side effects, but nonetheless they are effective
in controlling psychosis-driven behavioral disturbances and
aggression. Risperidone was superior to haloperidol in terms
of efficacy, while presenting a significantly more benign
side-effect profile. Risperidone at higher than 1.5-mg doses
is associated with increased EPS, although in some patients
with AD, EPS can occur even at lower dosages. Risperidone
was found to be effective and well tolerated over 13–46
months for nursing home residents with dementia and behav-
ioral disturbances, despite high rates of medical comor-
bidity and use of concomitant medications (163). A 6-week
randomized, double-blind, placebo-controlled study of olan-
zapine was conducted in 206 nursing home patients with
AD or VaD plus psychosis or severe agitation (164). Pa-
tients received either placebo or olanzapine in 5-mg, 10-mg,
or 15-mg doses. The most effective doses turned out to be
5 mg or 10 mg. A 15-mg dose was not better than placebo
but produced significant gait disturbance and sedation. In
some patients with AD, gait disturbance can occur even
at lower dosages. In a 10-week, double-blind, placebo-
controlled, randomized trial with nursing home residents
with dementia and psychosis, quetiapine (average dose 120
mg/day) was better than placebo in reducing symptoms of
agitation but not psychosis (165). A large, multicenter,
open-label study of quetiapine (average daily dose 100 mg)
found it to be useful for psychotic symptoms in the elderly,
many of whom had dementia (166). The most common side
effects associated with quetiapine were somnolence and
falls. Ziprasidone is the newest atypical antipsychotic, and
to date there are very few data available in the elderly.
Randomized, controlled studies are needed before ziprasi-
done can be recommended as the drug of first choice for
treatment of psychosis of AD. Patients with AD and psychosis
on conventional antipsychotics can be safely switched to
atypical antipsychotics to minimize the risk of EPS and TD
(167). Compared to conventional antipsychotics, atypical
antipsychotic drugs cause less TD (168). Cholinesterase in-
hibitors may benefit mild psychotic symptoms in dementia
patients (62,87). A recent study found the antidepressant
citalopram to be more efficacious than placebo in the short-
term hospital treatment of psychotic symptoms and behav-
ioral disturbances in nondepressed, demented patients (169).
These drugs may be considered in AD patients with psychotic
symptoms before antipsychotics are considered.
Downloaded from biomedgerontology.oxfordjournals.org at The Australian National University on March 23, 2011
Agitation
The most common behavioral disturbance associated
with AD is agitation, which affects nearly three fourths
of patients and typically increases in severity as the disease
progresses. Agitation involves verbal and physical aggres-
sion, increased psychomotor activity, repeated verbaliza-
tion, screaming, etc. Agitation often co-occurs with anxiety,
psychotic symptoms, and irritability. However, clinicians
should be sure to exclude potential causes unrelated to AD,
such as pain, medical illness, medication adverse effects, or
environmental provocation.
Mild to moderate agitation is best managed by non-
pharmacologic interventions, as environmental factors and
caregiver patient interaction can significantly influence agi-
tation. Severe agitation may need a trial of psychotropics.
Controlled clinical trials for the treatment of agitation have
reported efficacy of atypical antipsychotics (161,162,164),
antidepressants (148), beta-adrenergic blockers (170), and
anticonvulsants (divalproex, carbamazepine) (171,172). A
16-week RCT in community-dwelling patients with AD and
agitation did not find any statistically significant difference
between the group receiving trazodone, the group receiving
haloperidol, and the group receiving behavioral approaches
(behavior management techniques to caregivers). There was
slight worsening of cognition and function in the medica-
tion group (173). Uncontrolled studies and small controlled
studies have suggested use of gabapentin and buspirone for
the treatment of agitation (174,175).
Despite the widespread utilization of benzodiazepines
(BZ) in community-dwelling elders as well as in the nursing
home population, data supporting the use of BZ and other
antianxiety agents in AD are very limited. BZ may be used
for a short duration in AD patients who have moderate to
severe free-floating anxiety or who may be apprehensive
about particular events, such as medical procedures or
admission to the hospital or a LTCF. Although treatment
with BZ may be efficient in the short term, their long-term
usage is limited by their gradual decline in efficiency and
the potential side effects of sedation, decreased cognitive
functioning, loss of coordination and unsteadiness, and
paradoxical disinhibition of behavior (176). When in-
dicated, a BZ with a short half-life, such as lorazepam or
oxazepam, is recommended. BZ have not been rigorously
investigated in AD, and their effectiveness in controlling
behavioral disorders in patients with AD has not been
conclusively demonstrated. BZ perform better than placebo
but not as well as antipsychotics in reducing agitation in
patients with AD (177). Discontinuation of BZ has been
 MANAGEMENT OF ALZHEIMER’S DISEASE 345

found to improve cognitive performance in nursing home Table 7. Psychotropics in the Management of Behavioral and
patients with dementia (178). Psychological Symptoms of AD (BPSD)
Daily Dose
Sleep Disturbances Indicated Clinical
Medication Starting (mg) Therapeutic (mg) Condition
Sleep disorder is common in AD and may be manageable
with nonpharmacologic interventions in many cases (179). Antidepressants
SSRIs
The most disturbing sleep disturbances include day/night
reversal of sleep pattern and the waking by the patient of the Citalopram 10 mg 20–40 mg Depression, anxiety,
agitation
caregiver. Appropriate sleep hygiene (including regular sleep Sertraline 25 mg 50–100 mg Depression, anxiety
and waking times, limited daytime sleeping, avoidance Paroxetine 10 mg 10–20 mg Depression, anxiety
of fluid intake in the evening), calming bedtime rituals, and Mirtazepine 7.5–15 mg 15–30 mg Depression, anxiety

adequate daytime physical and mental activities should be
tried before pharmacological interventions. There is pre-
liminary evidence from 2 small open trials for elderly sub-
jects with dementia (180,181) suggesting that early-morning
or evening bright-light therapy may improve sleep (and
possibly behavior as well). It is important to investigate
sleep disorders such as restless leg syndrome, REM sleep
behavior disorder, nocturnal myoclonus, and sleep apnea,
which are relatively common in elderly individuals. Sleep
apnea contraindicates the use of benzodiazepines or other
agents that suppress respiratory drive. Short-term use of zol-
pidem (5–10 mg) may be considered in certain situations
(182). Other drugs that may be tried judiciously include tra-
zodone and sedating antidepressants such as mirtazepine.
Benzodiazepine (lorazepam, temazepam) use should be
limited to short-term use for a few days in certain situations,
such as a short hospital stay. Any drug used as a sleep aid
can increase the risk of falls. Patients should be counseled
not to use over-the-counter sleep aids containing anticho-
linergic agents such as diphenhydramine (present in Tylenol
PM) because of risk of delirium and hallucinations.
Initiating, Monitoring, and Maintaining
Safe Pharmacologic Treatment for BPSD
Selection of the right drug and the proper dosage should be
guided by the nature of the patient’s symptoms (Tables 7 and
8). A drug should be continued as long as it is effective, but no
longer than needed. Its efficacy can be gauged more easily if
realistic goals have been set and target behaviors specified
before initiating treatment. Achieving significant efficacy may
require a few weeks of treatment. Rapidly switching from one
agent to another deprives the patient of an adequate trial.
Recent data on beneficial effects of ChEIs and antidepressants
on behavioral disturbances including psychotic symptoms and
agitation suggests that the intuitive approach of treating agita-
ted AD patients experiencing psychotic symptoms with anti-
psychotics may not be the safest approach for many patients.
Preventing Premature Institutionalization
ChEI may postpone nursing home placement for AD
(183,184). Day care for people with AD can delay insti-
tutionalization. Potentially treatable BPSD are risk factors
for institutionalization, and treating these symptoms might
delay or prevent institutionalization. A comprehensive sup-
port and counseling intervention for spouse-caregivers of pa-
tients with AD reduced time to nursing home placement by
nearly 1 year, compared with those not receiving the inter-
vention (24,25). Interestingly, one of the key components
of that intervention was to teach the caregivers behavioral
Downloaded from biomedgerontology.oxfordjournals.org at The Australian National University on March 23, 2011
Venlafaxine 37.5 mg 75–150 mg Depression, anxiety
Antipsychotics
Risperidone 0.25 mg 0.5–1.5 mg Psychosis, aggression
Olanzapine 2.5 mg 5–10 mg Psychosis, aggression
Quetiapine 25 mg 50–200 mg Psychosis, aggression
Anticonvulsants
Valproate 125 mg 500–1000 mg Mania, aggression
Carbamazepine 100 mg 200–600 mg Mania, aggression
SSRI ¼ selective serotonin reuptake inhibitor.
management techniques to reduce difficult patient behaviors.
Many of these interventions can be easily combined and may
have an even greater impact on delaying institutionalization.
FACTORS MODIFYING TREATMENT DECISIONS
Treatment of Comorbidities
Several diseases are more common in AD because they
are a consequence of the dementing process. These diseases
include new onset seizures, respiratory and urinary infec-
tions, Parkinsonism, and pressure sores (185). In one study,
more than 60% of patients with AD suffered from 3 or more
comorbid conditions and complaints; virtually all (93%)
had at least 1 (186). A case-control study using 7195 death
certificates found that patients who died of AD had higher
incidences of Parkinson’s disease, seizures, sensory impair-
ments, infections, malnutrition, hip fractures and other in-
juries, and pressure sores, compared to control subjects
(187). Treatment of individuals with advanced AD should
weigh the possible benefits for the patient against the burden
imposed by such treatment. Most medical interventions
cause discomfort, especially to patients with dementia (56).
Patients with advanced AD do not recognize the need for
therapeutic interventions, do not cooperate with treatment,
and often actively oppose it. Minor routine procedures, such
as blood drawing or blood pressure measurement, typically
precipitate behavioral disturbances. The dementing process
also may limit the benefits of therapeutic interventions be-
cause of reduced life expectancy and decreased treatment
effectiveness. Preventive measures, such as restricted diets
and screening procedures, are appropriate only in the earlier
stages of AD. Similarly, treatment of chronic conditions such
as hypertension and diabetes should be aggressive only in
the earliest stages of AD. In more advanced stages, treat-
ment of comorbidities should be conservative and directed
toward prevention of potentially serious side effects (e.g.,
postural hypotension that may lead to falls and hip fracture).
346 GROSSBERG AND DESAI
Table 8. Principles of Pharmacotherapeutic Management
of Behavioral Disturbances in Dementia Patients
1. Use drugs only when secondary causes (environmental, medical) of
behavioral disturbances have been ruled out and nonpharmacologic
interventions have failed.
2. Review current medications and consider tapering or discontinuing
unnecessary, ineffective, or harmful medications.
3. Consider adverse drug reactions or drug–drug interactions as a
potential cause of behavioral disturbances.
4. Target symptoms and their impact on functioning should be
documented prior to initiation of drug therapy.
5. If pharmacotherapy is used, start low and go slow and use it in
conjunction with nonpharmacologic interventions.
6. Select agents based on target symptoms, side-effect profile, and
individual patient characteristics.
7. Give the medication for an adequate time at an adequate dose.
8. Closely monitor for and document side effects and beneficial effects.
9. If found beneficial, continue the medication for a few months. If the
patient has been stable for that period, consider decreasing or
discontinuing the medication.
10. Educate patient and family regarding the benefits and side effects of
medications.
Antibiotic therapy preferably should be limited to oral
preparations. Intravenous therapy is to be avoided in moder-
ate to severe AD patients because the demented patients
in advanced stages do not understand the need for the
medication and frequently try to remove the intravenous
catheters and often end up with physical restraints or psy-
chotropic drugs. Intramuscular administration of antibiotics
such as cephalosporins should be considered before intra-
venous therapy. The effectiveness of antibiotic therapy may
be limited by the recurrent nature of infections in advanced
dementia. Also, adverse effects of antibiotic use, such as
gastrointestinal upset, diarrhea, allergic reactions, etc., should
be factored in before the decision is made to administer
the drug.
Urinary Incontinence
Behavior modification, scheduled toileting, and prompted
voiding should be used to reduce urinary incontinence. Uri-
nary incontinence with donepezil has been reported (188),
and all ChEIs have a potential to precipitate or exacerbate
this problem. Treating urinary tract infection, fecal impac-
tion, and other causes of urinary incontinence may suffice
in many cases. Use of anticholinergic agents such as tolte-
radine and oxybutynin should be minimized, as these drugs
may counteract the effects of ChEIs.
Delirium
Delirium is a significant problem for patients with AD,
and it occurs much more frequently than it does in cog-
nitively intact patients (189). Possible causes of delirium
include an acute illness (urinary tract infection, respiratory
infection) or medication toxicity. Compounds with anticho-
linergic effects (e.g., tricyclic antidepressants, low-potency
antipsychotics, diphenhydramine, disopyramide phosphate)
or histamine-2 activity (cimetidine, ranitidine) are particu-
larly likely to cause delirium, but many other classes of
medications can do so (190). Many of these medications are
considered potentially inappropriate for use in the elderly
(191). Avoidance of unnecessary medications, use of the
lowest effective dose, using medications with least anticho-
linergic activity, vigilant monitoring aimed at early recog-
nition, a thorough search for causes, and prompt treatment
may diminish the prevalence and morbidity of delirium.
Neurologic Issues
In later stages, extrapyramidal signs such as rigidity may
become prominent, especially in patients treated with anti-
psychotic drugs (even the more modern ‘‘atypical’’ agents).
Downloaded from biomedgerontology.oxfordjournals.org at The Australian National University on March 23, 2011
Seizures have been reported in 10–20% of AD patients,
again, often late in the disease (192). Anticonvulsants such
as divalproex, carbamazepine, and oxcarbazepine may not
only benefit seizures but may also decrease agitation and
aggression in patients with late-stage AD. Myoclonus, or
brisk irregular muscle contraction, occurs in 5–10% of AD
patients (193). A high index of suspicion and treatment of
seizures and myoclonus in later stages of AD is recom-
mended. Recent epidemiological and clinicopathologic data
suggest overlaps between AD and cerebrovascular lesions
that may magnify the effects of mild AD pathology and
promote progression of cognitive and functional decline
(194). Many AD patients also have comorbid cerebrovas-
cular disease (CVD) or risk factors for CVD. Good control
of blood pressure, treatment of atrial fibrillation, and anti-
platelet therapy, such as low-dose aspirin, may help prevent
further strokes.
SITE-SPECIFIC ISSUES
Emergency Room (ER),
Inpatient General Medical, or Surgical Services
Patients with AD visit the ER twice as often as unaffected
patients with similar conditions; these patients also remain
hospitalized for a longer time (195). Lyketsos and col-
leagues reported that hospitalized patients with dementia
had longer stays, higher costs, and a greater frequency of
medication-induced psychosis and delirium (196). Statisti-
cally significant findings were discerned despite the likeli-
hood that many cases of dementia were unrecognized,
which reflects the substantial impact of dementia on clinical
services. For many patients with AD, hospitalization rep-
resents a failure to prevent an unintentional injury, properly
manage a chronic disorder, or use an appropriate alternate
therapy, such as Hospice or temporary LTCF stay. Transfer
of AD individuals to an ER or hospital exposes patients with
AD to serious risks, such as increased confusion, agitation,
anorexia, incontinence, and falls (197). These risks and po-
tential benefits of treating acute medical problems should
be discussed with the family before transfer. The risks are
even higher in more advanced AD patients because of the
very low rates of successful outcome in terms of improved
survival and quality of life after treatment. Transfer to an ER
or hospital should be used only when it is consistent with
the overall goals of care and not as a default option. Having
family members or aides stay with the patient may help de-
crease agitation and wandering that may occur in hospital-
ized patients with AD.
 MANAGEMENT OF ALZHEIMER’S DISEASE
Inpatient Psychiatric Units
Individuals with AD may need hospitalization to inpatient
psychiatric units for the treatment of psychotic, affective,
and behavioral symptoms that are causing harm to self
or others, severe symptoms not responding to outpatient
treatment, or if there is need for ECT (198,199). A thorough
search for psychosocial, general medical, or noncognitive
psychiatric difficulties that may be leading to the distur-
bance will often reveal a treatable problem. Both non-
pharmacologic and pharmacologic interventions can be tried
more readily and aggressively on inpatient units than in
outpatient settings. Clinical experience suggests that patients
with AD may not do well if treated in general adult units,
where younger violent patients may pose some danger. Ge-
riatric-psychiatry units, which are designed to address the
unique needs of the demented patient with staff trained in
the management of dementia patients, may be preferable.
Long-Term Care
According to the American Health Care Association,
more than 1.5 million individuals in the United States reside
in nursing homes. Within this population (elderly as well as
nonelderly persons), 67–77% have dementia (100,201,202).
Institutionalization offers many AD patients the best dura-
tion of survival, followed by a formal care package at home.
In the nursing home, AD is underrecognized and under-
treated. By the time patients with AD reach the nursing
home, the bulk of their needs are no longer for health care
but rather for custodial care. Most do not need high-tech
care. They need care that is mediated by touch and delivered
by professionals whose skilled eyes and hands can detect
deterioration–professions who can intervene early and who
can identify opportunities for improvement and rehabilita-
tion. Psychoactive agents are one of the most prevalent class
of drugs with potential for inappropriate use in elderly
LTCF residents (203). Staff of LTCF should receive edu-
cation about AD to reduce the use of unnecessary psycho-
tropics. These facilities should be tailored to meet the needs
of patients with dementia and to adequately address be-
havioral symptoms. Skills training for people with AD in
LTCF may lead to an improvement in personal care skills.
Structured activity programs can improve both behavior and
mood (204). LTCFs need to take advantage of the latest
thinking in design, which can help both staff and patients
with AD. AD-specific design features include high levels of
visual access, highly visible and signed toilet doors, indoor/
outdoor wander-safe areas, increased lighting, age-appro-
priate fixtures and fittings, and individualized personal space
(205). The interdisciplinary care model is recommended for
patient care to best address the increasingly complex needs
of AD residents in LTCF settings. The Omnibus Budget
Reconciliation Act of 1987 regulates the use of physical
restraints and many psychotropic medications in nursing
homes. Health professionals practicing in nursing homes
must be familiar with these regulations. Indications for anti-
psychotic medication treatment and available alternatives
and outcomes should be carefully documented. A clinical
strategy of carefully considering which patients may be
appropriate for withdrawal of antipsychotic medications and
for being prepared to maintain use of the medications in
347
some cases and reinstate them in others, as deemed clin-
ically necessary, is recommended. A structured education
program for nursing and medical staff has been shown to
decrease antipsychotic usage in the nursing home setting
without adverse outcomes (206). Pet therapy and/or the
introduction of the Eden Alternative may improve outcomes
in some, but not all, patients with dementia (207–209).
Special Care Dementia Unit
The social environment is also significant in mollifying
the behavioral manifestations of dementia. If demented indi-
Downloaded from biomedgerontology.oxfordjournals.org at The Australian National University on March 23, 2011
viduals are grouped together on a special care dementia unit,
many symptoms may be minimized. Grouping demented
patients together further eliminates the problem of demented
patients disrupting the routine of cognitively intact indi-
viduals by wandering into their rooms, rummaging through
their belongings, or approaching them repeatedly with ques-
tions and unwanted physical contact. Well-designed studies
are needed to demonstrate the benefits of such units.
MILD COGNITIVE IMPAIRMENT (MCI)
MCI is a cognitive disorder with a high rate of conversion
to AD over many years (210). Short-term memory loss is
the most common abnormality. Patients with MCI perform
similarly on memory tests when compared to patients with
AD, but they perform similarly to normal elderly controls on
other cognitive tests and in activities of daily living (197).
Neuropsychiatric symptoms in MCI have a prevalence inter-
mediate to that in healthy participants and those with AD
(108). Recent evidence suggests that most patients with MCI
eventually develop AD (211). Patients with MCI should be
carefully evaluated and followed. Biological markers, in-
cluding APOE, may be helpful in identifying patients at risk
for conversion to dementia. While controlled trials for MCI
treatments are in progress, patients may be offered empiric
treatment with vitamin E and ChEIs. The potential for ChEIs
to delay onset of dementia in patients with MCI is currently
being rigorously investigated. Patients with MCI may be
encouraged to participate in such studies with ChEIs.
THE FUTURE oF AD TREATMENT
Pharmacotherapy
Definitely effective treatments for AD are few. Research
to increase understanding of the underlying disease process
and to seek new and better treatments is robust. Clinical
research, with active patient participation, is a current and
valuable means of treatment development for AD, with
government- and private industry–sponsored therapeutic
trials currently numbering in the hundreds. Epidemiological
and postmortem studies have established a number of
testable hypotheses (212). Secretase inhibitors (beta and
gamma) may stall A-beta amyloid production, thus pre-
venting neuronal plaque formation that is theorized to cause
neuronal cell death. Such drugs are in a Phase-I stage of
study. Beta-sheet blockers latch onto critical portions of
spiral-shaped A-beta, helping them maintain their shape,
thereby stalling the formation of new fibrils and allowing
the body to clear A-beta from the brain, thus forestalling
plaque formation. Such drugs are also currently in devel-
348 GROSSBERG AND DESAI
opment. Studies involving metal chelators such as desfer-
rioxamine and clioquinol to reduce plaque formation are
also underway. The theory behind this is that metals such
as aluminum, iron, zinc, and copper promote A-beta aggre-
gation and plaque formation, and drugs that bind to these
metals (chelators) may prevent A-beta aggregation. Anti-
bodies targeted to plaques (amyloid) can mark them for
destruction by the immune system, resulting in increased
clearance of plaque and reduced neuronal loss, and in
animal studies, antibodies to beta-amyloid have enhanced
memory (213,214). An Alzheimer vaccine works on this
principle and is currently under investigation. However, the
initial human study with amyloid vaccine caused brain
inflammation and had to be halted. New research with a
more refined vaccine that has a high degree of selectivity
for the pathogenic target structures offers new hope (215).
Blocking of A-beta production with an antisense directed
against the amyloid precursor protein also improves memory
in animals (216). Chronically high levels of glutamate have
been implicated in causing neuronal cell loss. Glutamate
antagonists such as memantine (which is already approved
in Europe) may thus protect neuronal loss in AD patients.
Large multicenter trials are currently underway with nerve
growth factors (compounds that promote growth, survival,
and regeneration of neurons), as well as drugs such as mem-
antine. However, the key event that will provide direction
for cure would be a full understanding of AD etiology.
The potential usefulness of hormone replacement, anti-
inflammatory drugs, and Ginkgo biloba extract for the pre-
vention of AD is currently being studied. Further information
about these studies is available from the Alzheimer’s Disease
Education and Referral Center of the National Institutes of
Health (http://www.alzheimers.org/ir.html or 800-438-
4380). These and other promising areas of investigation
bring hope that in the near future we will be able to turn our
attention from the palliative treatment of AD to primary
prevention, or at least to delaying the progression of the
disease to its most disabling stages.
Research Involving Genetics of AD
A 30-year-old woman with a genetic disorder linked
to early onset of AD has become the first to successfully
undergo in vitro fertilization with preimplantation genetic
diagnosis (PGD) of the embryos to avoid passing the de-
fect on to her children (217). PGD, prenatal diagnosis, pre-
implantation embryo selection, and presymptomatic testing
has been offered to families of patients who have early-onset
familial AD. Complex legal and ethical issues surrounding
these interventions need to be addressed before these inter-
ventions can be routinely recommended. There is great poten-
tial for stem cell treatment of patients with AD, but ethical
issues will need to be addressed before fetal stem cell re-
search can be carried out.
Surgical Interventions
Low-flow cerebrospinal fluid (CSF) drainage using a
shunt is a recent surgical intervention that was found to be
relatively safe in the treatment of patients with AD (218).
The shunt is implanted in the lateral ventricle of the brain,
from which point it empties CSF into the peritoneal cavity.
The theory is that poor circulation of the CSF is contributing
to AD by allowing the deposition of amyloid and or other
toxins. The study also found promising results in 12 pa-
tients: either a 3-month improvement or stabilization. A
larger, randomized, double-blind, controlled clinical trial is
underway to elucidate the potential for this intervention in
the treatment of AD.
SUMMARY AND CONCLUSIONS
Downloaded from biomedgerontology.oxfordjournals.org at The Australian National University on March 23, 2011
AD is one of the principal causes of disability and de-
creased quality of life among the elderly and is a leading
obstacle to successful aging. AD is a treatable condition.
Today’s treatment options are greatly improved over those
available a few years ago. The complexity and heterogeneity
of AD requires comprehensive assessment and possibly
multiple layers of intervention for the patient as well as
the caregiver. Current management focuses on establishing
an early accurate clinical diagnosis, early institution of
ChEIs, treating medical comorbidities and dementia-related
complications, ensuring appropriate services are provided,
supporting caregivers, and treating cognitive and behavioral
problems and functional deficits with appropriate non-
pharmacological and pharmacologic interventions. A ther-
apeutic alliance between physician and caregiver is critical
to the success of AD management. AD is a terminal illness,
and the patients and caregivers should be given an early
opportunity to decide about intensity of care before the dis-
ease inevitably progresses. Physician involvement in ethical
issues raised in the management of AD and a multidisci-
plinary team approach is strongly recommended.
ChEIs should be considered in all patients with mild to
moderate AD. ChEIs have been shown to temporarily stabi-
lize cognition and ADL and may delay nursing home place-
ment and reduce demands on caregiver time. Preliminary
evidence also indicates that these benefits may extend to
patients with more advanced AD and rapidly progressive
AD as well as to patients with VaD and LBD. Patients not
responding to one agent in the class may respond to another.
Discontinuation should be monitored; deterioration during
withdrawal indicates therapeutic benefit and the medication
should be reinstated. Other drugs such as memantine look
promising in their effect in slowing functional decline
in patients with moderate to severe AD. Estrogen should not
be prescribed to treat AD.
Psychotropics play a critical role in the management of
moderate to severe behavioral disturbances in patients with
AD. Short-term programs directed toward educating family
caregivers about AD should be offered to improve caregiver
satisfaction. Intensive long-term education and support ser-
vices (when available) should be offered to caregivers of
patients with AD to delay time to nursing home place-
ment. Professional caregivers need higher expectations and
better training and support. Staff of long-term care facilities
should receive education about AD to reduce the use of
unnecessary psychotropics. This article is by no means ex-
haustive. Readers are encouraged to read other articles for
treatment of problems/issues that we may not have ade-
quately addressed in the management of AD (Table 9).
 MANAGEMENT OF ALZHEIMER’S DISEASE
Table 9. Further Recommended Reading Regarding Management
of Alzheimer’s Disease (AD)
1. Small GW, Rabins PV, Barry PP, et al. Diagnosis and treatment of
Alzheimer’s disease and related disorders: consensus statement of the
American Association for Geriatric Psychiatry, the Alzheimer’s
Association, and the American Geriatrics Society. JAMA.
1997;278:1363–1371.
2. Doody RS, Stevens JC, Beck C, et al. Practice parameter: management
of dementia (an evidence-based review). Neurology. 2001;56:1154–1166.
3. Suh Y, Checler F. Amyloid precursor protein, presenilins, and alpha-
synuclein: molecular pathogenesis and pharmacological applications
in Alzheimer’s disease. Pharmacol Rev. 2002;54:469–525.
4. Desai AK, Grossberg GT. Recognition and management of behavioral
disturbances in dementia. Primary Care Companion J Clin Psychiatr.
2001;3:93–109.
Patients with AD are at risk of becoming medical orphans
in a health system geared toward cure and in a culture where
it is ‘‘normal’’ for the elderly to suffer. AD patients and their
families have a right to receive competent, compassionate,
and consistent care. With appropriate treatment, we can
substantially reduce the number of AD patients receiving in-
appropriate medication, futile procedures, and hospitaliza-
tion and surgeries.
With active research in AD, some of the current re-
commendations may become outdated by the time of
publication of this article. Also, physicians must decide to
adopt any particular recommendation in the light of available
resources and the circumstances of individual patients.
Patients and their families have reason to be optimistic.
The intense ongoing research in the area of etiology and
treatment of AD offers hope and confidence that treatments
to delay onset of AD; to treat, inhibit, and reverse symp-
toms; and, ultimately, to prevent AD, will indeed be dis-
covered. Until then, patients and families can benefit from
the variety of pharmacologic and nonpharmacologic inter-
ventions described here.
ACKNOWLEDGMENT
Address correspondence to Abhilash K. Desai, MD, 808 Delta Pine
Lane, Sikeston, MO 63801-5735. E-mail: zachary@sbmu.net
REFERENCES
1. Hendrie HC. Epidemiology of dementia and Alzheimer’s disease. Am
J Geriatr Psychiatr. 1998;6(2 suppl 1):S3–S18.
2. Evans DA, Funkenstein HH, Albert MS, et al. Prevalence of Alzhei-
mer’s disease in a community population of older persons. JAMA.
1989;262:2551–2556.
3. Evans DA. Estimated prevalence of Alzheimer’s disease in the US.
Milbank Q. 1990;68:267–289.
4. Brookmeyer R, Gray S, Kawas C. Projections of Alzheimer’s disease
in the United States and the public health impact of delaying disease
onset. Am J Public Health. 1998;88:1337–1342.
5. Small GW, Rabins PV, Berry PP, et al. Diagnosis and treatment of
Alzheimer’s disease and related disorders: consensus statement of
the American Association for Geriatric Psychiatry, the Alzheimer’s
Association, and the American Geriatrics Society. JAMA. 1997;278:
1363–1371.
6. Khachaturian ZS. Diagnosis of Alzheimer’s disease. Arch Neurol.
1985;42:1097–1105.
349
7. Hardy J. The Alzheimer family of diseases: many etiologies, one pa-
thogenesis? Proc Natl Acad Sci USA. 1997;94:2095–2097.
8. Dunkin JJ, Anderson-Hanley C. Dementia caregiver burden: a re-
view of the literature and guidelines for assessment and intervention.
Neurology. 1998;51(suppl 1):S53–S60.
9. Goate A, Chartier-Harlin MC, Mullan M, et al. Segregation of a
missense mutation in the amyloid precursor protein gene with familial
Alzheimer’s disease. Nature. 1991;349:704–706.
10. Sherrington R, Rogaev EI, Liang Y, et al. Cloning of a gene bearing
missense mutations in early-onset familial Alzheimer’s disease.
Nature. 1995;375:754–760.
11. Levy-Lahad E, Wasco W, Poorkaj P, et al. Candidate gene for the
chromosome 1 familial Alzheimer’s disease locus. Science. 1995;269:
Downloaded from biomedgerontology.oxfordjournals.org at The Australian National University on March 23, 2011
973–977.
12. Gauthier S. Advances in the pharmacotherapy of Alzheimer’s disease.
CMAJ. 2002;166(5):616–623.
13. Wolfson C, Wolfson DB, Asgharian M, et al. A reevaluation of the
duration of survival after the onset of dementia. N Engl J Med. 2001;
344:1111–1116.
14. Salmon DP, Thomas RG, Pay MM, et al. Alzheimer’s disease can be
accurately diagnosed in very mildly impaired individuals. Neurology.
2002;59:1022–1028.
15. McKhann G, Drachman D, Folstein M, et al. Clinical diagnosis of
Alzheimer’s disease: report of the NINCDS-ADRDA Work Group
under the auspices of Department of Health and Human Services Task
Force on Alzheimer’s Disease. Neurology. 1984;34:939–944.
16. Mace NL, Rabins PV. The 36-Hour Day. A Family Guide to Care for
Persons With Alzheimer’s Dementia, Related Dementing Illnesses and
Memory Loss in Later Life. Revised ed. Baltimore, MD: John Hopkins
University Press; 1991.
17. Siegal AP, Siegal RS. Forget Me Not: Caring For and Coping With
Your Aging Parents. Berkeley, CA: Celestial Arts; 1993.
18. American College of Medical Genetics/American Society of Human
Genetics Working Group on ApoE and Alzheimer’s Disease.
Statement on use of apolipoprotein E testing for Alzheimer’s disease.
JAMA. 1995;274:1627–1629.
19. National Institute on Aging/Alzheimer’s Association Working Group.
Apolipoprotein E genotyping in Alzheimer’s disease. Lancet. 1996;347:
1091–1095.
20. Green RC. Risk assessment for Alzheimer’s disease with genetic
susceptibility testing: has the moment arrived? Alzheimer’s Care Q.
2002;Summer:208–214.
21. Schulz R, O’Brien AT, Bookwala J, et al. Psychiatric and physical
morbidity effects of dementia caregiving: prevalence, correlates, and
causes. Gerontologist. 1995;35:771–791.
22. Schulz R, O’Brien AT, Bookwala J, Fleissner K. Psychiatric and
physical morbidity effects of dementia caregiving: prevalence, cor-
relates, and causes. Gerontologist. 1995;35:771–791.
23. Rabins P, Mace N, Lusas M. The impact of dementia on the family.
JAMA. 1982;248:333–335.
24. Mittelman MS, Ferris SH, Steinberg G, et al. An intervention that
delays institutionalization of Alzheimer’s disease patients: treatment
of spouse caregivers. Gerontologist. 1993;33:730–740.
25. Mittelman MS, Ferris SH, Shulman E, et al. A family intervention to
delay nursing home placement of patients with Alzheimer’s disease:
a randomized controlled trial. JAMA. 1996;276:1725–1731.
26. Chiverton P, Caine E. Education to assist spouses in coping with
Alzheimer’s disease: a controlled trial. J Am Geriatr Soc. 1989;37:
593–598.
27. Brodaty H, Gresham M. Effect of training program to reduce stress in
carers of patients with dementia. BMJ. 1989;299:1375–1379.
28. Lawton MP, Brody EM, Saperstein AR. A controlled study of respite
service for care givers of Alzheimer’s patients. Gerontologist. 1989;29:
8–16.
29. Mohide EA, Pringle DM, Streiner DL, et al. A randomized trial of
family care giver support in the home management of dementia. J Am
Geriatr Soc. 1990;38:446–454.
30. Doraiswamy PM, Leon J, Cummings JL, Marin D, Neumann PJ.
Prevalence and impact of medical comorbidity in Alzheimer’s disease.
J Gerontol Med Sci. 2002;57A:M173–M177.
31. Fried LP, Tangen CM, Walston J, et al. Frailty in older adults:
evidence for a phenotype. J Gerontol Med Sci. 2001;56A:M146–
M156.
350 GROSSBERG AND DESAI
32. Maguire CP. Telling the diagnosis of dementia: consider each patient
individually. Int Psychogeriatr. 2002;14:123–126.
33. Pinner G, Bouman WP. To tell or not to tell: on disclosing the
diagnosis of dementia. Int Psychogeriatr. 2002;14:127–137.
34. Ross J. Rules over research on mental patients invalid. NY Law J.
1996;10:25–30.
35. Overman W Jr, Stoudemire A. Guidelines for legal and financial
counseling of Alzheimer’s disease patients and their families. Am J
Psychiatr. 1988;145:1495–1500.
36. Valcour VG, Masaki KH, Blanchette PL, et al. Driving and dementia.
J Am Geriatr Soc. 2002;50:1265–1267.
37. Porter MM, Whitton MJ. Assessment of driving with the global
positioning system and video technology in young, middle-aged, and
older drivers. J Gerontol Med Sci. 2002;57:M578–M582.
38. Margolis KL, Kerani RP, McGovern P, Songer T, Cauley JA, Ensrud
KE. Risk factors for motor vehicle crashes in older women. J Gerontol
Med Sci. 2002;57A:M186–M191.
39. Lundberg, et al. Dementia and driving: an attempt at a consensus.
Alzheimer’s Dis Assoc Disorders. 1997;11:28–37.
40. Dubinski, et al. Practice parameter: risk of driving and Alzheimer’s
disease. Neurology. 2000;54:2205–2211.
41. Spangenberg KB, Wagner MT, Hendrix S, Bachman DL. Firearm
presence in households of patients with Alzheimer’s disease and
related dementias. J Am Geriatr Soc. 1999;47:1183–1186.
42. Hughes JC, Louw SJ. Electronic tagging of people with dementia who
wander. BMJ. 2002;325:847–848.
43. Smith GE, Kokmen E, O’Brien PC. Risk factors for nursing home
placement in a population-based dementia cohort. J Am Geriatr Soc.
2000;48:519–525.
44. Yaffe K, Fox P, Newcomer R, et al. Patient and caregiver characteristics
and nursing home placement in patients with dementia. JAMA. 2002;
287:2090–2097.
45. Wilson SA. Transition to nursing home life: a comparison of planned
and unplanned admissions. J Adv Nurs. 1997;26:864–871.
46. Coyne AC, Reichman WE, Berbig LJ. The relationship between de-
mentia and elder abuse. Am J Psychiatr. 1993;150:643–646.
47. Lachs MS, Williams C, O’Brien S, et al. Risk factors for reported
elder abuse and neglect: a nine-year observational cohort study.
Gerontologist. 1997;37:469–474.
48. Michel JP, Pautex S, Zekry D, Zulian G, Gold G. End-of-life care of
persons with dementia. J Gerontol Med Sci. 2002;57A:M640–M644.
49. Reynish W, Andrieu S, Nourhashemi F, Vellas B. Nutritional factors
and Alzheimer’s disease. J Gerontol Med Sci. 2001;56A:M675–
M680.
50. Young KWH, Greenwood CE. Shift in diurnal feeding patterns in
nursing home residents with Alzheimer’s disease. J Gerontol Med Sci.
2001;56A:M700–M706.
51. Morley JE. Decreased food intake with aging. J Gerontol Med Sci.
2001;56A(Special Issue 2):81–88.
52. Van der Steen JT, Ooms ME, Mehr D, et al. Severe dementia and
adverse outcomes of nursing home-acquired pneumonia: evidence for
mediation by functional and pathophysiological decline. J Am Geriatr
Soc. 2002;50:439–448.
53. Finucane TE, Christmas C, Travis K. Tube feeding in patients with
advanced dementia: a review of the evidence. JAMA. 1999;282:1365–
1370.
54. Gillick MR. Sounding board: rethinking the role of tube feeding in
patients with advanced dementia. N Engl J Med. 2000;342:206–210.
55. Volicer L, Rheaume Y, Riley ME, et al. Discontinuation of tube feed-
ing in patients with dementia of the Alzheimer type. Am J Alzheimer’s
Care. 1990;5:22–25.
56. Volicer L, McKee A, Hewitt S. Dementia. Palliative care. Neurol Clin.
2001;19:867–885.
57. Volicer L, Rheaume Y, Brown J, et al. Hospice approach to the
treatment of patients with advanced dementia of the Alzheimer type.
JAMA. 1986;256:2210–2213.
58. O’Brien JT, Ballard CG. Drugs for Alzheimer’s disease. BMJ. 2001;
323:123–124.
59. Birks JS, Melzer D, Beppu H. Donepezil for mild and moderate
Alzheimer’s disease [Cochrane review]. In: The Cochrane Library.
Issue 2. Oxford: Update Software; 2002.
60. Olin J, Schneider L. Galantamine for Alzheimer’s disease [Cochrane
Review]. In: The Cochrane Library. Issue 2. Oxford: Update Software;
2002.
61. Birks J, Grimley Evans J, Iakovidou V, Tsolaki M. Rivastigmine for
Alzheimer’s disease [Cochrane Review]. In: The Cochrane Library.
Issue 2. Oxford: Update Software; 2002.
62. Cummings JL. Cholinesterase inhibitors: a new class of psychotropic
agents. Am J Psychiatr. 2000;157:4–15.
63. Fillit H, Gutterman EM, Brooks RL. Impact of donepezil on caregiving
burden for patients with Alzheimer’s disease. Int Psychogeriatr. 2000;
12:389–401.
64. Farlow M, Potkin S, Koumaras B. Analysis of outcome in retrieved
drop-out patients: a rivastigmine versus placebo, 26-week Alzheimer’s
Downloaded from biomedgerontology.oxfordjournals.org at The Australian National University on March 23, 2011
trial. Arch Neurol. In press.
65. Watkins PB, Zimmerman HJ, Knapp MJ, et al. Hepatotoxic effects of
tacrine administration in patients with Alzheimer’s disease. JAMA.
1994;271:992–998.
66. Waldemar G, Winblad B, Engedal K, et al. Donepezil benefits pa-
tients with either mild or moderate Alzheimer’s disease over one year.
Neurology.
67. Mohs R, Doody R, Morris J, et al. A 1-year, placebo-controlled
preservation of function survival study of donepezil in AD patients.
Neurology. 2001;57:481–488.
68. Dooley M, Lamb HM. Donepezil. A review of its use in Alzheimer’s
disease. Drugs Aging. 2000;16:199–226.
69. Carrier L. Donepezil and paroxetine: possible drug interaction. J Am
Geriatr Soc. 1999;47:1037.
70. Verrico MM, Nace DA, Towers AL. Fulminant chemical hepatitis pos-
sibly associated with donepezil and sertraline therapy. J Am Geriatr
Soc. 2000;48:1659–1663.
71. Grossberg GT, Stahelin HB, Messina JC, et al. Lack of adverse
pharmacodynamic drug interactions with rivastigmine and twenty-two
classes of medications. Int J Geriatr Psychiatr. 2000;15:242–247.
72. Farlow MR, Hake A, Messina J, et al. Response of patients with
Alzheimer’s disease to rivastigmine treatment is predicted by the rate
of disease progression. Arch Neurol. 2001;58:417–422.
73. Raskind MA, Peskind ER, Wessel T, Yuan W. Galantamine in AD:
a 6-month randomized, placebo-controlled trial with a 6-month ex-
tension: the Galantamine USA-1 Study Group. Neurology. 2000;54:
2261–2268.
74. Giacobini E, ed. Cholinesterase inhibitors: from the Calabar bean to
Alzheimer therapy. In: Cholinesterases and Cholinesterase Inhibitors.
London: Martin Dunitz; 2000:181–226.
75. Auriacombe S, Pere JJ, Loria-Kanza Y, Vellas B. Efficacy and safety
of rivastigmine in patients with Alzheimer’s disease who failed to
benefit from treatment with donepezil. Curr Med Res Opin. 2002;18:
129–138.
76. Robillard A, Arts R, Nasreddine Z, Rasmussen L. Efficacy of
galantamine in patients not responding to donepezil (18-week interim
results). J Neurol Sci. 2001;187(suppl 1):S59.
77. Robillard A, McKelvey R, Nasreddine Z. Galantamine improves sleep
in patients withdrawn from donepezil (preliminary results). J Neurol
Sci. 2001;187(suppl 1):S55.
78. Emre M. Switching cholinesterase inhibitors in patients with
Alzheimer’s disease. Int J Clin Pract Suppl. 2002;127:64–72.
79. Morris JC. Therapeutic continuity in Alzheimer’s disease: switching
patients to galantamine. Clin Ther. 2001;23(suppl A):A1–A2.
80. Doody RS, Geldmacher DS, Gordon B, et al. Open-label, multicenter,
phase 3 extension study of the safety and efficacy of donepezil in pa-
tients with Alzheimer’s disease. Arch Neurol. 2001;58:427–433.
81. Farlow MR, Anand R, Messina J Jr, et al. A 52-week study of the
efficacy of rivastigmine in patients with mild to moderately severe
Alzheimer’s disease. Eur Neurol. 2000;44:236–241.
82. Tariot PN, Solomon PR, Morris JC, et al. A 5-month, randomized,
placebo-controlled trial of galantamine in AD. The Galantamine USA-
10 Study Group. Neurology. 2000;54:2261–2268.
83. Feldman H, Gauthier S, Hecker J, et al. A 24-week, randomized,
double-blind study of donepezil in moderate to severe Alzheimer’s
disease. Neurology. 2001;57:613–620.
84. Tariot PN, Cummings JL, Katz IR, et al. A randomized, double-blind,
placebo-controlled study of the efficacy and safety of donepezil in
patients with Alzheimer’s disease in the nursing home setting. J Am
Geriatr Soc. 2001;49:1590–1599.
 MANAGEMENT OF ALZHEIMER’S DISEASE
85. Anand R, Koumaras B, Hartman RD. The effects of rivastigmine on
behavioral symptoms in severe AD patients in a nursing home setting.
Neurobiol Aging. 2002;21(suppl 1):S220–S221.
86. Erkinjuntti T, Kurz A, Gauthier S, et al. Efficacy of galantamine in
probable vascular dementia and Alzheimer’s disease combined with
cerebrovascular disease: a randomized trial. Lancet. 2002;359:1283–
1290.
87. McKeith I, Del Ser T, Spano P, et al. Efficacy of rivastigmine in
dementia with Lewy bodies: a randomized, double-blind, placebo-
controlled international study. Lancet. 2000;356:2031–2036.
88. Wesnes KA, McKeith IG, Ferrara R, et al. Effects of rivastigmine
on cognitive function in dementia with Lewy bodies: a randomized
placebo-controlled international study using the cognitive drug research
computerized assessment system. Dement Geriatr Cogn Disorders.
2002;13:183–192.
89. Tiraboschi P, Hansen LA, Alford M, et al. Early and widespread
cholinergic losses differentiate dementia Lewy bodies from Alzheimer
disease. Arch Gen Psychiatr. 2002;59:946–951.
90. Prasher VP, Huxley A, Haque MS. A 24-week, double-blind, placebo-
controlled trial of donepezil patients with Down syndrome and
Alzheimer’s disease—pilot study. Int J Geriatr Psychol. 2002;17:
270–278.
91. Farlow MR, Cyrus PA. Metrifonate therapy in Alzheimer’s disease:
a pooled analysis of four randomized, double-blind, placebo-con-
trolled trials. Dement Geriatr Cogn Disorders. 2000;11:202–211.
92. Winblad B, Poritis N. Memantine in severe dementia: results of the
9M-Best Study (benefit and efficacy in severely demented patients
during treatment with memantine). Int J Geriatr Psychiatr. 1999;14:
135–146.
93. Oken BS, Storzbach DM, Kaye JA. The efficacy of Ginkgo biloba on
cognitive function in Alzheimer’s disease. Arch Neurol. 1998;55:1409–
1415.
94. Sano M, Ernesto C, Thomas RG, et al. A controlled trial of selegiline,
alpha-tocopherol, or both as treatment for Alzheimer’s disease. N Engl
J Med. 1997;336:1216–1222.
95. Tabet N, Birks J, Grimley Evans J, et al. Vitamin E for Alzheimer’s
disease [Cochrane Review]. In: The Cochrane Library. Issue 4. Oxford:
Update Software; 2002.
96. Wilcock GK, Birks J, Whitehead A, et al. The effect of selegiline in
the treatment of people with Alzheimer’s disease: a meta-analysis of
published trials. Int J Geriatr Psychiatr. 2002;175–183.
97. Mulnard RA, Cotman CW, Kawas C, et al. Estrogen replacement
therapy for treatment of mild to moderate Alzheimer’s disease. JAMA.
2000;283:1007–1015.
98. Henderson VW, Paganini-Hill A, Miller BL, et al. Estrogen for
Alzheimer’s disease in women: randomized, double-blind, placebo-
controlled trial. Neurology. 2000;54:295–301.
99. Kyomen HH, Hennen J, Gottlieb GL, Wei JY. Estrogen therapy and
noncognitive psychiatric signs and symptoms in elderly patients with
dementia. Am J Psychiatr. 2002;159:1225–1227.
100. Kyomen HH, Satlin A, Hennen J, Wei JY. Estrogen therapy and
aggressive behavior in elderly patients with moderate-to-severe de-
mentia: results from a short-term, randomized, double-blind trial. Am
J Geriatr Psychiatr. 1999;7:339–348.
101. Zandi PP, Carlson MC, Plassman BL, et al. Hormone replacement
therapy and incidence of Alzheimer’s disease in older women: the
cache county study. JAMA. 2002;288:2123–2129.
102. Fillit HM. The role of hormone replacement therapy in the prevention
of Alzheimer’s disease. Arch Intern Med. 2002;162:1934–1942.
103. Ott BR, Belazi D, Lapane KL. Cognitive decline among female
estrogen users in nursing homes. J Gerontol Med Sci. 2002;57A:
M594–M598.
104. Petitti DB, Buckwalter G, Crooks VC, Chiu V. Prevalence of de-
mentia in users of hormone replacement therapy as defined by pre-
scription data. J Gerontol Med Sci. 2002;57A:M532–M538.
105. Petitti DB, Buckwalter G, Crooks VC, Chiu V. Prevalence of demen-
tia in users of hormone replacement therapy as defined by prescription
data. J Gerontol Med Sci. 2002;57A:M532–M538.
106. Finkel SI, Costa e Silva, Cohen G, et al. Behavioral and psychological
signs and symptoms of dementia: a consensus statement on current
knowledge and implications for research and treatment. Int Psycho-
geriatr. 1996;8(suppl 3):497–500.
351
107. Desai AK, Grossberg GT. Recognition and management of behavioral
disturbances in dementia. Primary Care Companion J Clin Psychiatr.
2001;3:93–109.
108. Lyketsos CG, Lopez O, Jones B, et al. Prevalence of neuropsychiatric
symptoms in dementia and mild cognitive impairment. JAMA. 2002;
288:1475–1483.
109. Small GW, Rabins PV, Barry PP, et al. Diagnosis and treatment of
Alzheimer’s disease and related disorders. JAMA. 1997;278:1363–
1371.
110. Patterson CJS, Gauthier S, Bergman H, et al. The recognition, as-
sessment and management of dementing disorders: conclusions from
the Canadian Consensus Conference on Dementia. Can Med Assoc J.
1999;160(suppl 12):S1–S15.
Downloaded from biomedgerontology.oxfordjournals.org at The Australian National University on March 23, 2011
111. Mega MS, Masterman DM, O’Connor SM, et al. The spectrum of
behavioral responses to cholinesterase inhibitor therapy in Alzheimer
disease. Arch Neurol. 1999;56:1388–1393.
112. Cott CA, Dawson P, Sidani S, Wells D. The effects of a walking/
talking program on communication, ambulation, and functional status
in residents with Alzheimer’s disease. Alzheimer’s Dis Assoc Dis-
orders. 2002;16:81–87.
113. Fiatarone MA, Marks EC, Ryan ND, et al. High-intensity strength
training in nonagenarians. Effects on skeletal muscle. JAMA. 1990;
263:3029–3034.
114. Singh MAF. Exercise comes of age: rationale and recommendations
for a geriatric exercise prescription. J Gerontol Med Sci. 2002;57A:
M262–M282.
115. Snyder M, Egan EC, Bruns KR. Efficacy of hand massage in de-
creasing agitation behaviors associated with care activities in persons
with dementia. Geriatr Nurs. 1995;16:60–63.
116. Rabins P, Bland W, Bright-Long L, et al. Practice Guideline for the
Treatment of Patients With Alzheimer’s Disease and Other Dementias
of Late Life. Practice Guidelines for the Treatment of Psychiatric
Disorders Compendium. Washington, DC: American Psychiatric
Association; 2002.
117. Robichaud L, Hebert R, Desrosiers J. Efficacy of a sensory integration
program on behaviors of inpatients with dementia. Am J Occup Ther.
1994;48:355–360.
118. Woods P, Ashley J. Simulated presence therapy: using selected mem-
ories to manage problem behaviors in Alzheimer’s disease patients.
Geriatr Nurs. 1995;16:9–14.
119. Baines S, Saxby P, Ehlert K. Reality orientation and reminiscence
therapy: a controlled cross-over study of elderly confused people. Br J
Psychiatr. 1987;151:222–231.
120. Kiernat JM. The use of life review activity with confused nursing
home residents. Am J Occup Ther. 1979;33:306–310.
121. Powell-Proctor L, Miller E. Reality orientation: a critical appraisal. Br
J Psychiatr. 1982;140:457–463.
122. Tappen RM. The effect of skill training on functional abilities of
nursing home residents with dementia. Res Nurs Health. 1994;17:
159–165.
123. Gerber GJ, Prince PN, Snider HG, et al. Group activity and cognitive
improvement among patients with Alzheimer’s disease. Hosp Com-
munity Psychiatr. 1991;42:843–845.
124. Karlsson I, Brane G, Melin E, et al. Effects of environmental stimu-
lation on biochemical and psychological variables in dementia. Acta
Psychiatr Scand. 1988;77:207–213.
125. Rovner BW, Steel CD, Shmuely Y, Folstein MF. A randomized trial
of dementia care in nursing homes. J Am Geriatr Soc. 1996;44:7–13.
126. Dunkin JJ, Anderson-Hanley C. Dementia caregiver burden: a review
of the literature and guidelines for assessment and intervention.
Neurology. 1998;51(suppl 1):S53–S60.
127. Knight BG, Lutzky SM, Macofsky-Urban F. A meta-analytic review
of interventions for caregiver distress: recommendations for future re-
search. Gerontologist. 1993;33:240–248.
128. King AC, Gaumann K, O’Sullivan P, Wilcox S, Castro C. Effects of
moderate–intensity exercise on physiological, behavioral, and emo-
tional responses to family caregiving: a randomized controlled trial.
J Gerontol Med Sci. 2002;57A:M26–M36.
129. Zarit SH, Stephens MA, Townsend A, Greene R. Stress reduction for
family caregivers: effects of adult day care use. J Gerontol Sci Soc.
1998;53B:S267–S277.
352 GROSSBERG AND DESAI
130. McCurry SM, Logsdon RG, Teri L. Behavioral treatment of sleep
disturbance in elderly dementia caregivers. Clin Gerontol. 1996;17:
35–50.
131. Burgio LD, Engel BT, Hawkins A, et al. A staff management system
for maintaining improvements in continence with elderly nursing home
residents. J Appl Behav Anal. 1990;23:111–118.
132. Schnelle JF, MacRae PG, Ouslander JG, et al. Functional incidental
training, mobility performance, and incontinence care with nursing
home residents. J Am Geriatr Soc. 1995;43:1356–1362.
133. Beck C, Heacock P, Mercer SO, et al. Improving dressing behavior
in cognitively impaired nursing home residents. Nurs Res. 1997;46:
126–132.
134. Burgio L, Scilley K, Hardin JM, Hsu C, Yancey J. Environmental
‘‘white noise’’: an intervention for verbally agitated nursing home
residents. J Gerontol Psychol Sci. 1996;51B:P364–P373.
135. Cohen-Mansfield J, Werner P. Management of verbally disruptive
behaviors in nursing home residents. J Gerontol Med Sci. 1997;52A:
M369–M377.
136. Schnelle JF, Cruise PA, Rahman A, Ouslander JG. Developing
rehabilitative behavioral interventions for long-term care: technology
transfer, acceptance, and maintenance issues. J Am Geriatr Soc. 1998;
46:771–777.
137. Katz IR. Diagnosis and treatment of depression in patients with
Alzheimer’s disease and other dementias. J Clin Psychiatr. 1998;
59(suppl 9):38–44.
138. Landes AM, Sperry S, Strauss ME. Apathy in Alzheimer’s disease.
J Am Geriatr Soc. 2001;49:1700–1707.
139. Olin JT, Schneider LS, Katz IR, et al. Provisional diagnostic criteria
for depression of Alzheimer’s disease. Am J Geriatr Psychiatr. 2002;
10:125–128.
140. Barak Y, Aizenberg D. Suicide amongst Alzheimer’s disease patients:
a 10-year survey. Dement Geriatr Cogn Disorders. 2002;14:101–103.
141. Eccles M, Clarke J, Livingston M, et al. North of England evidence
based guidelines development project; guideline for the primary care
management of dementia. BMJ. 1998;317:802–808.
142. Teri L, Gallagher-Thompson D. Cognitive-behavioral interventions
for treatment of depression in Alzheimer’s patients. Gerontologist.
1991;3:413–416.
143. Teri L, Uomoto J. Reducing excess disability in dementia patients:
training caregivers to manage patient depression. Clin Gerontol. 1991;
10:49–63.
144. Teri L, Logsdon RG, Uomoto, et al. Behavioral treatment of depres-
sion in dementia patients: a controlled clinical trial. J Gerontol Psychol
Sci. 1997;52B:P159–P166.
145. American Psychiatric Association. Practice guideline for the treatment
of patients with Alzheimer’s disease and other dementias of late life.
Am J Psychiatr. 1997;154:1–39.
146. Taragano FE, Lyketsos CG, Mangone CA, et al. A double-blind,
randomized, fixed-dose trial of fluoxetine vs. amitriptyline in the treat-
ment of major depression complicating Alzheimer’s disease. Psycho-
somatics. 1997;38:246–252.
147. Lyketsos CG, Sheppard JM, Steel CD, et al. Randomized, placebo-
controlled, double-blind clinical trial of sertraline in the treatment of
depression complicating Alzheimer’s disease: initial results from the
Depression in Alzheimer’s Disease Study. Am J Psychiatr. 2000;157:
1686–1689.
148. Nyth AL, Gottfies CG. The clinical efficacy of citalopram in treatment
of emotional disturbances in dementia disorders: a Nordic multicenter
study. Br J Psychiatr. 1990;157:894–901.
149. Nyth AL, Gottfries CG, Lyby K, et al. A controlled multicenter
clinical study of citalopram and placebo in elderly depressed patients
with and without concomitant dementia. Acta Psychiatr Scand. 1992;
86:138–145.
150. Katona CLE, Hunter BN, Bray J. A double-blind comparison of the
efficacy and safety of paroxetine and imipramine in the treatment of
depression with dementia. Int J Geriatr Psychiatr. 1994;2:352–354.
151. Rao V, Lyketsos CG. The benefits and risks of ECT for patients with
primary dementia who also suffer from depression. Int J Geriatr
Psychiatr. 2000;15:729–735.
152. Price TR, McAllister TW. Safety and efficacy of ECT in depressed
patients with dementia: a review of clinical experience. Convulsive
Ther. 1989;5:1–74.
153. Alexopoulos G, et al. The course of geriatric depression with ‘‘rever-
sible dementia’’: a controlled study. Am J Psychiatr. 1993;150:1693–
1699.
154. Blazer DG. Depression in late life: review and commentary. J Geron-
tol Med Sci. 2003;58A:249–265.
155. Wragg RE, Jeste DV. Overview of depression and psychosis in
Alzheimer’s disease. Am J Psychiatr. 1989;146:350–353.
156. Sweet RA, Nimgaonkar VL, Devlin B, et al. Increased familial risk of
the psychotic phenotype of Alzheimer’s disease. Neurology. 2002;
58:907–911.
157. Alexoupoulous GS, Silver JM, Kahn DA, et al. The Expert Consensus
Guideline Series: agitation in older persons with dementia. Postgrad
Med. [special report]. 1998: 1–88.
Downloaded from biomedgerontology.oxfordjournals.org at The Australian National University on March 23, 2011
158. Lanctot KL, Best TS, Mittmann N, et al. Efficacy and safety of
neuroleptics in behavioral disorders associated with dementia. J Clin
Psychiatr. 1998;59:550–561.
159. Schneider LS, Pollock VE, Lyness SA. A metaanalysis of controlled
trials of neuroleptic treatment in dementia. J Am Geriatr Soc. 1990;
38:553–563.
160. Scott K, Lawrence RM, Duggal A, Brooks E. Prescribing patterns for
psychotic and behavioral symptoms in dementia: a national survey.
Psychiatr Bull. 2002;26:288–290.
161. Katz IR, Jeste DV, Mintzer JE, et al. Comparison of risperidone and
placebo for psychosis and behavioral disturbances associated with
dementia. A randomized, double-blind trial. Risperidone Study Group.
J Clin Psychiatr. 1999;60:107–115.
162. DeDeyn PP, Rabheru K, Rasmussen A, et al. A randomized trial
of risperidone, placebo, and haloperidol for behavioral symptoms of
dementia. Neurology. 1999;53:899–901.
163. Goldberg RJ. Long-term use of risperidone for the treatment of demen-
tia-related behavioral disturbances in a nursing home population.
Int J Geriatr Psychopharmacol. 1999;2:1–4.
164. Street JS, Clark WS, Gannon KS, et al. Olanzapine treatment of
psychotic and behavioral symptoms in patients with Alzheimer’s
disease in nursing care facilities: a double-blind, randomized, placebo-
controlled trial. The HGEU Study Group. Arch Gen Psychiatr. 2000;
57:968–976.
165. Tariot PN, Schneider L, Katz I, et al. Quetiapine in nursing home
residents with Alzheimer’s dementia and psychosis. Am J Geriatr
Psychiatr. 2002;10(suppl 1):93.
166. McManus DQ, Arvanitis LA, Kowalcyk BB. Quetiapine, a novel
antipsychotic: experience in elderly patients with psychotic disorders.
Seroquel Trial 48 Study Group. J Clin Psychiatr. 1999;60:292–298.
167. Lane H, Chang Y, Su M, et al. Shifting from haloperidol to ris-
peridone for behavioral disturbances in dementia: safety, response
predictors, and mood effects. J Clin Psychopharmacol. 2002;22:4–10.
168. Jeste DV, Okamoto A, Napolitano J, et al. Low incidence of persistent
tardive dyskinesia in elderly patients with dementia treated with ris-
peridone. Am J Psychiatr. 2000;157:1150–1155.
169. Pollock BG, Mulsant BH, Rosen J, et al. Comparison of citalopram,
perphenazine, and placebo for the acute treatment of psychosis and
behavioral disturbances in hospitalized, demented patients. Am J
Psychiatr. 2002;159:460–465.
170. Shankle WR, Nielson KA, Cotman CW. Low dose propranolol
reduces aggression and agitation resembling that associated with orbito-
frontal dysfunction in elderly demented patients. Alzheimer’s Dis Assoc
Disord. 1995;9:233–237.
171. Porsteinsson AP, Tariot PN, Erb R, et al. Placebo-controlled study
of divalproex sodium for agitation and dementia. Am J Geriatr
Psychiatr. 2001;9:58–66.
172. Tariot PN, Erb R, Podgorski CA, et al. Efficacy and tolerability of
carbamazepine for agitation and aggression in dementia. Am J Psy-
chiatr. 1998;155:54–61.
173. Teri L, Logsdon RG, Peskind E, et al. Treatment of agitation in AD:
a randomized, placebo-controlled clinical trial. Neurology. 2000;55:
1271–1278.
174. Miller LJ. Gabapentin for treatment of behavioral and psychological
symptoms of dementia. Ann Pharmacother. 2001;35:427–431.
175. Desai AK, Grossberg GT. Buspirone in Alzheimer’s disease. Expert
Rev Neurotherap. 2003;3:19–28.
176. Nelson J, Chouinard G. Guidelines for the clinical use of benzo-
diazepines: pharmacokinetics, dependency, rebound and withdrawal.
Can J Clin Pharmacol. 1999;6:69–83.
 MANAGEMENT OF ALZHEIMER’S DISEASE
177. Stern RG, Duffelmeyer ME, Zemishlani Z, et al. The use of benzo-
diazepines in the management of behavioral symptoms in dementia
patients. Psychiatr Clin North Am. 1991;14:375–384.
178. Salzman C, Fisher J, Nobel K, et al. Cognitive improvement following
benzodiazepine discontinuation in elderly nursing home residents. Int
J Geriatr Psychiatr. 1992;7:89–93.
179. Satlin A. Sleep disorders in dementia. Psychiatr Ann. 1994;24:186–
190.
180. Satlin A, Volicer L, Ross V, et al. Bright light treatment of behavioral
and sleep disturbances in patients with Alzheimer’s disease. Am J
Psychiatr. 1992;149:1028–1032.
181. Mishima K, Okawa M, Hishikawa Y, et al. Morning bright light
therapy for sleep and behavior disorders in elderly patients with
dementia. Acta Psychiatr Scand. 1994;89:1–7.
182. Shaw SH, Curson H, Coquelin JP. A double-blind, comparative study
of zolpidem and placebo in the treatment of insomnia in elderly
psychiatric inpatients. J Int Med Res. 1992;20:150–161; correction
1992;20:494.
183. Knopman D, Schneider LS, Davis K, et al. Long-term tacrine
(Cognex) treatment effects on nursing home placement and mortality.
The Tacrine Study Group. Neurology. 1996;47:166–177.
184. Lopez OL, Becker JT, Wisniewski S, et al. Cholinesterase inhibitors
postpone nursing home placement for Alzheimer’s disease. J Neurol
Neurosurg Psychiatr. 2002;72:310–314.
185. Volicer L, Hurley AC. Comorbidity in Alzheimer’s disease. J Mental
Health Aging. 1997;3:5–17.
186. Leon J, Cheng CK, Neumann PJ. Alzheimer’s disease care: costs and
potential savings. Health Aff (Millwood). 1998;17:206–216.
187. Chandra V, Barucha NE, Schoenberg BS. Conditions associated with
Alzheimer’s disease at death: case-control study. Neurology. 1986;36:
209–211.
188. Hashimoto M, Imamura T, Tanimukai S, et al. Urinary incontinence;
an unrecognized adverse effect of donepezil. Lancet. 2000;356:568.
189. Levkoff SE, Evans DA, Liptzin B, et al. Delirium: the occurrence and
persistence of symptoms among elderly hospitalized patients. Arch
Intern Med. 1992;152:334–340.
190. Tune L, Carr S, Hoag E, Cooper T. Anticholinergic effects of drugs
commonly prescribed for the elderly: potential means for assessing
risk of delirium. Am J Psychiatr. 1992;149:1393–1394.
191. Beers MH. Explicit criteria for determining potentially inappropriate
medication use by the elderly. An update. Arch Intern Med. 1997;157:
1531–1536.
192. Mendez MF, Catanzaro P, Doss RC, et al. Seizures in Alzheimer’s
disease: clinico-pathologic study. J Geriatr Psychiatr Neurol. 1994;7:
230–233.
193. Hauser WA, Morris ML, Heston LL, Anderson VE. Seizures and
myoclonus in patients with Alzheimer’s disease. Neurology. 1986;36:
1226–1230.
194. Jellinger KA. Alzheimer disease and cerebrovascular pathology: an
update. J Neural Transm. 2002;109:813–836.
195. Torian LV, Davidson EJ, Sell L, et al. The effect of senile dementia on
acute medical care in a geriatric medicine unit. Int Psychogeriatr.
1994;4:231–239.
196. Lyketsos CG, Sheppard JM, Rabins PV, et al. Dementia hospitaliza-
tion and psychiatry. Am J Psychiatr. 2000;157:704–707.
197. Gillick MR, Serrell NA, Gillick LS. Adverse consequences of
hospitalization in the elderly. Soc Sci Med. 1982;16:1033–1038.
198. Rabins P, Nicholson M. Acute psychiatric hospitalization for patients
with irreversible dementia. Int J Geriatr Psychiatr. 1991;6:209–211.
199. Zubenko GS, Rosen J, Sweet RA, et al. Impact of psychiatric hos-
pitalization on behavioral complications of Alzheimer’s disease. Am J
Psychiatr. 1992;149:1484–1491.
353
200. Tariot PN, Podgorski CA, Blazina L, et al. Mental disorders in the
nursing home: another perspective. Am J Psychiatr. 1993;143:1446–
1449.
201. Mathews FE, Dening T. Prevalence of dementia in institutional care.
Lancet. 2002;360:225–226.
202. Macdonald AJD, Carpenter I, Box O, et al. Dementia and use of
psychotropic medication in non-ÔElderly Mentally Infirm’ nursing
homes in South East England. Age Ageing. 2002;31:58–64.
203. Avorn J, Gurwitz JH. Drug use in the nursing home. Arch Int Med.
1995;123:195–204.
204. Rovner BW, Steel CD, Shmuely Y, Folstein MF. A randomized trial
of dementia care in nursing homes. J Am Geriatr Soc. 1996;44:7–13.
205. Judd S, Marshall M, Phippen P, eds. Design for Dementia. London:
Downloaded from biomedgerontology.oxfordjournals.org at The Australian National University on March 23, 2011
Hawker; 1997.
206. Horwitz GJ, Tariot PN, Mead K, Cox C. Discontinuation of anti-
psychotics in nursing home patients with dementia. Am J Geriatr
Psychiatr. 1995;3:290–299.
207. Banks MR, Banks WA. The effects of animal-assisted therapy
on loneliness in an elderly population in long-term care facilities.
J Gerontol Med Sci. 2002;57A:M428–M432.
208. Coleman MT, Looney S, O’Brien J, Ziegler C, Pastorino CA, Turner
C. The Eden Alternative: findings after one year of implementation.
J Gerontol Med Sci. 2002;57A:M422–M427.
209. Morley JE, Flaherty JH. Putting the ‘‘home’’ back in nursing home.
J Gerontol Med Sci. 2002;57A:M419–M421.
210. Petersen RC, Stevens JC, Ganguli M, et al. Practice parameter: early
detection of dementia: mild cognitive impairment (an evidence-based
review). Neurology. 2001;56:1133–1142.
211. Morris JC, Storandt M, Miller JP, et al. Mild cognitive impairment
represents early-stage Alzheimer’s disease. Arch Neurol. 2001;58:
397–405.
212. Jhee SS, Shiovitz T, Crawford AW, Cutler NR. Beta-amyloid ther-
apies in Alzheimer’s disease. Expert Opin Investig Drugs. 2001;10:
593–605.
213. Morley JE, Farr SA, Flood JF. Antibody to amyloid beta protein
alleviates impaired acquisition, retention, and memory processing in
SAMP8 mice. Neurobiol Learning Memory. 2002;78:125–138.
214. Morley JE, Kumar VB, Bernardo AE, et al. Beta-amyloid precursor
polypeptide in SAMP8 mice affects learning and memory. Peptides.
2000;21:1761–1767.
215. Hock C, Konietzko U, Papassotiropoulos A, et al. Generation of anti-
bodies specific for beta-amyloid by vaccinating patients with Alzheimer
disease. Nat Med. 2002;Oct 15.
216. Kumar VB, Farr SA, Flood JF, et al. Site-directed antisense
oligonucleotide decreases the expression of amyloid precursor protein
and reverses deficits in learning and memory in aged SAMP8 mice.
Peptides. 2000;21:1769–1775.
217. Verlinsky Y, Rechitsky S, Verlinsky O, et al. Preimplantation diag-
nosis for early-onset Alzheimer disease caused by V717L mutation.
JAMA. 2002;287:1018–1021.
218. Silverberg GD, Levinthal E, Sullivan EV, et al. Assessment of low-
flow CSF drainage as a treatment for AD. Neurology. 2002;59:1139–
1145.
219. Reisberg B, Ferris SH, DeLeon MJ, Crook T. The Global Dete-
rioration Scale for assessment of primary degenerative dementia. Am
J Psychiatr. 1982;139:1136–1139.
220. Folstein MF, Folstein SE, McHugh PR. Mini Mental State: a practical
method for grading the cognitive state of patients for the clinician.
J Psychiatr Res. 1975;12:189–198.
Received December 2, 2002
Accepted December 17, 2002