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6.

11: Alzheimer Disease

Priority Medicines for Europe and the World


"A Public Health Approach to Innovation"

Background Paper

Alzheimer Disease
Opportunities to Address Pharmaceutical Gaps

By Saloni Tanna, Pharm.D; MPH


7 October 2004

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6.11: Alzheimer Disease

Table of Contents
1.
2.

Summary......................................................................................................................................3
Introduction.................................................................................................................................4
Cause.............................................................................................................................................4
3. Size and Nature of Disease Burden.........................................................................................4
Incidence and Prevalence............................................................................................................4
4. Control Strategy..........................................................................................................................9
Diagnosis......................................................................................................................................9
Research Directions in Diagnosis and Evaluation.................................................................11
Management...............................................................................................................................11
Pharmacological Therapy Review for AD...............................................................................11
Psychiatric Management of Non-Cognitive Symptoms........................................................14
Affordability and Feasibility.....................................................................................................15
5. Major Problem and Challenges for Disease Control:
Why Does the Disease Burden Persist?.................................................................................15
Risk Factors.................................................................................................................................16
Trends..........................................................................................................................................18
6. Past/Current Research into Pharmaceutical Interventions of AD....................................18
Drugs for Disease Modification...............................................................................................18
Drugs for Prevention and Disease Modification....................................................................19
7. Current Pharmaceutical Product Pipeline for AD Treatment.......................................21
Research into Emerging Technologies.....................................................................................22
Europe and the Fifth Framework Program for Alzheimers Disease...................................22
8. Opportunities for Research into New Pharmaceutical Interventions.............................23
Gaps Between Current Research and Potential Research Issues that Could Make a
Difference....................................................................................................................................24
9. Barriers to Closing the Alzheimer Pharmaceutical Gap....................................................25
10. European Union Funding Opportunities for AD.................................................................26
11. Conclusion.................................................................................................................................27
10 References..................................................................................................................................29

Annexes

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6.11: Alzheimer Disease

1. Summary
Alzheimer disease is a neuro-degenerative disease of the brain that causes changes in brain
function. AD usually affects people over the age of 65 years, with a progressive decline in
memory, thinking, language and learning capacity. Age is the strongest predictor for the
development and progression of AD and with the rapidly aging population of our society,
AD clearly poses a major health problem. An estimated 5-10% of the population aged 65
years and over and 40% of the population greater than 85 years of age are likely to be affected
by AD.
The pathophysiology of AD is related to the injury and death of neurons, especially in the
areas of the brain that are involved with memory and learning. Alzheimer disease is the most
common dementia, accounting for 50%-75% of the total, with a greater proportion in the
higher age ranges. There are nearly 18 million people with dementia in the world today. The
number of people with dementia is expected to increase steadily over the next 25 years. By
2025, there will be about 34 million people with dementia in the world.
There are currently no specific tests that may positively confirm the diagnosis of AD. AD
may be diagnosed on physical and neurological exams, and checking for signs of intellectual
impairment through standard tests of mental function. Definitive changes found in the brain
of affected AD patients are microscopic and can be seen only when a sample of brain tissue is
removed and examined, usually on autopsy.
At present, there is no cure for AD, or any pharmacologic therapy that can delay its onset
or affect the pathophysiology of the illness. The primary goals of treatment are to maximize
the patients ability to function in daily life, maintain quality of life, slow the progression of
symptoms, and treat depression or disruptive behaviors. The current pharmacologic
therapy for AD only provides symptomatic relief for a short period of time, six to eighteen
months.Error: Reference source not found , The only drugs approved in the US and several
parts of Europe for treating AD are cholinesterase inhibitors and the NMDA antagonist,
memantine. These drugs do not affect the pathology or progress of AD.
Management of AD is complex and clinicians and caregivers are confronted with numerous
challenges in managing the AD. Some of these include employing unique social and
environmental interventions; knowledge and use of increasingly sophisticated medications,
and providing individualized therapy to patients, working with care takers or varying
systems providing care.
Continuing efforts are still required. This includes developing medicines that would slow
progression, halt, or prevent AD from occurring. Additionally, challenges for clinical services
include early diagnosis, and intervening early with the most appropriate and effective
medicine. Furthermore, validated therapeutic targets need to be identified, and better animal
research models are needed which reflect the disease. Biotech and major industry also need
to recognize the potential market opportunities for AD and despite the high risk, the rewards
for effective medicines that could delay or halt the disease are huge. The high risks associated
6.11-3

6.11: Alzheimer Disease


with research and development and the lack of makers for disease progression need to be
overcome so that industry may confidently make further advances in this field and to
implement phase II and larger phase III trials for novel therapeutic agents.

2.

Introduction

Dementia is a generic term that describes the cognitive decline in brain function 1. There are
several causes of this condition, such as Alzheimer disease, AIDS, head injury etc. Some
conditions that cause dementia can be reversed, and others cannot. The two most common
forms of dementia in older people are Alzheimer disease and multi infarct dementia
(sometimes called vascular dementia). These types of dementia are irreversible. 2 Alzheimer
disease (AD) is the most common form of dementia; it accounts for 64 per cent of all
dementias.3
AD is characterized by a progressive decline in cognitive function. AD usually affects people
over the age of 65 years, with a progressive decline in memory, thinking, language and
learning capacity. AD should be differentiated from normal age-related decline in cognitive
function, which are more gradual and associated with less disability. 4 AD often starts with
mild symptoms and ends with severe brain damage. People with dementia lose their abilities
at different rates. On average, AD patients live from 8 to 10 years after they are diagnosed,
though the disease can last for as many as 20 years.Error: Reference source not found, 5

Cause
The pathophysiology of AD is related to the injury and death of neurons, especially in the
areas of the brain that are involved with memory and learning. Patients affected with AD,
show two specific microscopic changes-senile plaques (abnormal deposits of a protein called
amyloid) and neurofibrillary tangles (abnormal spiral filaments in neurons). Through some
unknown mechanism, senile plaques and neurofibrillary tangles prompt the injury and
death of neurons, and this subsequently produces the intellectual and behavioural
symptomatic changes evident in AD. 6
Currently, theories about the development of AD have focused on how the death of neurons
affects levels of essential brain chemicals called neurotransmitters. When injured neurons in
the hippocampus and cortex die, there is a corresponding drop in neurotransmitter
acetylcholine. Error: Reference source not found Other neurotransmitter systems are also
affected later in the disease e.g. glutamate, serotonin.

3.

Size and Nature of Disease Burden

Incidence and Prevalence


Exact estimates of the prevalence of dementia depend on the definition and specific
threshold used, but it is clear that the prevalence increases dramatically with age. The
syndrome affects approximately 5%-8% of individuals over age 65, 15%-20% of individuals
over age 75, and 25%-50% of individuals over age 85. Alzheimer disease is the most common
dementia, accounting for 50%-75% of the total, with a greater proportion in the higher age
6.11-4

6.11: Alzheimer Disease


ranges. Vascular dementia is probably next most common, but its prevalence is unknown.
The remaining types of dementia account for a much smaller fraction of the total. 7
Figure 1 compares the absolute level of Alzheimer disease burden (measured by DALYs as
"Alzheimer`s and other dementias" ) between the EU25, EU15, EU 10 and the world
(including the EU25) for different age groups. Although the differences in absolute values are
to be expected, females in all regions carry the higher burden of Alzheimer, in large part
because of their longer life expectancy. This gender divergence between males and females
begins in terms of burden of disease begins between the ages of 60-69.
Figure 1.

Alzheimer's Disease (DALYs)


2500000

2000000
World-F

1500000
World-M

1000000

EU25-F
EU15-F

500000

EU25-M
EU15-M

EU10-F
EU10-M

0
0-4

5-14 15-29 30-44 45-59 60-69 70-79

80+

Source: World Health Organization Global Burden of Disease Database

Figure 2 plots the burden of disease for Alzheimer disease for the different EU and World
regions as a fraction of all DALYs (both acute and chronic conditions) for different age
groups. Alzheimer`s disease increases to nearly 20% of the total disease burden (both acute
and chronic) among women in the EU15.
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6.11: Alzheimer Disease

Figure 2.

Source: World Health Organization Global Burden of Disease Database

The mode of onset and subsequent course of dementia depend on the underlying etiology.
Alzheimer disease has an insidious onset and slow decline in brain function, while vascular
dementia is characterized by a more acute onset and stepwise decline. The effective
management of dementia is a function of the underlying pathology and of the availability
and timely administration of effective treatment Error: Reference source not found
Dementia Worldwide 8:
There are nearly 18 million people with dementia in the world today. The number of
people with dementia is expected to increase steadily over the next 25 years (See also
Figures 1 and 2 showing age distribution). By 2025 there will be about 34 million people
with dementia in the world By 2025, 71% of people with dementia will live in developing
countries.
The overall incidence of dementia increases with age at 1% per year. This estimate is
lower for men and people of African or Asian origin.Error: Reference source not found
AD is more prominent in Europe and North America, and in developing countries
dementia appears to be rare. These differences are difficult to explain and may be a result
of poor diagnosis and survival bias due to high death rates at all ages.Error: Reference
source not found
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6.11: Alzheimer Disease

AD prevalence among those older than 60 years is about 5% for men and 6% for women.
With a growing aging population, these numbers are expected to increase rapidly over
the next 20 years. Error: Reference source not found

Dementia in Europe 9
Work from the European Community Concerted Action on the Epidemiology and
Prevention of Dementia group (EURODEM) allows countries participating in the study to
estimate the number of people likely to be affected by dementia-provided that the
accurate population statistics are made available.
EURODEM is able to provide data on the prevalence of moderate to severe dementia and
determine prevalence rates for men and women in 9 different age groups. The study
includes people living with dementia in institutions, nursing homes, residential care as
well as those living at home. The study was only based on diagnosed cases of dementia,
and the report acknowledges the problems related to this, since many people fail to get
diagnosed and are therefore excluded.
Data for this study comes from the following European countries: Germany, Finland,
France, Italy, The Netherlands, Norway, Portugal, Spain, Sweden, and UK.

Table 1. EURODEM Prevalence Rates for Men and Women in Nine Different Age
Groups for Dementia (1980-1990 Findings)Error: Reference source not found
Age group
30-59
60-64
65-69
70-74
75-79
80-84
85-89
90-94
95-99

Male
0.16%
1.58%
2.17%
4.61%
5.04%
12.12%
18.45%
32.1%
31.58%

Female
0.09%
0.47%
1.10%
3.86%
6.67%
13.50%
22.76%
32.25%
36.00%

Dementia in UK Error: Reference source not found


Dementia affects over 750,000 people in the UK with Alzheimer disease being the most
common form of dementia. (Table 3. shows the proportions of those with different forms
of dementia).
Over 18,000 people with dementia are under 65 years old.
Dementia affects one person in 20 aged over 65 years and one person in five over 80 years
of age.
It is estimated that by 2010, there will be about 840,000 people with dementia in the UK,
and this is expected to rise to over 1.5 million people with dementia by 2050.

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6.11: Alzheimer Disease


Table 2: Estimated Number of People with Dementia in the UK Using Population
Figures for 2001Error: Reference source not found
England
Scotland
Northern Ireland
Wales
Total

652,600
63,700
17,100
41,800
775,200

Table 3: Proportions of Dementia in the UKError: Reference source not found


Alzheimer disease
Vascular dementia
Dementia with Lewy bodies
Fronto-temporal dementia including Pick's
disease
Other dementias

55%
20%
15%
5%
5%

Dementia in Japan 10
By the end of Sept. 2003, there were 20,561 people over 100 years old in Japan, of which
84.6% were female. Prevalence of dementia increases with age with a prevalence of 1.5%
in the group aged 65-69 and 27.3% in the group aged 85 and over. In Japan dementia of
vascular type is more prevalent than Alzheimer type. Estimates of vascular versus
Alzheimer dementia in Japan are probably distorted because of cultural factors, i.e. it is
more acceptable to have a vascular disorder than a mental disorder.
Dementia in CanadaError: Reference source not found
There were an estimated 83,200 new cases of dementia in 2001. By 2011 new cases of
dementia are expected to reach 111,600 per year. Alzheimer disease affects 1 in 20
Canadians over age 65. By 2031: over 3/4 million Canadians are expected to have
Alzheimer disease and related dementias.
Dementia in the US 11
An estimated 4.5 million Americans have Alzheimer disease, according to data from 2000
U.S. census. This data also shows that by 2050, the number of Americans with Alzheimer
disease could range from 11.3 million to 16 million.
National direct and indirect annual costs of caring for individuals with Alzheimer
disease are at least $100 billion, according to estimates used by the Alzheimers
Association and the National Institute on Aging.
Alzheimer disease costs American business $61 billion a year, according to a report
commissioned by the Alzheimers Association. Of this amount, $24.6 billion covers
Alzheimer health care and $36.5 billion covers costs related to caregivers of individuals
with AD, including lost work productivity, absenteeism and worker replacement.

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6.11: Alzheimer Disease


More than 70 percent of people with AD live at home, where family and friends provide
almost 75 percent of their care. The remainder is paid care costing an average of U.S
$12,500 per year. Families pay most of this amount out of pocket. An estimated half of all
nursing home residents have Alzheimer disease or a related dementia disorder. The
average cost for nursing home care is estimated at $42,000 per year. The average lifetime
cost taking care of a patient with AD of care is $174,000.
Medicare costs for beneficiaries with Alzheimer disease are expected to increase 54.5
percent, from $31.9 billion in 2000 to $49.3 billion by 2010. Furthermore, Medicaid
expenditures on residential dementia care will increase 80 percent, from $18.2 billion to
$33 billion in 2010, according to a report commissioned by the Alzheimers Association.
The Alzheimers Association has given more than $150 million towards research grants
since 1982.
The federal government estimates spending approximately $640 million for Alzheimer
disease research in fiscal year 2003.

4.

Control Strategy

AD disease is a complex disease and its management is often challenging. Personality and
behavioural changes, and the eventual inability to perform activities of daily living lead to
dependence. As functional impairment deteriorates, health care utilization increases until
patients are forced to become institutionalized for around the clock supervision. Patients can
remain in severe stages of AD for several years. Error: Reference source not found, 12, Error: Reference
source not found

DiagnosisError: Reference source not found


There are currently no specific tests that may positively confirm the diagnosis of AD. AD
may be diagnosed on physical and neurological exams, and checking for signs of intellectual
impairment through standard tests of mental function. For a diagnosis of AD, the criteria
adapted from the National Institute of Neurological and Communicative Disorders and
Stroke and Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA)
include the following:
dementia established by examination and objective testing;
deficits in two or more cognitive areas;
progressive worsening of memory and other cognitive functions;
no disturbance in consciousness;
and onset between ages 40 and 90.
Absence of systemic disorders or other brain diseases, which could account for the deficits in
memory and cognition, should also be ruled out. Diagnostics tests such as MRI and CT are
also done to rule out medical causes of creased brain function. Definitive changes found in
the brain of affected AD patients are microscopic and can be seen only when a sample of
brain tissue is removed and examined, usually on autopsy.Error: Reference source not
found,Error: Reference source not found
Alzheimer disease is characterized primarily by a gradual onset of progressive symptoms,
including:13
6.11-9

6.11: Alzheimer Disease


memory loss
changes in personality
noticeable decline in cognitive abilities (including speech and understanding)
loss of executive function (decision-making)
losses impairing activities of daily living (dressing, eating, toileting, etc.)
Annex 6.11.1 identifies sources for the differential diagnosis of AD. The actual diagnostic
work-up for AD is very involved and requires several steps this includes an initial evaluation
including a medical history, a mental status evaluation, a clinical examination, and laboratory
tests.Error: Reference source not found
Alzheimer disease is the most common cause of dementia, however there are many disorders
that can cause or simulate dementia. To appropriately diagnose for AD, other forms of
dementia or diseases need to be ruled out. This includes the following:Error: Reference
source not found
Medication-induced dementia. Medication-induced dementia is the most frequent cause
of reversible dementia. To rule out a medication-induced dementia, a thorough drug
history and a review of all current medication (both prescription and over-the-counter)
needs be undertaken.
Metabolic/endocrine/nutritional/systemic
disorders.
Metabolic/endocrine/nutritional/
systemic disorders (e.g., hypothyroidism, B12 deficiency, and systemic infections) are
additional causes of reversible dementias and can be diagnosed with routine
laboratory tests. Tests recommended include blood count, sedimentation rate (if
indicated), electrolytes (including calcium), liver and renal function tests, urinalysis,
syphilis serology, B12 levels, thyroid function tests, and a toxicity screen (if medical
history and the physical exam so indicate).
Vascular dementia/hydrocephalus /tumors/hematoma. Vascular dementia (VaD) may
result as a sequel to any form of cerebrovascular disease. VaD is responsible for
approximately 20 percent of dementia cases and can Alzheimer disease.
Normal pressure hydrocephalus, brain tumors, and subdural hematoma, the most
common of the structural brain lesions, and stroke can also present with dementia.
Confirmation or exclusion of their presence usually requires a CT or MRI scan.
Depression. Depression is another common cause of dementia in the elderly population.
The following symptoms cognitive impairment symptoms may be present: confusion,
memory disturbance, and attention deficits, all of which can be mistaken for dementia.
Depression may also coexist with dementia and exacerbate the problem, causing; excess
disability. A good history and thorough mental-status is required as part of the
treatment plan. The DSM-IV criterion for diagnosis of depression is often referred to
confirm or rule out depression.
The clinical criteria and diagnosis of dementias, including AD, has not changed since the
1990s. Given the advantages of early diagnosis and early intervention, there is an urgent
need to revise the criteria for diagnosis so that the disease may be identified in the earlier
stages.14 The is much research in identifying the shift between EARLY cognitive changes
associated with dementia and that associated with normal aging, an area known as mild
6.11-10

6.11: Alzheimer Disease


cognitive impairment (MCI).Error: Reference source not found This remains a challenge for
both clinicians and researchers since the Mini Mental State Examination (MMSE), Dementia
Rating Scale and other evaluating tools are relatively insensitive to early cognitive
symptoms.Error: Reference source not found
A new blood test called APOE (apolipoprotein E) genotyping has been used to identify
individuals who carry the APOP-4 gene. The presence of this gene increases a persons risk
for AD and when the gene is present in a person with dementia, a diagnosis of AD is
supported. This test is not recommended as a predictive test in individuals who do not have
symptoms of cognitive impairment.Error: Reference source not found, Error: Reference source not found

Research Directions in Diagnosis and Evaluation


More research is needed for improved detection and evaluation of dementia, particularly in
the prodromal stages and early stages of MCI. Another research area is improved detection of
noncognitive symptoms, so as to facilitate quick and appropriate intervention. Development
of useful and timely outcome measures, including neuropsychological testing and functional
assessments are needed.Error: Reference source not found

ManagementError: Reference source not found


The primary goals of treatment are to maximize the patients ability to function in daily
life, maintain quality of life, slow the progression of symptoms, and treat depression or
disruptive behaviors.
Treatment of AD takes on a systematic approach. First, if there are medical conditions that
make Alzheimer symptoms worse that illness needs to be managed. There are several
medications such as alcohol, sedatives and antihistamines, that can also aggravate AD, and
these must be identified and removed, or switched to alternative medicinesError: Reference
source not found. Medications may also be administered to treat depression, while
antipsychotics medicines can be used to treat aggressive or violent behavior. Finally, caring
for the caregiver is another vital part of any treatment strategy for AD. Experts within this
field recognize that caregivers are at a high risk for depression and medical illness. As a
result, recommendations and guidance to community resources and support is integrated
into the overall management of the disease.Error: Reference source not found

Table 4: Therapeutics Options for Alzheimer disease 15, 16, 17, 18


Non Pharmacologic therapy
Stimulation: Group activities, discussion groups, music therapy, multisensory stimulation
Pharmacologic therapy
Cholinesterase inhibitors (or cholinergics): Donepezil, rivastigmine, galantamine
Glutamatergic agents: Memantine, D-cycloserine
Selegiline
Hormone replacement therapy (estrogen)
Anti-inflammatory drugs (NSAIDs)
6.11-11

6.11: Alzheimer Disease


Antioxidant therapies
Vitamin E
Nootropic Drugs
Ginko Biloba
Nicergoline
Piracetam
Therapy for psychiatric symptoms : behavioural disturbances, mood disorders, agitation
with dementia (e.g. delirium, depression, psychosis, insomnia, sundowning, aggression
or anger, osteoarthritic pain)

Pharmacological Therapy Review for AD


The current pharmacologic therapy for AD only provides symptomatic relief for a short
period of time, six to eighteen months.Error: Reference source not found, At present there is
no cure for AD, or any pharmacologic therapy that can delay its onset or affect the
pathophysiology of the illness. 19 The only drugs approved in the US and several parts of
Europe for short term alleviation of symptoms are cholinesterase inhibitors and memantine.
These drugs do not affect the pathology of AD, but allows the brain to compensate for the
loss of neurons that communicate via acetylcholine, a neurotransmitter.Error: Reference
source not found, Error: Reference source not found This section reviews the clinical efficacy of approved
and possible pharmacological therapies for AD.
Cholinesterase inhibitors
Cholinesterase inhibitors are a class of medicines that block cholinesterase-an enzyme that
breaks down the neurotransmitter acetylcholine. AD is linked with low levels of
acetylcholine, hence inhibiting or blocking the breakdown of acetylcholine through
cholinesterase inhibitors may help to improve brain function, and possibly slow deterioration
of cognitive function.Error: Reference source not found
Treatment effects have been demonstrated with several different cholinesterase inhibitors,
indicating that the class of agents is consistently better than placebo. However, the
disease eventually continues to progress despite treatment and the average effect is often
modest. However, global changes in cognition, behavior and functioning have been
detected by both physicians and caregivers, indicating that even small measurable
differences may be clinically significant.

These drugs are similar yet have distinct pharmacology profiles such as onset of action,
side effect profile, potential drug interactions, ease of administration (e.g. twice a day
versus three times a day), and route of metabolism. However, the clinically relevance of
these differences are unclear and the significance of these differences awaits head-tohead trials.Error: Reference source not found,Error: Reference source not found

This class of drugs is indicated for mild to moderate AD. However, no published results
are available for severe dementia, though open-label follow up from trials suggests that
these drugs continue working as the cholinergic deficit increases.Error: Reference source
not found

Benefits reported for these medications tend to occur at higher doses. However, the
higher the dose, the more likely the side effects.Error: Reference source not found
6.11-12

6.11: Alzheimer Disease

Given the increase in AD prevalence, more studies are needed to determine the role of
cholinergic medicines in patients with severe AD and to provide comparative data on
therapeutic options for this subset of patients.20

Cochrane reviews of the cholinesterase inhibitors suggest that treatment effects have been
demonstrated with several agents, and that this class is generally more efficacious than
placebo. See also Background Chapter 5. Positive changes in cognition, behavior and
function were demonstrated, however, the disease continues to progress and the treatment
effect is modest and short lived.Error: Reference source not found
Reviewers conclusions for donepezil: In selected patients with mild or moderate Alzheimer
disease treated for periods of 12, 24 and 52 weeks, donepezil produced modest
improvements in cognitive function. No improvements were present on patient selfassessed quality of life and data on many important outcomes are not available.
Furthermore, the 10mg dose showed only a marginal benefit to the 5mg dose. The
practical importance of these changes to patients and caregivers is unclear.21
Reviewers conclusions for galantamine: Patients in these trials were similar to those seen in
earlier anti dementia AD trials, and consisted predominantly of mildly to moderately
impaired outpatients with AD. Evidence from studies show that there was an overall
positive effect for trials of 3, 5 and 6 months in duration. Furthermore, there was
evidence for efficacy of galantamine on global ratings, cognitive tests, assessments of
ADLs (activities of daily living) and behaviour. Reviewers stated that the magnitude of
cognitive effect was similar to other cholinesterase inhibitors including donepezil,
rivastigmine, and tacrine. Also, galantamine's safety profile is similar to that of other
cholinesterase inhibitors with regard to cholinergically mediated gastrointestinal
symptoms. Longer-term use of galantamine has not been assessed in a RCTs
(randomized controlled trials) and is desirable. 22
Reviewers conclusions for Rivastigmine: Studies show that rivastigmine is beneficial for
people with mild to moderate AD. In comparisons with placebo, improvements were
seen in cognitive function, ADL, and severity of dementia with daily doses of 6 to 12 mg.
Further research is needed on dosage (frequency and quantity) in a search for ways to
minimize adverse effects. Moreover, RCTs greater than 26 weeks are needed to
determine the efficacy of rivastigmine. 23
The cholinesterase inhibitors (donepezil and rivastigime) may not be cost effective for the
management of AD 24 but the study that reached this conclusion has been challenged by the
industry which has asserted that it was under powered. Results of this study were asserted
to " incompatible with many drug company-sponsored observational studies and
advertisements claiming remarkable effects of cholinesterase inhibitors" .Error: Reference
source not found In addition, previous claims that donepezil can stabilize cognitive
deterioration and delay nursing home placement by two to three years have not been
validated by this study. The study also showed that the long-term use of donepezil cost the
UK National Health Service more than placebo.Error: Reference source not found The more
general understanding is that these drugs do not work in the more severe states of the
disease.
6.11-13

6.11: Alzheimer Disease


Improvements in cognitive functions for the first two years were significantly better than
placebo. This validates industry-sponsored studies. However, no benefits were seen in the
long term endpoints of institutionalization, and the experts state that improvements in
cognition does not reduce institutionalization as reported by pharmaceutical companies.
Error: Reference source not found
Glutamatergic agents
One of the pathological hypotheses suggested to cause AD is neurotoxic mechanisms
resulting is excessive amounts of amino acids being released. AD patients have a loss of
glutametergic pyramidal neurons, while the receptors NMDA (N-methyl-D-aspartate) are
preserved. An over stimulation of these receptors could lead to neuronal loss. Memantine, an
NMDA blocker, is effective in treating severe AD. The drug has been approved in Germany
since 1970s, but clinical trial data to support its use have been limited. Data from recent
clinical trials investigating the safety and clinical efficacy of memantine show that it is
effective for moderate to severe AD. The medication is still being studied and is approved in
the US and several European countries. Error: Reference source not found
Reviewers conclusions on Memantine: There is a short-term beneficial effect of memantine
compared to placebo for patients with moderate to severe AD. The effect of memantine in
patients with vascular dementia, Alzheimer disease and dementia of non-specified type at
six weeks showed that there were beneficial effects on cognition, activities of daily living, and
behaviour and in global impression of change. The drug is well tolerated and the incidence of
adverse effects is low. However, most of the trials so far reported have been small and not
long enough to detect clinically important benefits long term, therefore more studies that
are extended in duration are needed to determine the efficacy of memantine. 25

Psychiatric Management of Non-Cognitive Symptoms


Psychiatric and behavioural problems are present in up to 90% of patients with dementia. 26
Non-cognitive symptoms of dementia tend to evolve over time, so regular monitoring allows
adaptation of treatment strategies to current individual needs. For example, among the
behavioural disturbances common in Alzheimer disease, depression is more common early
in the illness, while delusions and hallucinations are more common in the middle and later
stages. Behavioural issues to be addressed include major depression and other depressive
syndromes, suicidal ideation or behaviour, hallucinations, delusions, agitation, aggressive
behavior, disinhibition, anxiety, apathy, and sleep disturbances.27
Early intervention is important since psychiatric symptoms can respond to treatment more
readily than cognitive and functional deficits.Error: Reference source not found Table 5.
shows the behavioural clusters manifested in AD and relevant classes of medications for
intervention.Error: Reference source not found

Table 5: Behavioural Clusters Matched with Potentially Relevant Classes of


MedicationsError: Reference source not found
6.11-14

6.11: Alzheimer Disease


Behaviour
Agitation/aggression

Anxiety
Apathy
Disturbed effect/mood
Altered ideation/perception

Agent
Antipsychotics,anticonvulsants, antidepressants,
anxiolytics
Antidepressants, anxiolytics, anticonvulsants
Antidepressants, stimulants
Antidepressants, anticonvulsants
Antispsychotics

Vegetative features

Antidepressants, anxiolytics, stimulants

There is sufficient evidence from randomized controlled trials to support the use of both
traditional and atypical antipsychotics for the management of agitation and psychosis in
dementia. Of the two classes atypical antipsychotics appear to be better tolerated
compared to traditional antipsychotics.Error: Reference source not found, Error: Reference source not
found

There is evidence that SSRIs (selective serotonin reuptake inhibitors) antidepressants may
be administered and are better tolerated than other antidepressants.

The American Academy of neurology practice guidelines conducted an in-depth review of


pharmacological therapies for non-cognitive symptoms in dementia. The expert panel
conclude that most studies in this area focus on mixed populations with dementia. Therefore,
it is not entirely possible to assess the efficacy of specific medications for patients with
specific form of dementias such as AD.Error: Reference source not found

Affordability and Feasibility


The financial costs of managing AD are enormous. The cost of illness is high in terms of both
public and private resources. Caregivers who are required to provide care and patients
affected by dementia also pay a high price in terms of their quality of life. Limited literature
is available on the affordability, accessibility and cost of AD management. Further studies are
required to assess the cost of disease management for AD. The following section provides
some information on the cost of managing AD or dementia where available.
UKError: Reference source not found
Although dementia is a major area of expenditure in the UK, over three-quarters of health
authorities surveyed (in 1997) were unable to identify the resources spent on dementia care.
There have been relatively few studies in this area. Estimated annual cost of Alzheimer
disease at between 5,400 and 5,800 million a year in the UK. Estimated costs associated
with Alzheimer disease at different stages of the disease revealed that over a three-month
period the total mean cost per patient with mild Alzheimer was 6,616, 10,250 for a person
with moderate Alzheimer and 13,593 for a person with severe Alzheimer disease in the UK.
The Alzheimers association of UK state that although all of these studies highlight the high
costs of dementia they still under-estimate the true cost. For example, the costs of caring by
partners and children of people with dementia are considerable. Also, what is often
overlooked is the cost of not intervening early in the disease. The greatest proportion of
6.11-15

6.11: Alzheimer Disease


direct costs of dementia care is also associated with institutional support. This is often
provided at a crisis point, which is always expensive and often precipitated by lack of
effective support.
US
In a report by Delagarza on the pharmacological management of Alzheimer disease, the
authors state that in the US AD accounts for $100 billion per year in medical and
custodial expenses, with the average cost per patient at US $27,000 annually. This
includes medical and nursing care.Error: Reference source not found
Canada
The annual cost of caring for patients with dementia has been estimated to range from $941
per patient with mild disease to $36,794 per patient with severe disease, with an average net
cost of about 4 billion dollars.Error: Reference source not found

5. Major Problem and Challenges for Disease Control: Why Does the
Disease Burden Persist?
A cure for AD is still not available and clinicians and caregivers are challenged with caring
for an increasing aging population affected by dementia. Increased life expectancy has seen a
rise in chronic medical disease and associated illnesses, including dementia. For example,
there will be an estimated 400% increase in population of North Americans aged 85 and
older by 2050, 40% of whom will develop dementia. Error: Reference source not found
Clinicians providing care for patients with dementia are confronted with numerous
challenges in managing AD. Some of which include employing unique social and
environmental interventions; knowledge and use of increasingly sophisticated medications,
and providing individualized therapy to patients, working with care givers or varying
systems providing care. The burden for the general practitioner is not necessarily an increase
in sophisticated medicines - it is really the lack of specific medicines for AD that is the
problem - the physician has a limited range of therapeutic options, e.g. frequently used
neuroleptics have mixed pharmacologies that can cause memory impairment, etc.
Management of AD is also complex since it requires differentiating and managing various
changing neuropsychiatric and behavioural problems. A balance also has to be reached
between aggressive intervention and palliative care continued treatment versus withdrawal
of medicines, and patient benefit versus caregiver burden. Managing AD is complex and
presents a major public health concern for the today and the future.Error: Reference source
not found,Error: Reference source not found

Risk Factors
The following are some of the risk factors that are thought to have some relationship on the
development of AD. Many of these risk factors are still being studied.

Table 6. Some Risk Factors Associated with Alzheimer diseaseError: Reference


source not found, Error: Reference source not found, Error: Reference source not found, 28
Risk factor
6.11-16

6.11: Alzheimer Disease


Age
Positive
family
history

High life expectancy. Normal aging process increases the risk of AD.
Studies indicate that AD may be inheritable. Relatives with AD (i.e. parent or
sibling) are at a risk for developing AD.
Recent research has identified the presenilin 1 gene on chromosome 14 and
the presenilin 2 gene on chromosome 1. Both genes appear to be strong
indicators for Alzheimer Disease at an early age of onset (before the age of
65). Error: Reference source not found
Preliminary research has also found markers on chromosomes 9, 10 and 12
that might be linked to late-onset Alzheimer Disease (over the age of 65).
Several research studies are underway collecting blood samples from people
with Alzheimer Disease and their family members. These samples enable
scientists to analyze DNA material within families with the intent of
identifying genes that may be responsible for causing Alzheimer
Disease.Error: Reference source not found

6.11-17

6.11: Alzheimer Disease

Risk factor
Down
Syndrome
Head injury

Education

Aluminum

Estrogen

Social,
productive
and
Physical
activity
Comorbid
diseases

Almost all individuals with Down syndrome over the age of 40 have changes to
brain cells characteristic of Alzheimer Disease. In these individuals, dementia
usually develops in 50's or 60's of age.
Some studies have shown that people who have had a head injury with loss of
consciousness have an increased chance of developing Alzheimer disease.
Research into the development of AD as a result of head injuries is
ongoing.Error: Reference source not found The increased risk is probably due to
the upregulation of APP seen after brain trauma.
Several studies have shown that people who have less than six years of formal
education appear to have a higher risk of developing AD. Low education may
reflect early experiences that were not beneficial to brain development. Higher
education is thought to delay the onset of symptoms of Alzheimer Disease
probably due to greater brain reserve or educational activities that may stimulate
brain activity. Education as a protective factor requires more study to determine
whether it is education that makes a difference or other factors related to it (e.g.,
income level).Error: Reference source not found,Error: Reference source not found
The correlation between AD and aluminum is still under debate in the scientific
community. Some studies have indicated that exposure to aluminum in drinking
water may increase the chances of individuals developing Alzheimer
Disease.Error: Reference source not found
Research has been conducted on estrogen and its impact on various diseases,
including AD. Current research indicates that combined estrogen therapy
(estrogen plus progestin) in women over the age of 65 doubled their risk of
developing Alzheimer Disease and Vascular Dementia, over a five-year period.
Research continues to investigate the effects of estrogen-only therapy on
cognition. Previous research has shown that women with Alzheimer Disease
who were treated with estrogen showed no sign of improvement. Error:
Reference source not found,Error: Reference source not found
Recent data from the CSHA-2 (Canada Study for Health and Aging) show that
regular physical activity was associated with reduced risk of AD. This
information supports previous clinical trials showing exercise to benefit
cognitive function. Identifying the protective effect of regular physical activity is
an important finding since it may represent a relatively safe and available
strategy to help prevent AD, as well as many other chronic conditions. The
CSHA-2 recommends that further research still needs to be conducted in this
area.Error: Reference source not found
Hypertension, high cholesterol, diabetes mellitus and low estrogen may affect
the development of AD. Co-morbid diseases that may affect the development of
AD are being researched.Error: Reference source not found ,Error: Reference source not
found,Error: Reference source not found

Other risk
factors
being
studied

Other factors being investigated by researchers in relation to Alzheimer Disease


include:
Existing diseases or conditions that a person may have (such as heart
disease, high cholesterol or high homocysteine levels in the blood)
Toxins in the environment (such as fertilizers or pesticides)
Antioxidants (such as vitamin E)
Lifestyle choices (such as wine and coffee consumption, and diet)

6.11-18

6.11: Alzheimer Disease


Trends
Age is the strongest predictor for the development and progression of AD. According to
ADEAR (Alzheimer disease Education and Referral Center), a service of the NIA (National
Institute of Ageing), the number of people with AD doubles every 5 years after the age of
65.Error: Reference source not found AD is a terminal disease, with deterioration in physical
and mental health over time. Cause of death is usually pneumonia and infections as a result
of the weakened immune system. 29 With the rapidly aging population of our society, AD
clearly poses a major health problem. There are approximately 8-10 million people affected
with AD within countries with strong pharmaceutical markets. (UK, USA, Spain, France,
Germany, Italy and Japan) and these numbers will most likely continue to rise as the baby
boomer generation approach 65 years of age. Pharmaceutical sales of cholinesterase
inhibitors, the only major approved class at present for AD, are estimated to be at
approximately 1 billion dollars, with about 60% of diagnosed AD patients receiving
medications. This market will most likely grow with a three to five fold increase with the
inclusion of patients diagnosed with MCI (mild cognitive impairment), a precursor to AD.
Much will depend on whether MCI is recognized as a reimbursable disease.

6. Past/Current Research into Pharmaceutical Interventions of AD


At present, all treatments for AD offer only modest symptomatic relief for periods between
six to eighteen months. Cholinergic therapies are the mainstay of AD management today.
Unfortunately, there are no drugs that can halt or reverse AD progression. This section
provides some information on some of the areas of ongoing research for AD. The past 5 years
has seen a growth in the number of drugs being developed for AD. Future compounds under
research are aimed at delaying, preventing progression of the illness and drugs that may
alleviate the underlying pathology.Error: Reference source not found, Error: Reference source not found

Drugs for Disease Modification


Secretase inhibitors. One of the features of AD pathophysiology is the accumulation of senile
plaques at the end of degenerating brain neurons. amyloid, a major constituent of these
plaques, is toxic to neurons in vitro and is considered to be responsible for the neuronal cell
loss in AD. and secretases are the two enzymes critically responsible for forming
amyloid. This discovery has prompted new therapies directed at blocking these enzymes,
thus preventing or slowing the progression of the disease. At present most of the research is
limited to animal testing.30
Metal chelation. As mentioned above, brain damage in Alzheimer disease is caused by
amyloid, but metal ions, such as zinc and copper, both of which accumulate in the brain with
old age, are also neurotoxic. Research has shown that these metals cause amyloid
aggregation, and the mixture of the two (i.e. amyloid and metal ions) results in the
production of hydrogen peroxide, which in turn causes oxidative damage. Clioquinol, an
antibiotic, which acts as a chelating agent, facilitates the removal of metal ions, and has the
potential to slow progression of AD. Phase II trial results have been promising and large
treatment trials are expected.Error: Reference source not found
6.11-19

6.11: Alzheimer Disease

Vaccine. Efforts to develop a vaccine so that an immune mediated response targets the
disease are still being investigated. The phase II trial of an active vaccination
approach in AD was stopped in 2001 since it resulted in meningoencephalitis
(inflammation of the brain and surrounding areas). Despite this set back, research
still continues in the area of safe vaccine development, which may be able to
combat AD.Error: Reference source not found The use of passive immunization is
less likely to cause the inflammation seen with the active vaccination approach.
Statins. High cholesterol, an increased risk factor for AD, has also been implicated in the
pathology of AD and is thought to promote amyloid production. New focus on
8th international conference on AD reports that an autopsy study in the US found
that a 10% increase in blood cholesterol level doubles the risk of amyloid
deposits in the brain. Clinical trials in the US to compare the progression of AD in
those taking statins versus placebo are to be launched.Error: Reference source not
found
Neurotransmitter targets. Cholinesterase inhibitors, are currently the only widely approved
class for the treatment of AD. This therapeutic class inhibits the enzyme acetylcholinesterase,
which breaks down acetylcholine in the synaptic cleft and therefore they increase
acetylcholine levels in the brain. These drugs, do not attack the underlying disease pathology,
instead they compensate for the loss of neurons that communicate via this enzyme.
Cholinesterase inhibitors appear to slow down cognitive decline, however the improvements
are very modest. Memantine, which works to inhibit the action of neurotransmitter
glutamate, has been launched in the US and some European countries. It has been approved
for moderate to severe patients Experts within the field suggest that the two classes may be
used in combination or combined with other therapies under development.Error: Reference
source not found, 31

Drugs for Prevention and Disease Modification


AD is an insidious disease; sometime years go by before symptoms become noticeable.
Disease prevention, therefore may be beneficial, and may decrease the prevalence of AD.
Studies assessing prevention are underway.

NSAIDS: One such prevention study is evaluating the use of NSAIDS (non steroidal antiinflammatory drugs) on AD. Preliminary results are promising, however AD researchers are
reluctant to recommend NSAIDS given the toxicities (gastrointestinal ulcers, renal toxicity,
hypertension) associated with taking these medicines. Researched are waiting for results
from large RCTs in order to weigh the risks versus benefits of NSAID therapy before making
any recommendations.Error: Reference source not found

Antioxidants. Pathological data indicates that oxidative stress and the accumulation of free
radicals results in neuronal damage in AD. There are several studies evaluating the effects of
antioxidative compounds on AD. Vitamin E and selegeline appear to delay progression.
Research continues on the use of antioxidative vitamins and large US studies are underway
6.11-20

6.11: Alzheimer Disease


to clarify the role of vitamin E in AD prevention.Error: Reference source not found , Error: Reference
source not found
A number of studies have evaluated selegeline for the treatment of AD. Most of
these studies show some improvement in cognition, however there is very little evidence to
support global improvements in cognition, functional ability and behavior. In a metanalysis
of 15 selegiline trials, authors concluded that there was insufficient evidence to recommend
its use for AD.Error: Reference source not found A chochrane review of selegeline for AD
concluded that there may be some benefit in cognition and its use may be promising.
However, at present there is insufficient evidence to recommend its use in practice.Error:
Reference source not found

Hormones. The attention and potential uses of hormone replacement therapy to treat AD
is derived from epidemiological, clinical, and neuropathological observations and are still
ongoing. Women are at a higher risk of developing AD than men since women are estrogen
deficient post menopause whereas men benefit from estrogen as testosterone undergoes
aromatization to estradiol. Estrogen is considered to have numerous beneficial properties
some of which were thought to be antioxidant and anti-inflammatory properties,
interactions with neurotransmitters such as acetylcholine and its ability to alter
apolipoprotein which could lower the risk of developing AD. Unfortunately, no studies to
date have demonstrated a positive impact on improving the biological course of AD. Studies
are still ongoing and need to assess the type of HRT administered, timing of HRT in AD,
effect of HRT with cholinergics. Currently, there is insufficient evidence for HRT in AD
management.Error: Reference source not found,Error: Reference source not found

Other Agents. Various other pharmacological agents to treat AD are being studied. Gingko
Biloba, a plant extract that contains numerous pharmacological properties, some of which are
thought to be antioxidative, anti-inflammatory or neurotransmitter modulators. Current
research suggests that the use of Gingko Biloba provides smaller effects that that of
cholinergics. Also, it is currently unknown which of the active components of this alternative
compound contributes to cognitive enhancing effects. Furthermore, the compound is a nonregulated supplement in several countries and standardized preparations are not
available.Error: Reference source not found

Table 7: Current and Some Potential Treatments for ADError: Reference source not
found
Symptomatic
Probable-in
use

Possible-in
clinical trial

Acetylcholinesterase
inhibitors
Donepezil
Rivastigmine
Galantamine
Muscarinic agonists
Inverse
Benzodiazepine
agonists
Transmitter releasing
factors/channel

Disease modification

Vitamin E
Acetylcholinesterase inhibitors
(?)
Memantine (?)
Ginkgo biloba (?)
Antioxidants
Estrogen
NSAIDS
Nootropics e.g. piracetam
NGF stimulators
Amyloid modifying drugs and

6.11-21

Cure
None

Nonevaccination
approaches are
in trial as are
the gamma
secretase
inhibitors

6.11: Alzheimer Disease


blockers

Possible-in
clinical
development

Nicotinic agonists
5HT6 antagonists
PDEIV inhibitors

vaccines (but secretases are


amyloid modifying drugs)
Kinase inhibitors
Tau-modifying agents
Amyloid-modifying agents
Gene product manipulation
Secretase blockers

Gene product
manipulation

7. Current Pharmaceutical Product Pipeline for AD Treatment


Currently there are numerous medicines under investigation in the pharmaceutical pipeline.
Both the European Agency for the Evaluation of Medicinal Products (EMEA) and the US
Food and Drug Administration (FDA) were reviewed to determine the current pipeline. Table
3 indicated the new medications under development for AD.

Table 8:. New Medicines in Development for Alzheimer disease32, 33


Drug name
271046 (5HT6
antagonist)
737552 (s-8510) 34
Abilify
(aripipazole)
Alzhemed
Ampalex (CX 516)

Apan-1, APAN
Breaker peptide
CPI-1189
DP 543
MEM 1003

MKC 2313
MPC 7869
Namenda
Nerve growth
factor (gene
therapy)
NS 2330
Phenserine tartate
SR 57667

Indication

Company

Development
Status

Alzheimer disease

GlaxoSmithKline

Phase 1

Alzheimer disease
Alzheimer disease

GlaxoSmithKline
Bristol-Myers Squibb

Phase II
Phase III

Alzheimer disease
Alzheimer disease,
mild cognitive
impairment
Alzheimer disease
Alzheimer disease
Alzheimer disease
Alzheimer disease
Alzheimer disease,
mild cognitive
impairment, vascular
dementia
Alzheimer disease
Alzheimer disease
Alzheimer disease,
neuropathic pain
Alzheimer disease

Neurochem
Cortex Pharmaceuticals

Phase III
Phase II

Praecis Pharmaceutical
Serono
Centaur Pharmaceutcals
Bristol-Myers Squibb
Memory Pharmaceuticals

Phase I
Phase I
Phase II
Phase II
Phase I

Mitsubishi Pharma
Mzriad Genetics
Forest Laboratories

Phase II
Phase II
Phase III

Ceregene

Phase I

Alzheimer disease,
Parkinson disease
Alzheimer disease
Alzheimer disease,
Parkinsons disease

Boehringer-Ingelheim
Pharmaceuticals
Axonyx
Sanofi-Synthelabo

Phase II

6.11-22

Phase II/III
Phase II

6.11: Alzheimer Disease


SR 57746

Alzheimer disease,
antimitotic
neuropathies (AIM),
multiple sclerosis

Sanofi-Synthelabo

6.11-23

Phase II

6.11: Alzheimer Disease


Research into Emerging Technologies

Proteomics involves the identification of unknown proteins following their separation.


The application of proteomics to Alzheimer disease (AD), is a very new and emerging
technology. Differences in protein expression and post-translational modification (mostly
oxidative modification) of proteins from AD brain and peripheral tissue, as well as in brain
from rodent models of AD, have yielded insights into potential molecular mechanisms of
neurodegeneration in AD. Further work in this area hopefully will bring new insights about
the pathology, biochemistry, and physiology of AD are beginning to. 35

Europe and the Fifth Framework Program for Alzheimer disease

Alzheimer disease is an important topic of the key action on "The aging population and
disabilities" of the European Union's Fifth Framework Programme. The European
commission recognizes the impact of AD on individuals and society and the urgent need for
treatments that can prevent, arrest and reverse degeneration and death of neurons. The
multidisciplinary projects launched with EU support set a prerequisite in the understanding
of the fundamental molecular and cellular mechanisms of AD and the development of
diagnostic tools that may identify patients at an early pre-symptomatic stage. Furthermore a
consortium of 21 of the most experienced AD laboratories from Europe and beyond are to
carry our research projects integrating data from studies with tissue cultures and genetically
modified animals into a clinical investigations of demented patients. A broad array of biotechnological methods is also to be used. Results of these studies will lead to diagnostic
screening strategies combing genetic, pathophysiological and biomarker information. Annex
6.11.2 is the records of the current fifth framework research projects related to AD. 36
Six EU-funded projects were launched in 2000 with a total EU support of 2 million over 3
years. The ultimate aim of the projects is to diagnose, prevent, delay the onset or treat
Alzheimer disease.37

Five of the 6 projects seek to understand the mechanisms involved in neurodegeneration


and complement each other by studying various aspects of these mechanisms. All aim at
identifying and testing potential therapeutic strategies, for instance anti-inflammatory drugs.
Two pharmaceutical industries are already involved as partners in two projects and
others will be involved in others when new potential therapeutic targets are identified.
One project focuses on the needed improvement of cost-effective early diagnosis of
dementia and on the differential diagnosis among the various types of dementia.
Differentiating Alzheimer disease from other dementias is indeed important, since some of
6.11-24

6.11: Alzheimer Disease


the latter can be treated. This project will essentially try and define widely available
diagnostic procedures, by comparison to positron emission tomography (PET), a little
available and expensive non-invasive metabolic imaging technique.
5827

6.11-25

6.11: Alzheimer Disease

8. Opportunities for Research into New Pharmaceutical Interventions


A great deal more is known about AD and dementia than previously, but new found
knowledge and new drugs currently being studies also pose new questions. The following
sections are some opportunities of research for AD.

Cholinergic therapies only bring about a temporary relief in AD symptoms, and it is not
possible to predict who will respond. It is also unclear whether patients who do not
respond to one anticholinesterase inhibitor will respond to another. Systematic clinical
research is needed to answer these clinical questions. Furthermore, ways of measuring,
determining response, and assessing when medications need to be stopped remain
unclear and need to be addressed.38
There may also be a need for more comparative clinical trials of these agents to determine
which agent offers the greatest benefit and causes least resistance. The effective and
appropriate administration of cholinergic and other medicines requires good baseline
assessment with validated scales for objective measurement. Further work is required
and practice guidelines are needed to assist clinicians in effectively diagnosing patients
suspected with AD. There is also a need for better scales for the non-cognitive
symptoms.Error: Reference source not found,Error: Reference source not found
Cholinesterase inhibitors are licensed for use in mild to moderate AD and at present,
there is insufficient data on their safety and efficacy in severe AD. Further studies are
required to assess this.Error: Reference source not found,Error: Reference source not found
More comparative trials evaluating multiple cholinergic medicines, as well as
combination therapy with different classes for drugs, also remains unanswered and welldesigned RCTs, with clear indications for appropriate doses for various stages of AD are
needed.Error: Reference source not found
Additional well-designed studies, adequately powered, are needed to assess the
beneficial properties of anti-inflammatory compounds such as ginkgo biloba, ibuprofen,
and cerebrolysin.Error: Reference source not found
Studies are also needed to compare and assess different formulations and doses of
vitamin E in altering the course of AD.Error: Reference source not found
Research recommendations for management of non-cognitive behavioural disturbances:
There is a need for more randomized clinical trials on the pharmacological treatment of
anxiety, disinhibition, compulsive behaviors, wandering, agitation, and sleep
disturbances associated with AD. Studies are required to assess which behavioural
disturbance are best treated with pharmacological and non-pharmacological therapies.
Furthermore, comparative studies are needed comparing anxiolytic, tri-cyclic
antidepressants, SSRIs and novel antipsychotic medicines in AD.Error: Reference source
not found
AD is a complex disease overlaid with neuro-psychotic and behavioural symptoms, and
management rarely responds to medicines alone. Important factors other than cognitive
functions and activities of daily living need to be studied. Behavioural modification and
education combined with drug therapies as well as caregivers interventions require
systematic clinical research. This will include time to institutionalization, quality of life
6.11-26

6.11: Alzheimer Disease


issues as well as economic evaluations.Error: Reference source not found,Error: Reference source not
found

Gaps Between Current Research and Potential Research Issues that Could Make a
Difference
A review of currently available treatments suggests a number of areas for further study.
Some of these recommendations are within the realm of improved evaluation and
assessment.39
Improved detection and evaluation of dementia, especially in the prodromal and early
stages, when treatment that slows progression would be more likely to be beneficial.
This implies the development of a reliable diagnostic tool.
There is a clear need for increase biomarkers for measuring disease progression the lack
of these means that trials of disease modifying therapies will not move ahead as rapidly
as possible. The use of surrogate endpoints e.g. imaging also needs more investigation.
(see below).
Development of consensus on clinically meaningful outcome measures and hard
endpoints, such as institutionalization and mortality.Error: Reference source not found
Within the field of pharmacologic therapy, there is a critical need for medicines with
greater ability to improve cognition or at least halt the progression of dementia. Areas
that are already being actively studied in patients with AD include cholinergic agonists,
vitamin E, NSAIDs and antioxidants.Error: Reference source not found
Despite the progression in the areas mentioned above, research and development needs
to further identify and test new cognition-enhancing medicines based on the
pathophysiology and information learned about the disease from neuroscience and
molecular genetics. For example, pharmacologic agents that prevent or slow amyloid
deposition or remove precipitated amyloid which might serve to prevent or reverse
AD.Error: Reference source not found
Other research directions that can greatly affect management of AD, is the optimal
pharmacologic treatment of noncognitive symptoms, including psychosis, agitation,
depressions and sleep disturbances. Many current recommendations are based on smalluncontrolled studies or agents no longer in common use and/or at doses well above
those used in current practice. There is, therefore, a critical need for randomized
controlled studies and guidelines on up-to-date treatments for non-cognitive symptoms
present in AD.Error: Reference source not found
Clinical questions that need to be further evaluated and studied include what to treat?
There is a problem surrounding the terminology, and diagnosis associated with
dementia and AD. Confusion remains about when to initiate treatment; how to treat -i.e.
what agents to start, how to switch drugs in the case of decreased efficacy, intolerance,
adverse effects or drug interactions and how long to treat AD.Error: Reference source not
found
In addition to symptomatic or palliative options, increased knowledge of the anatomical,
cellular and molecular basis of AD, together with the identification of new drug targets,
which may prevent, slow or delay its onset are needed. These possibilities may be
expedited by the further progress in research and development of improved animal;
introduction of more efficient and effective clinical trials, and the use of non-invasive
6.11-27

6.11: Alzheimer Disease

imaging to monitor the progression of the disease. It has been estimated that delaying
the onset of AD by approximately 5 years would reduce the numbers dramatically by
about 50% by 2050.40
Combination therapies are likely to offer maximum benefit in longer term disease
modification. See Background Chapter 7.1

9. Barriers to Closing the Alzheimer Pharmaceutical Gap

Lack of validated targets. AD requires a clinical diagnosis, and at present,


there are no reliable tests to confirm a diagnosis. Definitive diagnosis can only be
made postmortem from brain tissue. Despite years of research, there is still an
unclear understanding on the pathogenesis of AD. Further research is still
needed at the basic neuroscientific level. Companies are already investing large
amounts of money in AD, but the high risk and cost coupled with long clinical
trials in disease modification, mean that at most a company could only take one or
two approaches forward in disease modification trials at present. The problem is
the high risk and the lack of markers to increase confidence in moving from Phase
II to large Phase III trials.
Lack of animal models. There are no good animal models that reflect the
disease state. Those models that do exist model only aspects of pathology e.g.
amyloid over expression. Equally as important is the issue of access to animal
models. Current animal models are not readily accessibly for research and drug
screening at the preclinical level because of intellectual property and licensing
issues. Many of these models belong to academia (not industry) and institutes and
the costs of the models are prohibitive to academic scientists and small biotech
companies.
Barriers in the design and implementation of clinical trials. Long trials are
needed to determine the efficacy and safety of AD medicines. In an effort to
control AD at the early stages, clinical studies are evaluating the effectiveness of
therapies at mild cognitive impairment (MCI) stages, which is considered the
prodromal stage to AD. Guidelines for MCI studies have not been established.
Another area that requires further work is the design and outcomes measures for
AD prevention. Scientific evidence has determined that neuropathology processes
resulting in AD occurs several years prior to the onset of AD symptoms. However,
conducting long-term clinical studies to monitor a patients progression or decline
in function is costly and requires a lot of effort.
Lack of surrogate markers. The lack of surrogate markers for therapeutic
endpoints remains a major barrier in the clinical development of efficacious AD
drugs. The availability of such surrogates would benefit and hasten AD drug
development. Any reliable predictor of clinical outcome will step up the
development of effective AD medicines. Much work in this area is already
ongoing, however continued efforts are still required. Commonly accepted
markers in cerebrospinal fluid (CSF) or blood such as alpha -amyloid and tau are
still not adequately validated and may not be sensitive for longitudinal
progression and treatment effects on AD. Additionally, neuroimaging markers, as
determined by MRI are reasonably validated and sensitive for use in long-term
6.11-28

6.11: Alzheimer Disease

trials but are not suitable for short-term duration, proof of-concept trials. There is
also a need to develop an infrastructure to speed up validation studies, such as
large-scale biologic sample collection from ongoing aging populations. The
availability and development of specific imaging technology such as Positron
Emission Tomography (PET) to determine whether changes in the brain or its
function can be identified before the person develops symptoms of the disease is
also needed. Error: Reference source not found
Barriers in academia41. Academic drug discovery and development programs
are usually under funded and lack infrastructure, in terms of staff and equipment
especially at the preclinical level. Furthermore, the lack of communication,
interaction and collaboration between necessary research groups can limit drug
discovery and research. Today, science and medicine requires an interdisciplinary
approach to solving medical conditions.
Barriers in biotechnology 42 AD drug discovery and development is
considered high risk and attracting capital for early high-risk projects is very
difficult, especially when the return on investment is questionable or long-term.
The cost of conducting clinical trials is also another major barrier to small
companies: risks are high and the probabilities of scientific success low. Therefore,
external funding is important. EUROPA, the European commission group to
improve innovation proposes that a small business innovation research
programme (SBIR) mechanism-like that employed in public funding in the US, be
introduced into the FP6-through integrated projects. This will speed up the
creation of new companies and provide capital for small-to-medium sized
enterprises. In the US SBIR mechanisms amounts to US 1.3 billion dollars. 43
Regulatory barriers. Another barrier that affects both the pharmaceutical and
biotech industry is the lack of international harmonization of clinical trials and
regulatory requirements. Designing trials that meet individual requirements is
costly and timely. A further barrier to drug development is the definition of
therapeutic effectiveness of AD medicines. The FDA requires that medicines show
superiority to placebo on a performance-based test and a measure of global
clinical function. Outcome measures are still unspecific and need to be established
by the medical community. Other outcome efficacy measures that affect AD
function are needed to guide drug development, and registration.

10. European Union Funding Opportunities for AD


New and emerging science and technologies (NEST) is a new activity within the 6th
Framework Program (2002-2006), supporting scientific research with the potential to open
new fields for European science and technology. It will also help to consolidate European
efforts in emerging fields of research. NEST activities will also assist in planning future
activities in the European Research Area. They will help to sustain projects that will need
larger-scale support in future European research programs. The overall budget for NEST
within FP6 is 215 million. 44
The following activities set by the FP6 will further enable research and development into AD.

Scientists internet networks - SINAPSE Error: Reference source not found


6.11-29

6.11: Alzheimer Disease


The European Commission is setting up a network called SINAPSE (Scientific
Information for Policy Support in Europe), which will put science at the service of policy
development. The network began its work in 2003, and has a number of different
functions:
To develop an electronic library of scientific opinions and advice which will give
public authorities seeking expert advice on scientific issues,
the opportunity to check whether any work has been done on the subject;
enable the Commission to conduct informal scientific consultations,
give the scientific community and other stakeholders the chance to initiate
discussions on potentially contentious scientific issues and
to provide a secure network for discussions between scientists.

Giving advice on research Error: Reference source not found


The European Research Advisory Board is a high-level independent advisory committee,
made up of 45 top experts from EU countries, which provides advice on the design and
implementation of EU research policy. It focuses on realizing the European Research
Area, and on using policy instruments such as the Community Research and
Development Framework Programme.

11. Conclusion
AD is the most common cause of dementia in people aged > 65 and affects more than 18
people worldwide. This number will increase considerably in the future and will present
enormous financial burdens to health care systems. Thus, there is an urgent need for effective
medicines. Currently only symptomatic treatment is available. While there is research and
development already in this area, much work still is required. This includes: basic research in
the pathophysiology of the disease and its risk factors; noninvasive and clinically effective
diagnostics tools; wider scale outcome efficacy measures for the disease function and
progress and developing medicines that slow progression, halt, or prevent AD from
occurring. Additionally, challenges for clinical services include early diagnosis, and
intervening early with the most appropriate and effective medicine. Error: Reference source
not found
There are several barriers to closing the obvious pharmaceutical "gaps" with regard to AD.
Specific recommendations include the following:
The EU and EU-based philanthropic organizations need to recognize and help overcome the
various scientific and systemic barriers to improving pharmaceutical R&D for Alzheimer
disease and provide funding for making animal models more accessible and affordable. Also
new grant agreements should be implemented that compensate investigators and institutions
while making the models more widely available. There is a need for improved AD
assessment tools, with increased sensitivity and efficiency for patient evaluation for AD
primary prevention. More specifically, curtailing time requirements for clinical staff, data
monitoring and data entry could decrease costs for trials.

6.11-30

6.11: Alzheimer Disease


An important research goal should also be the development and evaluation of new
instruments in relevant domains that are sensitive, reliable, and valid for detecting changes
in normal aging and early AD. Furthermore, it would be helpful if these can be selfadministered and not require significant professional involvement. New uses of technology,
such as computerized assessments and telephonic methods are some options and may be
desirable in this field.
There needs to be more collaboration and a multidisciplinary approach in the areas of
research and development for AD. Neurobiologists, clinicians, medical chemicals need to
work together. Funding resources and guidelines that can assist scientists in preclinical drug
development is required.
New funding models should be explored which can support core research facilities and nontenured staff in academic institutions, such as the creation of endowments for facilities and
pharmaceutical and biotech consortia.

6.11-31

6.11: Alzheimer Disease

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