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Type 2 Diabetes, Cognition, and Dementia


in Older Adults: Toward a Precision
Health Approach
Brenna Cholerton,1 Laura D. Baker,2 Thomas J. Montine,1 and Suzanne Craft 2

■ IN BRIEF There has been a concurrent dramatic rise in type 2 diabetes and
dementia in the United States, and type 2 diabetes shares common genetic
and environmental risk factors and underlying pathology with both vascular
and Alzheimer’s dementias. Given the ability to identify this at-risk population
and a variety of potential targeted treatments, type 2 diabetes represents
a promising focus for a precision health approach to reduce the impact of
cognitive decline and dementia in older adults.
Department of Pathology, Stanford
1

A
University, Palo Alto, CA
confluence of factors related type 2 diabetes and dementia reach
2
Sticht Center on Aging, Department of
Internal Medicine, Wake Forest University, to dietary changes, sedentary epidemic proportions in the United
Winston-Salem, NC lifestyle, and an aging popu- States, the need to identify methods
Corresponding author: Brenna Cholerton, lation in Western cultures has led to of prevention and treatment grows
bchol@stanford.edu a rapid rise in the incidence of type 2 increasingly important.
DOI: 10.2337/ds16-0041 diabetes, a disease that carries enor- Recently, there has been an
mous burden in terms of health and emphasis on precision medicine, a
©2016 by the American Diabetes Association.
Readers may use this article as long as the work
economic outcomes. Increasingly, model of focused identification and
is properly cited, the use is educational and not type 2 diabetes is recognized as a ma- treatment of disease based on indi-
for profit, and the work is not altered. See http://
creativecommons.org/licenses/by-nc-nd/3.0
jor contributor to cognitive decline vidual risk, as it applies to dementia.
for details. and dementia in older adults. As both Even more compelling than preci-

210 SPECTRUM.DIABETESJOURNALS.ORG
cholerton et al.

sion medicine is the aspirational goal insulin resistance or type 2 diabetes ence insulin receptor expression and
of precision health, through which that indirectly damage the brain, function in the dentate gyrus and
graded surveillance based on risk dis- vascular brain injury from the vas- CA1 area of the hippocampus (17).
closes preclinical pathophysiological culopathic consequences of insulin Together, these studies support insu-
processes that motivate interventions resistance and type 2 diabetes, dis- lin as an important factor in normal
that preserve health and prevent clin- ruption of the ability of insulin to memory functioning. Potential mech-
ical expression of disease. The ability perform its normal actions in the anisms for the influence of insulin
to identify an at-risk population, to brain in patients with type 2 diabetes, on memory include regional effects
detect pathological changes early in or some combination of these. of insulin on cerebral glucose metab-
the disease process, and to select from olism, influence on components of
Insulin in the Brain
a variety of potential targeted treat- the long-term potentiation cascade,
Sensitivity of target cells in the pe-
ments make type 2 diabetes an ideal and modulation of acetylcholine and
riphery and in the central nervous
focus for a precision health approach norepinephrine, neurotransmitters
system (CNS) to insulin, a peptide
to reducing the impact of dementia. that are known to influence cognitive
hormone secreted by pancreatic
function.

FROM RESEARCH TO PRACTICE


Type 2 Diabetes and Cognition β-cells, is suppressed in type 2 diabe-
in Older Adults tes. First recognized as a principle reg- Chronic Effects of
Type 2 diabetes is a robust predictor ulator of peripheral glucose, insulin Hyperinsulinemia on Cognition
of cognitive impairment and decline also has been identified as a key factor Despite the beneficial effects of acute
in older adults. Multiple population- in memory and other cognitive pro- hyperinsulinemia in the CNS, pro-
based studies have reported an asso- cesses. Insulin is readily transported longed elevated levels of circulat-
ciation between type 2 diabetes and into the CNS across the blood-brain ing insulin may exert an opposing
cognitive impairment (1–4), and barrier via a saturable, receptor- influence on cognition. Sustained
older adults with type 2 diabetes ex- mediated process, which likely ac- peripheral hyperinsulinemia reduc-
perience global cognitive decline at a counts for the majority of available es insulin transport into the brain
rate that is double those without type insulin in the brain (11). Additionally, (18). Prolonged insulin resistance,
2 diabetes over a 5-year period (5). recent evidence suggests that insulin is a syndrome characterized by high
General cognitive slowing, thought also produced in the brain, a process peripheral insulin and diminished
to be a marker for accelerated brain that is potentially regulated by the insulin-mediated glucose clearance,
aging and dementia risk, is related to Wnt/β-catenin/NeuroD1 pathway underlies the development of type 2
type 2 diabetes in middle-aged and in the hypothalamus (12), although diabetes. Among people with type 2
older adults (6,7), and interactions this has yet to be verified in human diabetes, reductions in brain volume
between type 2 diabetes and genet- studies. Regardless of source, the (most prominently in the frontal and
ic risk predict more rapid decline in CNS is rich with insulin receptors, temporal lobes) and corresponding
cognitive speed (8). With regard to most prominently in areas important impairments in cognition are found
specific cognitive domains, associa- for learning and memory, including in comparison to nondiabetic control
tions between type 2 diabetes or even the hippocampus, amygdala, para- subjects (19,20). Even in the absence
prediabetic levels of insulin resistance hippocampal gyrus, thalamus, and of hyperglycemia, declarative memory
are most commonly reported with caudate-putamen (13). impairment has been observed in indi-
both episodic memory and decreased viduals with chronic hyperinsulinemia
Role of Insulin in Learning and
executive function, including verbal (21), consistent with a deleterious role
Memory
fluency, working memory, processing of insulin resistance on cognitive func-
The salutary effects of acute insulin
speed, cognitive flexibility, and cogni- tion. Subtle cognitive changes that can
administration on cognition are well
tive control (7). Executive function, accompany early stages of insulin re-
documented. In rats, acute intrace-
which may be most predictive of sistance due to aging, type 2 diabetes,
rebroventricular insulin administra-
functional performance, also declines and other factors may eventually de-
tion improves memory on a passive-
more rapidly among older women velop into clinically significant cogni-
avoidance task and enhances spatial
with type 2 diabetes (9). Conversely, tive impairment, including dementia
memory via potentially age-depen-
remaining free from diabetes has been (Figure 1).
dent inflammatory reduction pro-
associated with preserved cognitive cesses (14,15). In humans, acute Toward a Precision Medicine
function in women >80 years of age intravenous and intranasal insulin Model for Dementia: Type
(10). administration (while maintaining 2 Diabetes as a Target Risk
Several mechanisms may underlie euglycemia) consistently improves Factor
these associations, including periph- declarative memory performance Precision health uses emerging knowl-
eral metabolic derangements from (16). Learning also appears to influ- edge about specific diseases to identi-

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were treated with insulin (and there-


fore likely to be in the more severe
stages of the disease) at baseline (26).
A type 2 diabetes diagnosis appears to
raise the risk for Alzheimer’s disease
dementia independently (although
likely with additive effects) from
vascular or other dementias or from
APOE E4 gene status (26,27). Among
patients already diagnosed with
Alzheimer’s disease dementia, an in-
creased prevalence of type 2 diabetes
(35 vs. 18% in nondemented control
subjects) and impaired glucose toler-
ance (46 vs. 24%) was reported (28).
Despite strong results from obser-
vational studies, recent explorations
into genome-wide associations for
■ FIGURE 1. Mechanism of type 2 diabetes–associated cognitive dysfunction. AD, type 2 diabetes susceptibility loci,
Alzheimer’s disease; BBB, blood-brain barrier; T2DM, type 2 diabetes mellitus.
as well as Mendelian randomization
Reprinted from Umegaki K. Type 2 diabetes as a risk factor for cognitive impair-
(MR) studies that combine genetic
ment: current insights. Clin Interv Aging 2014;9:1011–1019. This is an open-access
factors for type 2 diabetes, have
article distributed under the Creative Commons attribution license, which permits
failed to find an association with
unrestricted use, distribution, and reproduction in any medium, provided the origi-
Alzheimer’s disease dementia (29,30).
nal work is properly cited.
However, in a follow-up MR study
fy optimal and targeted interventions outcomes (24). Although many of that examined single nucleotide poly-
based on individually determined risk these studies examined risk related morphisms independently according
factors. To effectively adapt the con- to all-cause dementia, there is to their specific biological mecha-
cept of precision health to cognitive evidence that two specific subtypes, nism, Alzheimer’s disease dementia
impairment and dementia in older Alzheimer’s disease dementia and risk correlated negatively with insu-
adults, it is imperative to first identify vascular dementia, are most strongly lin sensitivity only (31), a finding that
groups of differing risk. associated with type 2 diabetes. is not surprising given the wealth of
Dementia develops as a result of literature that connects insulin dys-
a complex interplay of clinical and Type 2 Diabetes and function with Alzheimer’s disease
biological factors and is beset by Alzheimer’s Disease Dementia dementia–specific neuropathological
multiple underlying pathological The importance of the connection be- changes. In addition, a recent exam-
features. People with type 2 diabetes tween type 2 diabetes and Alzheimer’s ination of genome-wide association
represent an important risk group for disease dementia is perhaps best cap- study data found significant overlap
cognitive impairment and dementia tured by the term “type 3 diabetes,” between single-nucleotide polymor-
caused by both Alzheimer’s disease coined to describe a portion of pa- phisms (SNPs) associated with type
dementia and vascular brain injury. tients who develop Alzheimer’s dis- 2 diabetes and Alzheimer’s disease,
For example, a recent meta-analysis ease dementia presumably as a result providing initial evidence that the
found that type 2 diabetes was of diabetes-related injury and de- two diseases may indeed share genetic
associated with a 60% increase in generation (25). Meta-analytic data risk. Among the shared type 2 dia-
risk for all-cause dementia (22), and demonstrate a 56% increased risk for betes and Alzheimer’s risk–associated
a population-based longitudinal Alzheimer’s disease dementia among SNPs, those responsible for immune
study found a 16% increased risk for individuals with type 2 diabetes (22). regulation, cell signaling, and long-
dementia even among those in which Among the studies included in the term potentiation were strongly
type 2 diabetes onset was recent meta-analysis was the prospective, represented (32). Further investi-
(23). Furthermore, type 2 diabetes community-based Rotterdam study, gation into the shared genetic risk
increases the risk of mortality in which found that type 2 diabetes profile between type 2 diabetes and
patients who already have dementia, significantly increased the risk of Alzheimer’s disease may lead to tar-
suggesting that targeted intervention Alzheimer’s disease dementia, with geted and more effective prevention
at any point may improve health greater risk apparent in people who and intervention approaches.

212 SPECTRUM.DIABETESJOURNALS.ORG
cholerton et al.

There are several potential mecha- Aβ peptide and hyperphosphory- injury to the brain, including hypox-
nisms by which type 2 diabetes may lated τ, the predominant features in ic events, ischemia, and blood-brain
induce the neuropathological changes Alzheimer’s disease dementia neu- barrier leakage. Dysfunction of vas-
of Alzheimer’s disease. Chronic ropathology, as well as associated cular endothelial cells secondary to
peripheral hyperinsulinemia caused structural and cognitive changes. insulin resistance and inflammation
by insulin resistance in type 2 dia- Despite evidence from in vitro is a characteristic consequence of type
betes ultimately lowers brain insulin and animal studies that insulin resis- 2 diabetes, and disruption of white
levels and results in desensitization tance modulates the predominant matter networks is seen on neuroim-
of neuronal insulin receptors, which pathological features of Alzheimer’s aging in patients with type 2 diabetes
may in turn lead to decreased clear- disease dementia, along with the (45–47). Furthermore, white matter
ance of beta amyloid (Aβ) peptide consistently reported increased risk dysfunction is associated with poor-
(33) and increased hyperphosphor- for Alzheimer’s disease dementia er cognitive performance in patients
ylation of τ protein, which forms associated with type 2 diabetes, with type 2 diabetes (46–48).
neurofibrillary tangles (34). In vivo, recent imaging studies have produced Type 2 diabetes is frequently
insulin modulates Aβ levels and pro- reported to be more strongly cor-

FROM RESEARCH TO PRACTICE


somewhat conflicting results. For
motes release of intracellular Aβ; example, among nondemented par- related with vascular dementia
thus, reduced sensitivity to insulin in ticipants in the Mayo Clinic Study of than with other types, including
the brain may reduce clearance of Aβ Aging (42), type 2 diabetes and ele- Alzheimer’s disease dementia. Indeed,
to extracellular compartments (33). vated A1C levels were associated with a recent meta-analysis of prospective
Furthermore, soluble Aβ binds to the brain hypometabolism in Alzheimer’s studies that examined the risk of
insulin receptor and disrupts its sig- disease dementia–specific brain dementia in patients with type 2 dia-
naling capacity as well as long-term regions; however, these factors did betes reported a pooled relative risk
potentiation induction, which forms not correlate with significant amy- of 2.27 for vascular dementia (22).
the basis for learning and memory, loid accumulations (42). Similarly, Interestingly, new evidence suggests
an effect that is prevented by insulin among participants enrolled in the the increased risk for vascular demen-
pretreatment (35,36). Insulin also Alzheimer’s Disease Neuroimaging tia may be especially prominent in
inhibits phosphorylation of τ pro- Initiative, type 2 diabetes was associ- women; women with type 2 diabetes
tein, possibly through its regulation ated with lower bilateral frontal and had a 19% greater chance of vascular
of glycogen synthase kinase 3β, a parietal cortical thickness, but not dementia than men (49). In addition,
downstream target in the insulin sig- with cerebrospinal fluid (CSF) Aβ42 those with longer duration and ear-
naling pathway (37). In a conditional levels or with amyloid accumulations lier age of onset of type 2 diabetes
knockout mouse model in which the by neuroimaging (43). Conversely, were more likely to develop vascular
insulin receptor gene was inactivated total and phosphorylated CSF τ pro- dementia.
in the CNS, phosphorylation of τ and teins were negatively associated with Vascular burden in dementia is
the presence of tangle pathology was type 2 diabetes. These findings may substantial but often co-occurs with
significantly increased (38,39). Type support a pathway to Alzheimer’s other pathology (50). It is important
2 diabetes also causes apoptosis in the disease dementia that is less depen- to note that vascular risk factors may
hippocampus via a number of other dent on Aβ in people with type 2 interact synergistically to amplify
dementia-associated processes that are diabetes. Future studies that incor- the effects of the Alzheimer’s dis-
independent of Aβ and τ, including porate human τ imaging will help ease cascade. For example, vascular
increased oxidative stress, reduction to clarify whether the typical course dysfunction may be associated with
of caspases, disturbed expression of Alzheimer’s pathology is altered in progression of both amyloid and τ
of apoptosis-regulator genes, and the insulin-resistant brain. pathology (51). In patients already
defective mitochondrial function diagnosed with Alzheimer’s disease
(40). Recently, a nontransgenic ani- Type 2 Diabetes and Vascular dementia and mild cognitive impair-
mal model for Alzheimer’s disease Dementia ment, both cognitive and affective
dementia was developed that relies Vascular disease represents a principle dysfunction were increased among
on prolonged insulin resistance in factor in accelerated brain aging, and those with insulin resistance (52,53),
the brain (41). In this model, rats are vascular brain injury is an important and treating vascular risk factors
injected with intracerebroventricular contributor to cognitive dysfunction helped to slow cognitive decline (54).
streptozotocin to induce insulin resis- in older adults (44). Type 2 diabetes The strong association between type
tance and subsequently demonstrate is a known risk factor for cardiovas- 2 diabetes and vascular contribu-
multiple and progressive Alzheimer’s cular and cerebrovascular disease and tions to dementia should be carefully
disease dementia–like changes in the may increase susceptibility to large considered when implementing treat-
brain, including accumulation of the and small caliber vessel–mediated ment and prevention measures.

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Precision Health: Early on individuals’ disease risk. Currently, intervention trials suggests that in-
Detection approved pharmacological treatments creasing insulin sensitivity via dietary
To effectively target and treat de- for Alzheimer’s disease are prescribed modification may play a key role in
mentia associated with type 2 diabe- comprehensively, regardless of specific overall dementia risk reduction.
tes, such treatment would be most disease risk and despite known lim-
Physical Exercise
effective when implemented as early ited effectiveness. Given the impact An increasingly sedentary lifestyle
as possible, preferably during a la- of type 2 diabetes on risk for both present in Western cultures is likely
tent or prodromal phase when the vascular and Alzheimer’s diseases, in- also a key factor in the rise in type 2
neuropathological changes are not terventions that target insulin resis- diabetes in recent years. Aerobic ex-
yet significant enough to result in tance may have significant potential ercise, which is known to be an effec-
significant overt clinical symptoms to affect the clinical symptomatology tive treatment for diabetes and related
(55). Importantly, both type 2 diabe- associated with Alzheimer’s disease conditions, also has potent salutary
tes and dementia are associated with dementia. effects in the brain. Increased physical
prolonged prodromal phases, and al- activity is consistently linked with im-
Diet
though symptoms may not be overt, proved learning and memory, both in
A typical Western diet consists of
current advances permit early identi- humans and in animal models (65).
high levels of saturated fats and sim-
fication of both syndromes. The benefits of exercise on cognitive
ple carbohydrates, a pattern of con-
It is now established that the function have been demonstrated in
sumption that substantially raises the
pathophysiological processes underly- healthy older adults and in adults
risk of insulin resistance and type 2
ing dementia may begin years or even with cognitive impairment, and ex-
diabetes and related cognitive im-
decades before clinical manifestation ercise appears to have positive impli-
pairment. Conversely, improving the
of symptoms (56,57). Similarly, the cations for the reduction of dementia
dietary profile may produce protec-
insulin resistance syndrome is asso- risk (66–69). The favorable effects
tive effects on cognitive functioning
ciated with a silent phase before the of exercise likely are exerted through
and Alzheimer’s disease dementia risk
onset of frank diabetes, during which multiple pathways known to be influ-
(60). In animals, diets high in either
the pancreas is able to compensate by enced by insulin, including improved
saturated fat or sucrose modify pro-
producing adequate levels of insulin cardiovascular and cerebrovascular
cessing of the amyloid precursor pro-
to lower peripheral glucose levels. function, anti-inflammatory process-
tein, elevate Aβ-related cerebrovas-
Midlife is thus frequently identi- es, and enhanced insulin-dependent
cular disturbance, and reduce brain
fied as a potentially crucial period energy metabolism. Thus, aerobic
insulin signaling and expression of
of intervention. Impaired glucose exercise has the potential to modify
insulin-degrading enzyme (61,62).
tolerance and other cardiovascular multiple processes compromised in
Evidence from population-based
risk factors during midlife may be pathological brain aging.
studies generally supports that an im-
particularly associated with impaired Regular exercise during midlife,
proved dietary profile, in particular, a
cognition and, later, dementia risk when many pathological disease
Mediterranean diet, leads to a reduced
(58). Thus, this period may be an processes likely begin, has been
risk of age-related cognitive decline
important point for widespread inter- linked to reduced dementia risk and
and dementia (63). In an intervention
vention in pursuit of precision health improved cognitive profile in older
trial (64) aimed at examining the ef-
for the aging brain. For example, a adults (70,71). Among older adults,
fects of diet on cognitive function and
recent study of late-middle-aged those who exercised for at least 30
CSF biomarkers in older adults with
participants demonstrated a positive minutes per day, 5 days per week, for
and without cognitive impairment,
association between elevated insulin at least 10 years demonstrated lower
subjects were assigned to a 4-week
resistance and amyloid deposition brain Aβ deposition (using Pittsburgh
isocaloric diet that consisted of either
(59). Thus, developing wide-scale compound B on positive emission
high saturated fat/high simple carbo-
prevention and treatment meth- tomography [PET] scan) (72). Given
hydrates (HIGH; a pattern associat-
ods early in the course of insulin its multiple beneficial effects in the
ed with type 2 diabetes and insulin
resistance may lead to substantial brain, regular physical exercise is
resistance) or low saturated fat/low
reductions in the burden of both type recommended to help reduce the
simple carbohydrates (LOW). In this
2 diabetes and dementia in later years. negative cognitive effects of type 2
study, diet intervention influenced
diabetes.
Precision Health: Approaches insulin sensitivity, Alzheimer’s dis-
to Intervention ease dementia biomarker profile, lev- Intranasal Insulin
The precision medicine model as- el of oxidative stress, and cognition. Augmenting insulin in the CNS via
sumes that innovative treatments The confluence of population-based intranasal insulin administration is
will target specific risk factors based evidence, animal models, and initial one promising and innovative ap-

214 SPECTRUM.DIABETESJOURNALS.ORG
cholerton et al.

proach currently under investiga- macological intervention employed. Treatment with pioglitazone in
tion. Animal models and human Metformin, the typical first-line ther- patients with both type 2 diabetes
studies support that insulin may be apy for treatment of type 2 diabetes, and Alzheimer’s disease dementia
transported effectively into the CNS has been both lauded for potential produced improvement in general
via intranasal administration without cognition-enhancing effects (82,83) cognitive status and declarative
substantially affecting peripheral in- and identified as a potential risk verbal memory, as well as improved
sulin levels (73–75). Initial studies factor in increased cognitive impair- regional cerebral blood flow in the
examining younger adult participants ment (84) among patients with type parietal lobe, after 6 months of
found that acute intranasal adminis- 2 diabetes. However, the association treatment (93,94). However, another
tration improved both verbal memory between metformin and cognition is trial that was designed primarily to
and mood (76). Subsequently, intra- murky because of multiple factors, assess the safety of pioglitazone in
nasal insulin was found to improve including the fact that those taking nondiabetic patients with Alzheimer’s
verbal memory acutely in nondiabetic metformin for many years may be at disease dementia failed to show any
subjects with Alzheimer’s disease de- higher risk for cognitive impairment improvements on secondary cognitive
as a function of the disease process

FROM RESEARCH TO PRACTICE


mentia or amnestic mild cognitive and functional outcome measures
impairment (MCI) without affecting rather than the medication per se. (95).
plasma insulin or glucose (77,78). Conversely, treated versus untreated Interestingly, a recent in vitro
Research into the chronic effects of type 2 diabetes may confer a differ- model suggested that a subclinical
regular and long-acting formula- ing risk for cognitive decline due to dose of rosiglitazone may produce
tions demonstrated improved gen- vascular injury versus amyloid depo- more beneficial effects on Aβ clear-
eral cognitive abilities, declarative sition (85). A recent meta-analysis ance than higher doses (96). Thus,
memory, and aspects of executive found no significant effect of treat- follow-up studies that use lower doses
function, including verbal and non- ment type across multiple cognitive may be illuminating. Furthermore,
verbal working memory and selective domains among older adults with the larger trials above included
attention, among healthy control type 2 diabetes, although there ap- patients with clinically diagnosed
subjects and participants with MCI peared to be protective effects on ver- Alzheimer’s disease dementia; it is
and early Alzheimer’s disease (79–81). bal learning, working memory, and possible that treating insulin resis-
In addition, changes in CSF Aβ42 executive function for those who only tance before the onset of clinically
and τ/Aβ42 ratios over the course used metformin (86). significant dementia (e.g., MCI) may
of treatment were associated with Peroxisome proliferator–activated produce more favorable cognitive
cognitive and functional changes receptor-γ (PPAR-γ) agonists, which results.
for insulin-treated participants. On act specifically to reduce insulin
resistance, may help to normalize Aβ Practical Treatment
fluorodeoxyglucose PET imaging,
levels in the brain and to improve Considerations
the intranasal insulin-treated group
associated behavioral symptoms. Given the relationship between type
showed reduced progression of hy-
Ongoing in vitro and animal studies 2 diabetes and subsequent clinical
pometabolism in the bilateral frontal,
show beneficial effects of these agents effects on vascular or Alzheimer’s pa-
right temporal, bilateral occipital, and
via reduced inflammation, enhanced thology, it is reasonable to provide
right precuneus/cuneus regions over
clearance of Aβ, reductions in hyper- guidelines to patients at multiple
a 4-month treatment period (80).
phosphorylation of τ, and improved levels of intervention. Primary pre-
Cumulative results to date thus sup-
synaptic plasticity (Figure 2) (87–89). vention of type 2 diabetes and other
port intranasal insulin administration
However, clinical trials using metabolic and vascular diseases may
as a potentially effective intervention
these medications have been less ultimately be crucial to curtailing
in older adults with cognitive impair-
convincing. Although early pilot the rapid increase in the cognitive
ment or type 2 diabetes. A phase 3
studies suggested improved cognition, disorders of aging. Thus, instituting
clinical trial is underway to examine
a more favorable plasma Aβ40/42 dietary and exercise guidelines at
the effectiveness of intranasal insulin
ratio, and enhanced regional cerebral midlife or before, particularly among
in people with early cognitive changes
blood flow in patients with MCI those most at risk for cardiovascular
associated with Alzheimer’s disease.
or early Alzheimer’s disease (90), disease or diabetes, is particularly im-
Type 2 Diabetes Treatments subsequent phase 3 clinical trials portant. Once diabetes has been diag-
Although early treatment of type 2 di- using rosiglitazone failed to show nosed, targeted secondary prevention
abetes may reduce the risk for compli- cognitive improvement in patients methods designed to reduce or even
cations, including cognitive decline, with mild to moderate Alzheimer’s reverse the impact of the disease early
there may be differential effects in disease dementia (91,92). Pioglitazone on, including diet, exercise, and any
the brain related to the type of phar- has produced similarly mixed results. necessary medical treatments, should

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■ FIGURE 2. Targets of thiazolidinedione (TZD) drugs in Alzheimer’s disease. TZDs can bind to PPAR-γ receptors and other
pathways that regulate energy metabolism in cellular and animal models of Alzheimer’s disease. In cognition and behavioral
tests, these drugs increase the memory performance of the animals and also decrease Aβ deposits, accelerating amyloid plaque
clearance. At more cellular levels, TZDs promote neuronal survival, differentiation, and synaptic plasticity and also increase
phagocytosis and reduce neuroinflammation in both astrocytes and microglia. In the mitochondria, TZDs induce biogenesis and
enhance the mitochondrial function observed by a rise in respiratory complex activities and decrease in oxidative stress. Finally,
TZDs are capable of reducing τ phosphorylation through the inhibition of different kinase activities and the later formation of
the neurofibrillary tangles presented in Alzheimer’s disease. Reprinted from Pérez MJ, Quintanilla RA. Therapeutic actions of
the thiazolidinediones in Alzheimer’s disease. PPAR Res 2015;2015:957248. This is an open-access article distributed under the
Creative Commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided
the original work is properly cited.

be considered. In particular, those Summary Acknowledgments


at risk for cognitive decline, includ- With an aging population and con- This work was supported by National
ing patients with a family history of current rise in chronic health condi- Institutes of Health grants P50AG005135
dementia, additional vascular risk tions has come a rapid escalation in and P50NS062684.
factors, or a diagnosis of MCI, may the incidence of both type 2 diabetes Duality of Interest
be best targeted for education and and dementia. The risk for cognitive
No potential conflicts of interest relevant to
intervention. Referral for detailed impairment and dementia is increased this article were reported.
cognitive assessment and intervention among those with type 2 diabetes,
should be considered for those who and insulin resistance represents a References
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