DZ2 Si Conditii Relationate in Rel Cu Dementa
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Journal of Alzheimer’s Disease 20 (2010) 723–736 723DOI 10.3233/JAD-2010-091687IOS Press
Review
Type 2 Diabetes and Related Conditions in
Relation to Dementia: An Opportunity for
Prevention?
Jose A. Luchsinger∗
Gertrude H. Sergievsky Center, Columbia University, New York, NY, USATaub Institute for Research of Alzheimer’s Disease and the Aging Brain, Columbia University, New York, NY, USA
Division of General Medicine, Department of Medicine, Columbia University College of Physicians and Surgeons,
New York, NY, USA
Department of Epidemiology, Joseph P. Mailman School of Public Health, Columbia University, New York, NY, USA
Accepted 11 February 2010
Abstract. This manuscript provides a comprehensive review of the epidemiologic evidence linking type 2 diabetes (T2D) and
its precursor conditions, elevated adiposity and hyperinsulinemia, to dementia. The mechanisms relating these conditions to
dementia may be vascular and non-vascular. Elevated adiposity in middle age is related to a higher risk of dementia but the data
on this association in old age is conflicting. Several studies have shown that hyperinsulinemia, a consequence of higher adiposity
and insulin resistance, is also related to a higher risk of dementia, including late onset Alzheimer’s disease (LOAD). Studies haveconsistently shown a relation of T2D with higher dementia risk, but the associations are stronger for vascular dementia compared
to LOAD. A large proportion of the world population may be at increased risk of dementia given the trends for increasing
prevalence of overweight, obesity, hyperinsulinemia, and T2D. However, these associations may present a unique opportunity for
prevention and treatment of dementia. There are several known modalities that are effective in the prevention and T2D and the
reduction of hyperinsulinemia including lifestyle interventions, metformin, thiazolideniodones, and acarbose. Several studies in
the prevention and treatment of T2D are currently measuring cognitive outcomes and will provide information on whether T2D
treatment and prevention can prevent cognitive decline and dementia.
Keywords: Adiposity, Alzheimer’s disease, cognitive impairment, glucose, hyperinsulinemia, insulin, obesity, overweight, type
2 diabetes
INTRODUCTION
Late onset Alzheimer’s disease (LOAD) is the mostcommon form of dementia, accounting for between70% to over 90% of all cases [1], and its prevalence isexpected to quadruple by the year 2047 in the US [2].As much as 50% of the population aged 85 years andolder, the fastest growing segment of the population,
∗Correspondence to: Jose A. Luchsinger, MD, 630 West 168thSt., PH19, New York, NY 10032, USA. Tel.: +1 212 305 4730; Fax:+1 212 305 2526; E-mail: [email protected].
may have LOAD [3]. Vascular dementia (VaD) is the
second most common form of dementia, although it
varies widely dependingon the criteria used [4]. Mixed
dementia is a term that has been coined to describe
the mix of clinical features of LOAD and VaD. Other
types of dementia such as frontotemporal dementia and
Lewy body dementia occur less commonly and will not
be covered in this review. The reference to dementia
in this review is a reference to LOAD, VaD, or mixed
dementia. It is important to point out that patholo-
gy studies suggest that dementia, including LOAD, is
more heterogeneous than previously recognized [5], in
ISSN 1387-2877/10/$27.50 © 2010 – IOS Press and the authors. All rights reserved
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724 J.A. Luchsinger / Type 2 Diabetes and Related Conditions in Relation to Dementia
addition to the observation that elderly peoplewith nor-
mal cognition have brain pathology usually ascribed todementia. Thus, some propose that the classification of
dementia into LOAD, VaD, andmixeddementia should
no longer be used. This is particularly important for
the topic at hand because Type 2 diabetes (T2D) and
its related disorders are known to cause cerebrovas-
cular disease, and it is not surprising that they cause
VaD. Whether they cause LOAD or Alzheimer’s dis-
ease (AD) pathology is a matter of controversy. Pre-
dementia cognitive impairment is of importance as a
potential target for secondary prevention. Mild cog-
nitive impairment (MCI) has been used to describe a
transitional state between normal cognitive functionand LOAD dementia [6,7] and has thus been target-
ed for interventions [8]. Individuals with MCI do not
have dementia but have memory complaints without
loss of function in their daily activities [7]. While gen-
eral cognitive performance is well preserved, memory
performance on standardized tests falls below expec-
tations for age and education. MCI can be classified
in amnestic and non-amnestic MCI. It is believed that
amnestic MCI is an early stage of LOAD, while non-
amnestic MCI, such as executive MCI, is less specific
to LOAD [6]. Persons with amnestic MCI progress to
LOAD at the rate of nearly 10% to 15% per year [6]compared to 1 to 2% in elderly persons with normal
cognition [7]. The prevalence of amnestic MCI varies
between 3% and 20% depending on the criteria ap-
plied [9], and increases from about 1% in persons 60
years old to 25% at age 85 [10]. Risk factors for de-
mentia can be studied in epidemiologic studies through
the outcomes of cognitive impairment or decline, MCI,
anddementia itself dementia, and this review will cover
evidence examining these outcomes.
This review attempts to cover the prevention of de-
mentia, not its treatment. Thus far, trials of vitamin
E [8] and homocysteine related vitamins [11] did notprevent cognitive decline in persons without dementia.
One trial of hypertension demonstrated a reduced risk
of dementia in its treatment arm [12,13], but several
were negative. Trials of statins in the prevention of
cognitive decline have also been negative [14] despite
epidemiological data suggestive of a benefit [15]. T2D
and its related conditions have surfaced as potential
modifiable risk factors for dementia. This manuscript
reviews the evidence linking these conditions to de-
mentia and potential modalities of diabetes prevention
that may be used in the prevention of dementia.
BURDEN OF OBESITY, INSULIN
RESISTANCE, AND TYPE 2 DIABETES
According to 2007 prevalence data from the Centers
for Disease Control and Prevention (CDC), T2D now
affects nearly 24 million people in the US, an increase
of more than 3 million in approximately two years [16].
T2D disproportionately affects the elderly, and almost
25% of the population 60 years and older had T2D in
2007. Another 57 million people have pre-diabetes,
making the prevalence of T2D and prediabetes over
50% in persons 60 years and older. It is projected that
a third of Americans born in 2000 will develop T2D,
with the highest lifetime risk among Hispanics (males,
45.4% and women, 52.5%) [17]. A rise in adiposity, or
body fat, is the cause of the increase in T2D [18]. Ab-
dominal adiposity, the accumulation of body fat around
the waist, also named central adiposity, seems to be the
most important predictor of T2D [19] and cardiovas-
cular disease [20]. Two-thirds of American adults are
overweight or obese [21]. The prevalence of abdomi-
nal obesity among US adults has increased continuous-
ly during the past 15 years. T2D risk rises with over-
weight/obesity (body mass index, BMI 25 kg/m2),
lack of physical activity, increasing age (45 years),
and family history [22]. T2D is also higher in African
Americans (11.8%) and Hispanics (10.4%) comparedto non-Hispanic Whites (6.6%) [23]. Those with oth-
er metabolic syndrome components (high blood pres-
sure, low HDL cholesterol, and high triglycerides) are
at higher risk of T2D [24,25]. The common link of
these conditions (obesity, prediabetes, T2D, high blood
pressure, low HDL cholesterol, and high triglycerides)
is insulin resistance [26]. There are two underlying
mechanisms which lead to the onset of clinical T2D,
the resistance of target tissues that dispose of glucose,
such as muscle, to the actions of insulin (insulin resis-
tance resulting in hyperinsulinemia) and inadequate in-
sulin secretion from pancreatic β -cells [27]. The most
important contributing factors to insulin resistance are
obesity and a sedentary lifestyle, largely because of a
decrease in insulin sensitivity that leads to hyperinsu-
linemia [28–30]. In the natural history of progression
to T2D, pancreatic β -cells initially increase insulin se-
cretion in response to insulin resistance causing hyper-
insulinemia and are able to effectively maintain glu-
cose levels below the T2D range. When β -cell func-
tion begins to decline, insulin production is inadequate
to overcome the insulin resistance, and blood glucose
levels rise, resulting in pre-diabetes and T2D. Insulin
resistance, once established, remains relatively stable
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over time. Therefore, progression of T2D is a result
of worsening β -cell function with preexisting insulinresistance and hyperinsulinemia.
An implication of the natural history describedabove
is that when an epidemiologic study finds a relation be-
tween the components of this continuum and dementia
we cannot be certain if we are looking at a surrogate
marker of one of the other components (e.g., T2D is a
marker of past adiposity or hyperinsulinemia, obesity
is a marker of hyperinsulinemia) or if the important ex-
posure is the one we are examining. The answer could
be that there is an aggregate effect of all the compo-
nents in the lifespan. Biessels has published a review
that describes how individual components of the nat-
ural history that lead to T2D may affect cognition in
different critical periods of the lifespan [31].
POTENTIAL MECHANISMS RELATING
ELEVATED ADIPOSITY,
HYPERINSULINEMIA, AND TYPE 2
DIABETES WITH DEMENTIA
These conditions are related to cerebrovascular dis-
ease [32–37]. Elevated adiposity [38], hyperinsuline-
mia, T2D [39], and their clustering with other vascular
risk factors [40] are risk factors for stroke. In addition,insulin or related byproducts may affect the amyloid
cascade [41]. Thus, we classify the mechanisms link-
ing this continuum with LOAD as cerebrovascular and
non-cerebrovascular.
Cerebrovascular mechanisms
Brain infarcts
Strokes, ascertained by clinical history [42] or as
brain infarcts on MRI [43], are related to a higher risk
of dementia including LOAD. The mechanisms for this
association are not clear. However, pathology studies
have demonstrated that the presence of amyloid plaques
is lower in brains of persons with dementia who also
have infarcts [44,45], suggesting that the presence of
infarcts is an insult that lowers the threshold of amy-
loid in the brain that is necessary to cause dementia.
The Religious Orders Study, a study of religious or-
ders across the United States based at Rush Universi-
ty in Chicago, found that T2D was related to infarcts
on autopsy but not AD pathology in persons with de-
mentia [46]. This observation suggests that the main
mechanism linking T2D to dementia is the presence of
infarcts, which lowers the burden of amyloid necessary
to cause memory decline and dementia. However, the
Honolulu-Asia Aging Study [47], a study of Japanese-Americans, found that T2D was related to AD pathol-
ogy, particularly in persons with the APOE-ε4 allele.
The Adult Changes in Thought Study, based at the Uni-
versity of Washington, reported that persons without
DM and with dementia had a greater amyloid-β pep-
tide load and in the cerebral cortex, while those with
both T2D and dementia patients had more microvas-
cular infarcts. The number of microvascular infarcts
was greater in persons with dementia and treated T2D,
whereas amyloid plaque load tended to be greater for
persons with dementia with untreated T2D [48]. The
interaction between infarcts and amyloid pathology in
persons with dementia and T2D seems complicated and
more studies are needed.
White matter disease
White matter disease, ascertained as white matter
hyperintensities (WHI) or leukoaraiosis on brain imag-
ing represents microvascular disease in the brain or de-
myelination. Some studies show an increase of WHI
in persons with T2D [49], which may suggest a mi-
crovascular ischemic insult in the brain. However, the
nature of WHI is still a matter of controversy. WHI are
thought to be ischemic in origin in the same way that
infarcts are [50] and have thus been proposed as sur-rogate markers of cerebrovascular disease [50]. How-
ever, recent evidence shows that WHI are common in
LOAD and maybe related to cerebral amyloid angiopa-
thy [51–54]. Thus, some WHI may be due to amyloid
disease and contribute to the development of LOAD.
WHI are commoncorrelates of cognitive impairment in
T2D [49], but it is unclear whether this WHI are mark-
ers of microvascular injury or may represent a process
related to amyloid deposition.
Non-cerebrovascular mechanisms
Hyperinsulinemia and amyloid-β ( Aβ ) clearance
Hyperinsulinemia is a plausible risk factor forLOAD
independent of cerebrovascular disease because a) in-
sulin can cross the blood brain barrier [55], and pe-
ripheral insulin infusion in the elderly may affect Aβ 42levels in the cerebrospinal fluid (CSF) [56], a surrogate
marker of Aβ clearance in the brain and an indirect
marker of LOAD risk; b) there are insulin receptors
in the brain including the hippocampus and entorhinal
cortex [57], structures affected early in LOAD [58];
c) insulin degrading enzyme (IDE) has been linked to
clearance of Aβ in the brain, and insulin and Aβ are
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both competing substrates for IDE [59]; and d) insulin
in the brain can increase the deposition of Aβ and tauprotein phosphorylation, which are central to the patho-genesis of LOAD [55]. The pathways relating insulinin the periphery with Aβ clearance in the brain are mul-tiple and complex. Craft and colleagues have reviewedhow peripheral hyperinsulinemia affects Aβ clearancein the brain [60]. A potential pathway is that peripheralhyperinsulinemia downregulates insulin uptake in theblood brain barrier due to saturation over physiolog-ic levels [61]. This may result in reduction of insulinlevels in the brain and downregulation of expression of IDE [62] and reduction in IDE mediated amyloid re-duction [59]. This complex observation has been used
to support the use of rosiglitazone, an insulin sensitiz-er [63,64], and intranasal insulin [65] in the treatmentof LOAD.
Advanced products of glycosylation ( AGE )AGE are most closely linked with glycemia and di-
abetes, as elevated glucose concentration promotes theMaillard reaction and AGE accrual. In a hyperglycemicenvironment, diabetic animal and human tissues con-tain increased AGE and upregulation of its receptor(RAGE) [66–68]. In fact, the most recognized AGE,hemoglobin A1c, represents the standard-of-care fortracking T2D glycemic control. AGE contribute impor-
tantly to diabetic complications. AGE in the basementmembranes of vessels promote vascular leakage [69].AGE is associated with diabetic nephropathy [70,71],retinal neovascularization [72,73], and diabetic neu-ropathy [74]. Increased expression of RAGE is ob-served in LOAD [75–77]. Expression of RAGE is en-hanced in blood vessels near Aβ deposits in LOADbrain [75,78]. Along with increased total amount of RAGE in AD brain, there is a shift of RAGE distri-bution from neuron to microvasculature [79]. Aβ 1−40and Aβ 1−42 transport in the blood brain barrier can beblocked by RAGE-specific IgG or sRAGE, providingevidence of a potential target for prevention of LOAD
in persons with T2D.
Lipoprotein related proteins ( LRP)LRP is a family of lipoprotein receptors that affect
lipid metabolism. LRP-1, found in the liver and oth-er tissues, clears Aβ from plasma and also mediatestransport of Aβ out of the brain [79,80]. LRP-1 is di-minished in insulin resistance without affecting lipidlevels [80]. Thus, LRP-1 is a plausible mechanismlinking hyperinsulinemia with Aβ and LOAD. SolubleLRP (sLRP) facilitates the clearance of Aβ by LRP-1and may be a therapeutic candidate for the treatment of LOAD [81,82].
Specific products of adipose tissue
Adipose tissue used to be thought as a fat depot,and it is increasingly recognized as a functioning or-
gan. In fact, it produces important factors such as lep-
tin and adiponectin, in addition to inflammatory fac-
tors [83]. Leptin is positively correlated with insulin,
while adiponectin is inversely correlated. Because
these factors correlate with insulin, it is not clear at this
point if they have a direct role in cognitive impairment
or are simply markers of hyperinsulinemia. However,
a recent longitudinal analysis in the Framingham study
showed that high leptin levels, which correlate posi-
tively with insulin levels, were related to a lower risk
or LOAD [84] and larger brain volumes. This is not
consistent with the hypothesis that high insulin levels
cause LOAD, but may indicate an independent effect
of leptin on neurodegeneration as suggested by animal
studies [85].
SUMMARY OF PROSPECTIVE
EPIDEMIOLOGICAL STUDIES LINKING
ADIPOSITY, HYPERINSULINEMIA, AND
DIABETES TO DEMENTIA
Adiposity
Elevated BMI in middle age may be associated with
higher dementia risk [86,87]. A recent study showed
that central adiposity in middle age was related to a
higher risk of dementia in older age [88]. Higher BMI
at ages 70, 75, and 79 years may also predict higher
dementia risk [89]. However, there have been reports
of no association at mid-life [90] and of lower BMI
related to higher LOAD risk [91,92] at older ages. A
study in Northern New York City [93] found that in
younger elderly (65 to 76 years of age), the associa-
tion between BMI quartiles and LOAD resembles a U
shaped-curve, while in the oldest old (> 76 years) high-
er BMI is related to a lower LOAD risk. This U-shaped
association has been reported for the relation between
adiposity and cardiovascular mortality [94] and under-
scores the difficulty in studying the effects of adiposi-
ty in older age [95]. This study also found that high-
er waist circumference is related to higher LOAD risk
in the younger elderly, but not in the oldest old. The
Cardiovascular Health Study recently reported that el-
evated self-reported BMI at age 50 years was associ-
ated with a higher risk of dementia, while BMI at age
65 or older in the same individuals did not [96]. This
study underscores the importance of the period in life at
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which adiposity is ascertained in relation to dementia.
Themost importantexplanationfor the paradox linkinglow weight in old age to dementia seems to be weight
loss. The mechanisms for this are not entirely clear.
They may include loss of olfaction [97,98], one of the
earliest manifestations of LOAD, which may lead to
decreased caloric intake, forgetfulness of meals [99],
and metabolic changes related to LOAD that are not
well understood. In this regard, LOAD is accompanied
by abnormalities in brain insulin signaling [100] which
could affect appetite and food intake. It is not clear
if weight loss is a consequence of LOAD, a parallel
process, or if it is related to potential causes of LOAD,
such as insulin resistance [101].
Hyperinsulinemia
Several cross-sectional studies show an association
between hyperinsulinemia and an increased risk of
LOAD [102–104]. Two longitudinal studies, one in
elderly Japanese Americans in Hawaii [105] and an-
other in elderly Black, Caribbean Hispanic, and Non-
Hispanic Whites in New York City [106], found that
the risk of incident LOAD was higher in persons with
hyperinsulinemia independent of a history of stroke.
These studies also found that the risk of LOAD related
to hyperinsulinemia was higheramongpersonswith theAPOE-ε4. The Nurses’ health study found that higher
C-peptide levels, a measure of insulin secretion [107],
and fasting insulin levels arerelated to cognitive decline
in women [108–110]. There is a paucity of prospective
epidemiologic studies exploring the relation between
markers of hyperinsulinemia and LOAD and more are
needed.
Type 2 diabetes
T2D has been related to a two-fold higher risk of
developing MCI amongpostmenopausal women [111].
A multiethnic study in elderly from New York city
found that T2D was related to a higher risk of cognitive
impairment-no dementia with stroke although the effect
on cognitive impairment-no dementia without stroke
was not evident after adjusting for demographic vari-
ables and the presence of APOE-ε4 allele [112]. An
Italian study showed a non-statistically significant in-
crease of MCI with T2D in an elderly population [113],
while a Canadian study found that T2D was related on-
ly to vascular cognitive impairment-no dementia [114].
A study inNew York City found that T2D was related to
a higher risk of both amnestic and non-amnestic MCI,
underliningthe importance of T2D for both LOAD and
vascular cognitive impairment [115]. A recent studyin Olmstead county, Minnesota found that presence of
T2D was not related to MCI risk, but longer T2D dura-
tion and treatment with insulin, a surrogate marker of
T2D duration, were related to higher MCI risk [116].
Numerous studies have examined the relation be-
tween T2D and dementia. Table 1 shows the results
of some representative prospective studies in different
countries and age groups. In general, the association
between T2D and dementia seems to be stronger for
vascular dementia compared to LOAD, but these ob-
servations are inconsistent. Some studies have also re-
ported an interaction between T2D and the APOE-ε4
allele, while others have not found this interaction. Im-
portantly, the same study in Japanese Americans re-
ported no associations between T2D and dementia at
midlife [117], but strong associations when T2D was
ascertained in old age [47], underlining the importance
of when in the lifespan T2D is examined. This is of
particular importance because T2D is more common in
elderly people and may not be diagnosed in the same
subjects in younger age.
The diagnosis of T2D is somewhat arbitrary and
many cases go undetected. Few studies have examined
the relation between continuous measures of glycemia
and dementia. One study in postmenopausal womenfound that the risk of MCI and dementia increased with
each 1% elevation in glycosylated hemoglobin, a sta-
ble measure of glucose levels, even in women without
T2D [118]. Glycosylated hemoglobin in persons with-
out T2D correlates with both glucose intolerance and
insulin resistance, and this study underscores the con-
tinuous nature of the relation between these constructs
and higher dementia risk.
Metabolic syndrome
There is limited evidence on the association between
the metabolic syndrome and dementia in the elderly.
One study in 2,632 black and white elders found that
the metabolic syndrome was associated with a higher
risk of cognitive decline, particularly among those with
high inflammatory markers [119]. A cross-sectional
study in Europeans found that LOAD prevalence was
higher in persons with the metabolic syndrome [120].
In Northern New York City, the metabolic syndrome
was not related to LOAD risk, while T2D and hyperin-
sulinemia were [121]. The discrepancy between these
studies could be due to the fact that the study in New
York City was conducted in an older population, eth-
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Table 1Summary of representative prospective epidemiologic studies relating Type 2 diabetes (T2D) with dementia
First author, Year of Publication
Setting Findings
Leibson, 1997 [159] Rates of dementia in 1455 persons 45 yearsand older with T2D in Rochester, Minnesotawere compared to population rates.
Relative risk (RR) relating T2D and all cause dementia was1.66 (95% confidence interval (CI): 1.34–2.05), RR relatingT2D with AD was 2.27 for men (95% CI:1.55–3.31) and 1.37for women, (95% CI: 0.94–2.01).
Brayne, 1998 [160] 2609 persons 75 years and older in Cam-bridge, England
Odds ratios (OR) relating T2D with all cause dementia was2.62 (0.89–7.75), and 1.44 (1.05–17.00) for AD.
Ott, 1999 [161] 6370 persons 55 years and older in Rotter-dam, The Netherlands
T2D related to both all cause dementia [RR = 1.9 [95% CI= 1.3 to 2.8]) and AD (RR 1.9 [1.2–3.1]). Risk of dementiahighest in persons treated with insulin (RR 4.3; 95% CI: 1.7–10.5]).
Curb, 1999 [117] 3,774 Japanese American men in Hawaii,United States, aged 45 to 68 years at the timeof T2D ascertainment and between 71 to 93years at the time of dementia ascertainment.
RR relating T2D with VD was 1.48; 95%CI: 0.79,2.78), and0.98 (95% CI: 0.48,1.99) for AD
Peila, 2002 [47] 2,574 Japanese-American men aged 77yearson averageenrolledin the Honolulu-AsiaAg-ing Study, Hawaii, United States. T2D wasascertained in older age
RR for total dementia was 1.5 (95% CI: 1.01–2.2), 1.8 for AD(95% CI: 1.1–2.9), 2.3 for vascular dementia (95% CI: 1.1–5.0). Individuals with both T2D and the APOE ε4 allele hadan RR of 5.5 (CI 2.2–13.7) for AD compared with those withneither risk factor.
Arvanitakis, 2004 [162] 824 persons older than 55 years from the Re-ligious Orders Study in the United States
Hazard ratio (HR) relating T2D with AD was 1.65 (95% CI:1.10–2.47).
Luchsinger, 2004 [122] 1138 persons aged 65 years and older fromNorthern Manhattan, United States
Hazard ratio relating T2D and AD was 2.4 (95% CI: 1.8–3.2).
Schnaider-Beeri,2004 [163]
1,892 male civil servants aged 40 to 65 attime of T2D ascertainment in Israel
OR relating T2D at midlife with dementia 30 years later was2.83 [95% CI = 1.40 to 5.71]).
Xu, 2004 [164] 1,301 persons aged 75 years and older inStockholm, Sweden
HR for T2D were 1.5 (95% CI 1.0 to 2.1) for dementia, 2.6(95% CI 1.2 to 6.1) for VaD, and 1.3 (95% CI 0.9 to 2.1) forAD.
Whitmer, 2005 [165] 8,845 participantsofa healthmaintenanceor-ganization in California, United States, whowere between the ages of 40 and 44 at thetime of T2D ascertainment
HR relating T2D with dementia was 1.46, (95% CI: 1.19 to1.79)
Xu, 2007 [166] 1,173 persons without known T2D aged 75years and older in Stockholm, Sweden
Borderline T2D diagnosed with plasma glucose was associatedwith adjusted hazard ratios (95% CIs) of 1.67 (1.04–2.67) fordementia and 1.77 (1.06–2.97) for AD.
Irie, 2008 [167] 2547 persons 65 years and from the Cardio-vascular Health Study in the United States.
RR for AD 1.42 (95% CI: 1.02–1.97) but was 4.53 (95% CI:2.47–8.30) when the APOE-ε4 allele was also present. Therewas no association with vascular dementia.
nically diverse, and with a high prevalence of vascularrisk factors [122]. In Japanese Americans,the metabol-ic syndrome in middle age was associated with VaD,but not LOAD [123].
CAN DEMENTIA BE PREVENTED THROUGH
THE PREVENTION OR TREATMENT OF T2D?
T2D prevention
There are four types of interventions that have beendemonstrated to decrease the risk of T2D in persons
at risk though the increase of insulin sensitivity and
the reduction of insulin levels: Lifestyle intervention
(diet, exercise), metformin, acarbose, and rosiglita-
zone [124]. These interventions are also used to treat
T2D. Other treatments of T2D, such as sulfonylureas
and insulin [125], do not increase insulin sensitivity
and are not used for T2D prevention. Thus, they are
not discussed.
Lifestyle interventions
Lifestyle interventions are the most effective [126]
way to lose weight, improve insulin sensitivity, and
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prevent T2D. The Finnish diabetes prevention study
(FDPS) was a trial of lifestyle intervention versus nointervention in 522 middle aged persons with over-
weight or obesity and glucose intolerance [127]. The
lifestyle intervention consisted of counseling to de-
crease weight, decreasedintake of total fats and saturat-
ed fats, increased intakeof fiber, andincreased physical
activity. The risk of T2D was decreased by approx-
imately 58% in the intervention group after approxi-
mately three years of follow-up. This improvement
was achieved mostly through improved insulin sensi-
tivity, not increased insulin secretion [128]. More im-
portantly, lifestyle improvements and the risk of T2D
remained lower in the intervention group several years
after stopping the counseling [129]. Although lifestyle
interventions are difficult to adopt and maintain [130],
the experience of the FDPS indicates not only that the
intervention is effective and feasible, but that its effects
remain years after stopping counseling.
Another landmark study of lifestyle intervention is
the Diabetes Prevention Program (DPP). The DPP was
a trial of lifestyle versus metformin versus placebo in
over 3,000 participants with glucose intolerance [131].
The lifestyle intervention, which consisted of a pro-
gram to achieve weight loss and increased physical ac-
tivity, was the most effective with a 58% reduction in
theincidence of T2Dcomparedto placebo after 3 years,a reduction similar to that achieved in the FDPS. After
3 years the DPP became an observational study called
the DPP outcomes study (DPPOS), but participants re-
mained in their randomization groups and persons in
the placebo groupreceived a lifestyle intervention. The
DPPOS recently reported that benefits in the prevention
of T2D continue after 10 years of follow-up [132].
Importantly, both the FDPS and DPPOS include
comprehensive neurocognitive batteries starting in
2009 which will permit the explorationof whether T2D
prevention through lifestyle interventions prevents cog-
nitive decline and dementia in middle aged persons.
There is a rich literature of relatively small short term
studies of exercise and its effects on cognition [133],
which demonstrate a clear benefit of exercise particu-
larly on executive functions. The assessment of cog-
nition in the FDPS and DPPOS will allow the specific
examination of the effects of long term improvements
of insulin sensitivity and T2D risk on memory, and
non-memory cognitive abilities.
Thiazolidinediones
Thiazolideniodones are PPAR-γ agonists and potent
insulin sensitizers [134]. The Diabetes reduction as-
sessment with ramipril and rosiglitazone medication
(DREAM) trial demonstrated in over 5000 participantswith impaired glucose tolerance that the thiazolidine-
dione rosiglitazone was effective in preventing T2D
during 3 years of intervention. Rosiglitazone seems to
be as effective as lifestyle interventions in preventing
T2D and provides twice the risk reduction compared to
metformin or acarbose [124]. In addition, thiazolidine-
diones are potent anti-inflammatory drugs [135]. Giv-
en the common role of inflammation the pathogenesis
of T2D [136] and AD [60,137], this anti-inflammatory
effect could also decrease the risk of AD. However,
the thiazolidinediones have been consistently shown to
have a higher risk of heart failure and edema [138–
141], and there are recent concerns of other cardio-
vascular adverse effects with rosiglitazone [142]. Pi-
oglitazone, another thiazolideniodone,has an increased
risk of edema and congestive heart failure, but seems
to lacks the other cardiovascular side effects associat-
ed with rosiglitazone [143]. Based on their powerful
insulin sensitizing actions, they are being studied as a
potential treatment of AD based on the hypothesis that
treating hyperinsulinemia lowers Aβ deposition and
AD progression. One pilot 6 month trial of rosiglita-
zone in 30 subjects with mild AD or AMCI showed
that persons receiving 4 mg daily had better delayed
recall at months 4 and 6 and better selective attentionat month 6, and plasma Aβ decreased in persons on
placebo while there was no change in persons on treat-
ment [63]. There was a decrease in insulin levels at 6
months demonstrating the metabolic effects of rosigli-
tazone and better cognitive performance was related to
lower insulin levels. A randomized placebo controlled
trial lasting 24 weeks of rosiglitazone 2, 4, or 8 mg in
511 persons with mild to moderate LOAD found no
effect in their primary outcomes (ADAS-COG) in the
ITT analysis [64]. There was a significant interaction
between APOE-ε4 and ADAS-COG, and persons on 8
mg rosiglitazone without any APOE-ε4 allele showed
an improvement in ADAS-COG (and improvements in
insulin levels), while person with APOE-ε4 showed no
benefit. However a recent Phase III trial of rosiglita-
zone (NCT00428090) in mild to moderateLOAD failed
to show a benefit [144]. It is possible, however, that the
useof thiazolidinedionesin MCI could improve therisk
of dementia. The Rosiglitazone Effects on Cognition
for Adults in Later Life (RECALL; NCT00242593)
study is examining the effects of rosiglitazone on cog-
nition in persons with MCI and is estimated to finish
in 2010. The Pioglitazone or Exercise to Treat Mild
Cognitive Impairment (POEM; NCT00736996) is ex-
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730 J.A. Luchsinger / Type 2 Diabetes and Related Conditions in Relation to Dementia
ploring the effects of pioglitazonecompared to exercise
or placebo in persons with MCI and is scheduled to endin 2011. The major limitation of thiazolidinediones in
the prevention of dementia is the class side effects of
edema and congestive heart failure, and the concerns
with increased cardiovascular morbidity with rosiglita-
zone compared to pioglitazone, which are still a matter
of debate.
Metformin
Metformin is a medication belonging to the biguan-
ide class [145,146]. It treats and prevents diabetes
by suppression of hepatic glucose output, increasing
insulin-mediated glucose disposal, by increasedintesti-
nal glucose use, and by decreasing fatty acid oxida-
tion [147]; this is accompanied by reduced require-
ments for pancreatic insulin secretion and relatively
lower insulin levels in blood in response to glucose
load. While the mechanisms for the action of met-
formin are not completely understood, it clearly re-
duces insulin levels [148], inflammation and thrombo-
sis [149], and the risk of the metabolic syndrome [150]
and diabetes [151] in persons without diabetes. The
largest and longest experience for metformin in per-
sons without diabetes has been in the DPP. Metformin
was more effective than placebo but less effective than
lifestyle interventions in preventing T2D [131], and itclearly improved insulin sensitivity an decreased in-
sulin levels [148]. While metformin is a less potent
insulin sensitizer compared to thiazolidinediones and
lifestyle intervention, it has been proven to effectively
and safely prevent T2D. Its usual side effect is gastroin-
testinal intolerance, and its worse side effect, acidosis,
is rare and occurs in persons with severe congestive
heart failure, liver disease, or renal disease [145]. One
recent study in cellular models showed that metformin
increases the production of Aβ through upregulation of
β -secretase [152], and the authors raised the concern
that metformin could increase the risk of LOAD. How-
ever, this study needs to be replicated, and the relevance
of its findings to humans demonstrated. The effect of
metformin on cognition will be assessed in the met-
formin arm of the DPPOS. Additionally, there is an on-
going Phase II trial of metformin (NCT00620191) test-
ing whether metformin can decrease cognitive decline
and dementia in persons with MCI.
Acarbose
Acarbose reduces the risk of diabetes by decreas-
ing carbohydrate absorption in the intestine and post-
prandial insulin levels [153] but adherence to acarbose
is poor due to gastrointestinal side effects [153]. To the
best of my knowledge, there are no trials of acarbosein the prevention of dementia.
Diabetes treatment in the prevention of dementia
One of the implications of the body of work sum-
marized in this article is that persons with T2D are at
increased risk of dementia and that its treatment could
affect dementia risk. This could happen in two poten-
tial ways. It is possible that tighter T2D control could
improve the risk of dementia in T2D. The three control
parameters followed in clinical practice are glycemia,
measured with hemoglobin A1c, blood pressure, andlipids, measured with low density lipoprotein. The
recently finalized “Action to Control Cardiovascular
Risk in Diabetes–Memory in Diabetes” (ACCORD-
MIND; NCT00182910) study will be able to answer
whether tighter control in these parameters reduces
the risk of cognitive decline and dementia in persons
with T2D [154]. One of the consequences of tight
glycemic control is hypoglycemia, and a recent obser-
vational study in elderly persons with T2D demonstrat-
ed that hypoglycemia was related to higher risk of de-
mentia [155]. An as of yet unpublished analysis of
data from the Informatics in Diabetes Education andTelemedicineStudy (IDEATel) [156], a randomizedtri-
al of telemedicineversus usual care in 2169 elderly per-
sons with T2D, showed that persons in the intervention
group, which showed better control parameters com-
pared to usual care, had less global cognitive decline
during a maximum of 6 years of follow-up. Impor-
tantly, the glycemic control goals of IDEATel followed
glycemic guidelines which are less stringent than the
goals in ACCORD, which showed increased mortality
in its tight glycemic control arm [157] and less likely
to lead to hypoglycemia.
The other way in which T2D control could affect
dementia risk is with the type of medication used to
achieve glycemic control. In general, medications used
to treat T2D can be classified into insulin or insulin sec-
retagogues (sulfonylureas) or insulin sensitizers (met-
formin or thiazolidinediones) [125]. A newer class of
T2D medication, the incretins, increase insulin secre-
tion but also seem to improve insulin sensitivity and
induce weight loss [158]. Given the possible role of
hyperinsulinemia in AD pathology, one could specu-
late that insulin sensitizing medications could decrease
the risk of LOAD compared to other medications. This
has not been demonstrated and needs to be tested.
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J.A. Luchsinger / Type 2 Diabetes and Related Conditions in Relation to Dementia 731
SUMMARY AND CONCLUSIONS
Many epidemiologic studies have shown that T2D
and its precursors, elevated adiposity and hyperinsu-
linemia, are related to a higher risk of dementia. In
general, these associations seem to be stronger for VaD
compared with LOAD. Pathologic data seem to suggest
that cerebrovascular disease decrease the threshold of
amyloid burden needed to manifest dementia. Howev-
er, experimental and basic studies have demonstrated
plausible links between hyperinsulinemia and products
of hyperglycemia (e.g., AGE) in amyloid. The possibil-
ity that elevated adiposity, hyperinsulinemia, and T2D
increase the risk of dementia is alarming because a ma- jority of the adult population in the US have these con-
ditions. However, these conditions can be treated and
prevented, presenting a potential opportunity for de-
mentia prevention. Ongoing clinical trials will answer
whether interventions proven to improve insulin sensi-
tivity and decrease T2D risk can prevent dementia, in-
cluding lifestyle interventions, thiazolidinediones, and
metformin. We will also soon find out whether tight
diabetes control can improve dementia risk in persons
with T2D. There are no proven ways to modify the
risk of dementia. Ongoing clinical trials of amyloid
specific treatments such as vaccines, β -secretase, and
γ -secretase inhibitors will tell us in the next five years
if targeting amyloid can treat or prevent dementia. If
these trials are negative or of modest success, we may
only have the treatment and prevention of vascular and
metabolic conditions as potential ways to prevent de-
mentia in the near future.
ACKNOWLEDGMENTS
Dr. Luchsinger’s work in this review was support-
ed by grants from the National Institute on Aging
(AG026413, AG07232), NCMHD (P60 MD00206),
ISOA/ADDF (270901) the American Diabetes Asso-
ciation (7-08-CR-41) and by the Florence and Herbert
Irving Clinical Research Scholar’s Award.
The author’s disclosure is available online (http://
www.j-alz.com/disclosures/view.php?id=335).
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