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Journal of Alzheimers Disease 20 (2010) 723736


DOI 10.3233/JAD-2010-091687
IOS 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, USA
Taub Institute for Research of Alzheimers 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 Alzheimers disease (LOAD). Studies have
consistently 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, Alzheimers disease, cognitive impairment, glucose, hyperinsulinemia, insulin, obesity, overweight, type
2 diabetes

INTRODUCTION
Late onset Alzheimers disease (LOAD) is the most
common form of dementia, accounting for between
70% to over 90% of all cases [1], and its prevalence is
expected to quadruple by the year 2047 in the US [2].
As much as 50% of the population aged 85 years and
older, the fastest growing segment of the population,
Correspondence to: Jos
e A. Luchsinger, MD, 630 West 168th
St., PH19, New York, NY 10032, USA. Tel.: +1 212 305 4730; Fax:
+1 212 305 2526; E-mail: jal94@columbia.edu.

may have LOAD [3]. Vascular dementia (VaD) is the


second most common form of dementia, although it
varies widely depending on 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 pathology 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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J.A. Luchsinger / Type 2 Diabetes and Related Conditions in Relation to Dementia

addition to the observation that elderly people with normal cognition have brain pathology usually ascribed to
dementia. Thus, some propose that the classification of
dementia into LOAD, VaD, and mixed dementia 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 cerebrovascular disease, and it is not surprising that they cause
VaD. Whether they cause LOAD or Alzheimers disease (AD) pathology is a matter of controversy. Predementia cognitive impairment is of importance as a
potential target for secondary prevention. Mild cognitive impairment (MCI) has been used to describe a
transitional state between normal cognitive function
and LOAD dementia [6,7] and has thus been targeted for interventions [8]. Individuals with MCI do not
have dementia but have memory complaints without
loss of function in their daily activities [7]. While general cognitive performance is well preserved, memory
performance on standardized tests falls below expectations 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 nonamnestic 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 applied [9], and increases from about 1% in persons 60
years old to 25% at age 85 [10]. Risk factors for dementia can be studied in epidemiologic studies through
the outcomes of cognitive impairment or decline, MCI,
and dementia itself dementia, and this review will cover
evidence examining these outcomes.
This review attempts to cover the prevention of dementia, not its treatment. Thus far, trials of vitamin
E [8] and homocysteine related vitamins [11] did not
prevent 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 dementia 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]. Abdominal adiposity, the accumulation of body fat around
the waist, also named central adiposity, seems to be the
most important predictor of T2D [19] and cardiovascular disease [20]. Two-thirds of American adults are
overweight or obese [21]. The prevalence of abdominal obesity among US adults has increased continuously during the past 15 years. T2D risk rises with overweight/obesity (body mass index, BMI 25 kg/m 2 ),
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%) compared
to non-Hispanic Whites (6.6%) [23]. Those with other metabolic syndrome components (high blood pressure, 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 resistance resulting in hyperinsulinemia) and inadequate insulin secretion from pancreatic -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 hyperinsulinemia [2830]. In the natural history of progression
to T2D, pancreatic -cells initially increase insulin secretion in response to insulin resistance causing hyperinsulinemia and are able to effectively maintain glucose levels below the T2D range. When -cell function 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

J.A. Luchsinger / Type 2 Diabetes and Related Conditions in Relation to Dementia

over time. Therefore, progression of T2D is a result


of worsening -cell function with preexisting insulin
resistance and hyperinsulinemia.
An implication of the natural history described above
is that when an epidemiologic study finds a relation between 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 exposure is the one we are examining. The answer could
be that there is an aggregate effect of all the components in the lifespan. Biessels has published a review
that describes how individual components of the natural 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 disease [3237]. Elevated adiposity [38], hyperinsulinemia, 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 linking 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 amyloid in the brain that is necessary to cause dementia.
The Religious Orders Study, a study of religious orders across the United States based at Rush University in Chicago, found that T2D was related to infarcts
on autopsy but not AD pathology in persons with dementia [46]. This observation suggests that the main
mechanism linking T2D to dementia is the presence of
infarcts, which lowers the burden of amyloid necessary

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to cause memory decline and dementia. However, the


Honolulu-Asia Aging Study [47], a study of JapaneseAmericans, found that T2D was related to AD pathology, particularly in persons with the APOE-4 allele.
The Adult Changes in Thought Study, based at the University of Washington, reported that persons without
DM and with dementia had a greater amyloid- peptide load and in the cerebral cortex, while those with
both T2D and dementia patients had more microvascular 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 imaging represents microvascular disease in the brain or demyelination. Some studies show an increase of WHI
in persons with T2D [49], which may suggest a microvascular 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 surrogate markers of cerebrovascular disease [50]. However, recent evidence shows that WHI are common in
LOAD and may be related to cerebral amyloid angiopathy [5154]. Thus, some WHI may be due to amyloid
disease and contribute to the development of LOAD.
WHI are common correlates of cognitive impairment in
T2D [49], but it is unclear whether this WHI are markers of microvascular injury or may represent a process
related to amyloid deposition.
Non-cerebrovascular mechanisms
Hyperinsulinemia and amyloid- (A) clearance
Hyperinsulinemia is a plausible risk factor for LOAD
independent of cerebrovascular disease because a) insulin can cross the blood brain barrier [55], and peripheral insulin infusion in the elderly may affect A 42
levels in the cerebrospinal fluid (CSF) [56], a surrogate
marker of A 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 A in the brain, and insulin and A are

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J.A. Luchsinger / Type 2 Diabetes and Related Conditions in Relation to Dementia

both competing substrates for IDE [59]; and d) insulin


in the brain can increase the deposition of A and tau
protein phosphorylation, which are central to the pathogenesis of LOAD [55]. The pathways relating insulin
in the periphery with A clearance in the brain are multiple and complex. Craft and colleagues have reviewed
how peripheral hyperinsulinemia affects A clearance
in the brain [60]. A potential pathway is that peripheral
hyperinsulinemia downregulates insulin uptake in the
blood brain barrier due to saturation over physiologic levels [61]. This may result in reduction of insulin
levels in the brain and downregulation of expression of
IDE [62] and reduction in IDE mediated amyloid reduction [59]. This complex observation has been used
to support the use of rosiglitazone, an insulin sensitizer [63,64], and intranasal insulin [65] in the treatment
of LOAD.
Advanced products of glycosylation (AGE)
AGE are most closely linked with glycemia and diabetes, as elevated glucose concentration promotes the
Maillard reaction and AGE accrual. In a hyperglycemic
environment, diabetic animal and human tissues contain increased AGE and upregulation of its receptor
(RAGE) [6668]. In fact, the most recognized AGE,
hemoglobin A 1c , represents the standard-of-care for
tracking T2D glycemic control. AGE contribute importantly to diabetic complications. AGE in the basement
membranes of vessels promote vascular leakage [69].
AGE is associated with diabetic nephropathy [70,71],
retinal neovascularization [72,73], and diabetic neuropathy [74]. Increased expression of RAGE is observed in LOAD [7577]. Expression of RAGE is enhanced in blood vessels near A deposits in LOAD
brain [75,78]. Along with increased total amount of
RAGE in AD brain, there is a shift of RAGE distribution from neuron to microvasculature [79]. A 140
and A142 transport in the blood brain barrier can be
blocked by RAGE-specific IgG or sRAGE, providing
evidence 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 other tissues, clears A from plasma and also mediates
transport of A out of the brain [79,80]. LRP-1 is diminished in insulin resistance without affecting lipid
levels [80]. Thus, LRP-1 is a plausible mechanism
linking hyperinsulinemia with A and LOAD. Soluble
LRP (sLRP) facilitates the clearance of A by LRP-1
and 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 organ. In fact, it produces important factors such as leptin and adiponectin, in addition to inflammatory factors [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 positively 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 association between BMI quartiles and LOAD resembles a U
shaped-curve, while in the oldest old (> 76 years) higher 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 underscores the difficulty in studying the effects of adiposity in older age [95]. This study also found that higher 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 elevated self-reported BMI at age 50 years was associated 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

J.A. Luchsinger / Type 2 Diabetes and Related Conditions in Relation to Dementia

which adiposity is ascertained in relation to dementia.


The most important explanation for the paradox linking
low 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 [102104]. Two longitudinal studies, one in
elderly Japanese Americans in Hawaii [105] and another in elderly Black, Caribbean Hispanic, and NonHispanic 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 higher among persons with the
APOE-4. The Nurses health study found that higher
C-peptide levels, a measure of insulin secretion [107],
and fasting insulin levels are related to cognitive decline
in women [108110]. There is a paucity of prospective
epidemiologic studies exploring the relation between
markers of hyperinsulinemia and LOAD and more are
needed.

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underlining the importance of T2D for both LOAD and


vascular cognitive impairment [115]. A recent study
in Olmstead county, Minnesota found that presence of
T2D was not related to MCI risk, but longer T2D duration and treatment with insulin, a surrogate marker of
T2D duration, were related to higher MCI risk [116].
Numerous studies have examined the relation between 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 observations are inconsistent. Some studies have also reported an interaction between T2D and the APOE-4
allele, while others have not found this interaction. Importantly, the same study in Japanese Americans reported 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 women
found that the risk of MCI and dementia increased with
each 1% elevation in glycosylated hemoglobin, a stable measure of glucose levels, even in women without
T2D [118]. Glycosylated hemoglobin in persons without T2D correlates with both glucose intolerance and
insulin resistance, and this study underscores the continuous nature of the relation between these constructs
and higher dementia risk.

Type 2 diabetes
Metabolic syndrome
T2D has been related to a two-fold higher risk of
developing MCI among postmenopausal 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 variables and the presence of APOE-4 allele [112]. An
Italian study showed a non-statistically significant increase of MCI with T2D in an elderly population [113],
while a Canadian study found that T2D was related only to vascular cognitive impairment-no dementia [114].
A study in New York City found that T2D was related to
a higher risk of both amnestic and non-amnestic MCI,

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 hyperinsulinemia 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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J.A. Luchsinger / Type 2 Diabetes and Related Conditions in Relation to Dementia


Table 1
Summary of representative prospective epidemiologic studies relating Type 2 diabetes (T2D) with dementia

First author, Year of


Publication
Leibson, 1997 [159]

Setting

Findings

Rates of dementia in 1455 persons 45 years


and older with T2D in Rochester, Minnesota
were compared to population rates.

Relative risk (RR) relating T2D and all cause dementia was
1.66 (95% confidence interval (CI): 1.342.05), RR relating
T2D with AD was 2.27 for men (95% CI:1.553.31) and 1.37
for women, (95% CI: 0.942.01).

Brayne, 1998 [160]

2609 persons 75 years and older in Cambridge, England

Odds ratios (OR) relating T2D with all cause dementia was
2.62 (0.897.75), and 1.44 (1.0517.00) for AD.

Ott, 1999 [161]

6370 persons 55 years and older in Rotterdam, The Netherlands

T2D related to both all cause dementia [RR = 1.9 [95% CI


= 1.3 to 2.8]) and AD (RR 1.9 [1.23.1]). Risk of dementia
highest 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 time
of T2D ascertainment and between 71 to 93
years at the time of dementia ascertainment.

RR relating T2D with VD was 1.48; 95%CI: 0.79,2.78), and


0.98 (95% CI: 0.48,1.99) for AD

Peila, 2002 [47]

2,574 Japanese-American men aged 77 years


on average enrolled in the Honolulu-Asia Aging Study, Hawaii, United States. T2D was
ascertained in older age

RR for total dementia was 1.5 (95% CI: 1.012.2), 1.8 for AD
(95% CI: 1.12.9), 2.3 for vascular dementia (95% CI: 1.1
5.0). Individuals with both T2D and the APOE 4 allele had
an RR of 5.5 (CI 2.213.7) for AD compared with those with
neither risk factor.

Arvanitakis, 2004 [162]

824 persons older than 55 years from the Religious Orders Study in the United States

Hazard ratio (HR) relating T2D with AD was 1.65 (95% CI:
1.102.47).

Luchsinger, 2004 [122]

1138 persons aged 65 years and older from


Northern Manhattan, United States

Hazard ratio relating T2D and AD was 2.4 (95% CI: 1.83.2).

Schnaider-Beeri,
2004 [163]

1,892 male civil servants aged 40 to 65 at


time of T2D ascertainment in Israel

OR relating T2D at midlife with dementia 30 years later was


2.83 [95% CI = 1.40 to 5.71]).

Xu, 2004 [164]

1,301 persons aged 75 years and older in


Stockholm, 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) for
AD.

Whitmer, 2005 [165]

8,845 participants of a health maintenance organization in California, United States, who


were between the ages of 40 and 44 at the
time of T2D ascertainment

HR relating T2D with dementia was 1.46, (95% CI: 1.19 to


1.79)

Xu, 2007 [166]

1,173 persons without known T2D aged 75


years and older in Stockholm, Sweden

Borderline T2D diagnosed with plasma glucose was associated


with adjusted hazard ratios (95% CIs) of 1.67 (1.042.67) for
dementia and 1.77 (1.062.97) for AD.

Irie, 2008 [167]

2547 persons 65 years and from the Cardiovascular Health Study in the United States.

RR for AD 1.42 (95% CI: 1.021.97) but was 4.53 (95% CI:
2.478.30) when the APOE-4 allele was also present. There
was no association with vascular dementia.

nically diverse, and with a high prevalence of vascular


risk factors [122]. In Japanese Americans, the metabolic syndrome in middle age was associated with VaD,
but not LOAD [123].
CAN DEMENTIA BE PREVENTED THROUGH
THE PREVENTION OR TREATMENT OF T2D?

at risk though the increase of insulin sensitivity and


the reduction of insulin levels: Lifestyle intervention
(diet, exercise), metformin, acarbose, and rosiglitazone [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.

T2D prevention
There are four types of interventions that have been
demonstrated to decrease the risk of T2D in persons

Lifestyle interventions
Lifestyle interventions are the most effective [126]
way to lose weight, improve insulin sensitivity, and

J.A. Luchsinger / Type 2 Diabetes and Related Conditions in Relation to Dementia

prevent T2D. The Finnish diabetes prevention study


(FDPS) was a trial of lifestyle intervention versus no
intervention in 522 middle aged persons with overweight or obesity and glucose intolerance [127]. The
lifestyle intervention consisted of counseling to decrease weight, decreased intake of total fats and saturated fats, increased intake of fiber, and increased physical
activity. The risk of T2D was decreased by approximately 58% in the intervention group after approximately three years of follow-up. This improvement
was achieved mostly through improved insulin sensitivity, not increased insulin secretion [128]. More importantly, 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 program to achieve weight loss and increased physical activity, was the most effective with a 58% reduction in
the incidence of T2D compared to 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 remained in their randomization groups and persons in
the placebo group received 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 exploration of whether T2D
prevention through lifestyle interventions prevents cognitive 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 particularly on executive functions. The assessment of cognition 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- agonists and potent
insulin sensitizers [134]. The Diabetes reduction as-

729

sessment with ramipril and rosiglitazone medication


(DREAM) trial demonstrated in over 5000 participants
with impaired glucose tolerance that the thiazolidinedione 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, thiazolidinediones are potent anti-inflammatory drugs [135]. Given 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 cardiovascular adverse effects with rosiglitazone [142]. Pioglitazone, another thiazolideniodone, has an increased
risk of edema and congestive heart failure, but seems
to lacks the other cardiovascular side effects associated 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 A deposition and
AD progression. One pilot 6 month trial of rosiglitazone 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 attention
at month 6, and plasma A decreased in persons on
placebo while there was no change in persons on treatment [63]. There was a decrease in insulin levels at 6
months demonstrating the metabolic effects of rosiglitazone 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-4 and ADAS-COG, and persons on 8
mg rosiglitazone without any APOE-4 allele showed
an improvement in ADAS-COG (and improvements in
insulin levels), while person with APOE-4 showed no
benefit. However a recent Phase III trial of rosiglitazone (NCT00428090) in mild to moderate LOAD failed
to show a benefit [144]. It is possible, however, that the
use of thiazolidinediones in MCI could improve the risk
of dementia. The Rosiglitazone Effects on Cognition
for Adults in Later Life (RECALL; NCT00242593)
study is examining the effects of rosiglitazone on cognition in persons with MCI and is estimated to finish
in 2010. The Pioglitazone or Exercise to Treat Mild
Cognitive Impairment (POEM; NCT00736996) is ex-

730

J.A. Luchsinger / Type 2 Diabetes and Related Conditions in Relation to Dementia

ploring the effects of pioglitazone compared to exercise


or placebo in persons with MCI and is scheduled to end
in 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 rosiglitazone compared to pioglitazone, which are still a matter
of debate.
Metformin
Metformin is a medication belonging to the biguanide class [145,146]. It treats and prevents diabetes
by suppression of hepatic glucose output, increasing
insulin-mediated glucose disposal, by increased intestinal glucose use, and by decreasing fatty acid oxidation [147]; this is accompanied by reduced requirements for pancreatic insulin secretion and relatively
lower insulin levels in blood in response to glucose
load. While the mechanisms for the action of metformin are not completely understood, it clearly reduces insulin levels [148], inflammation and thrombosis [149], and the risk of the metabolic syndrome [150]
and diabetes [151] in persons without diabetes. The
largest and longest experience for metformin in persons without diabetes has been in the DPP. Metformin
was more effective than placebo but less effective than
lifestyle interventions in preventing T2D [131], and it
clearly improved insulin sensitivity an decreased insulin 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 gastrointestinal 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 A through upregulation of
-secretase [152], and the authors raised the concern
that metformin could increase the risk of LOAD. However, 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 metformin arm of the DPPOS. Additionally, there is an ongoing Phase II trial of metformin (NCT00620191) testing whether metformin can decrease cognitive decline
and dementia in persons with MCI.
Acarbose
Acarbose reduces the risk of diabetes by decreasing carbohydrate absorption in the intestine and postprandial 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 acarbose
in the prevention of dementia.
Diabetes treatment in the prevention of dementia
One of the implications of the body of work summarized 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 potential 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, and
lipids, measured with low density lipoprotein. The
recently finalized Action to Control Cardiovascular
Risk in DiabetesMemory in Diabetes (ACCORDMIND; 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 observational study in elderly persons with T2D demonstrated that hypoglycemia was related to higher risk of dementia [155]. An as of yet unpublished analysis of
data from the Informatics in Diabetes Education and
Telemedicine Study (IDEATel) [156], a randomized trial of telemedicine versus usual care in 2169 elderly persons with T2D, showed that persons in the intervention
group, which showed better control parameters compared to usual care, had less global cognitive decline
during a maximum of 6 years of follow-up. Importantly, 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 secretagogues (sulfonylureas) or insulin sensitizers (metformin or thiazolidinediones) [125]. A newer class of
T2D medication, the incretins, increase insulin secretion but also seem to improve insulin sensitivity and
induce weight loss [158]. Given the possible role of
hyperinsulinemia in AD pathology, one could speculate that insulin sensitizing medications could decrease
the risk of LOAD compared to other medications. This
has not been demonstrated and needs to be tested.

J.A. Luchsinger / Type 2 Diabetes and Related Conditions in Relation to Dementia

SUMMARY AND CONCLUSIONS


Many epidemiologic studies have shown that T2D
and its precursors, elevated adiposity and hyperinsulinemia, 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. However, experimental and basic studies have demonstrated
plausible links between hyperinsulinemia and products
of hyperglycemia (e.g., AGE) in amyloid. The possibility that elevated adiposity, hyperinsulinemia, and T2D
increase the risk of dementia is alarming because a majority of the adult population in the US have these conditions. However, these conditions can be treated and
prevented, presenting a potential opportunity for dementia prevention. Ongoing clinical trials will answer
whether interventions proven to improve insulin sensitivity and decrease T2D risk can prevent dementia, including 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, -secretase, and
-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 dementia in the near future.

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ACKNOWLEDGMENTS
Dr. Luchsingers work in this review was supported by grants from the National Institute on Aging
(AG026413, AG07232), NCMHD (P60 MD00206),
ISOA/ADDF (270901) the American Diabetes Association (7-08-CR-41) and by the Florence and Herbert
Irving Clinical Research Scholars Award.
The authors disclosure is available online (http://
www.j-alz.com/disclosures/view.php?id=335).

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