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Journal of Alzheimer’s Disease 20 (2010) 723–736 DOI 10.3233/JAD-2010-091687 IOS Press

Review

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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 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 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, Alzheimer’s disease, cognitive impairment, glucose, hyperinsulinemia, insulin, obesity, overweight, type 2 diabetes

INTRODUCTION

Late onset Alzheimer’s 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: Jose´ 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 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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addition to the observation that elderly people with nor- mal 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 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 function and 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,

and dementia 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 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 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/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 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 insulin resistance and hyperinsulinemia. An implication of the natural history described above 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 may be 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 common correlates 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 for LOAD 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 42 levels 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 tau protein phosphorylation, which are central to the patho- genesis of LOAD [55]. The pathways relating insulin in the periphery with Aβ clearance in the brain are mul- tiple and complex. Craft and colleagues have reviewed how peripheral hyperinsulinemia affects Aβ clearance in the brain [60]. A potential pathway is that peripheral hyperinsulinemia downregulates insulin uptake in the blood brain barrier due to saturation over physiolog- ic 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 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 treatment of LOAD.

Advanced products of glycosylation (AGE) AGE are most closely linked with glycemia and di- abetes, as elevated glucose concentration promotes the Maillard reaction and AGE accrual. In a hyperglycemic environment, diabetic animal and human tissues con- tain increased AGE and upregulation of its receptor (RAGE) [66–68]. In fact, the most recognized AGE, hemoglobin A 1c , represents the standard-of-care for tracking T2D glycemic control. AGE contribute impor- tantly 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 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 LOAD brain [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 40 and Aβ 1 42 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 oth- er tissues, clears Aβ from plasma and also mediates transport of Aβ out of the brain [79,80]. LRP-1 is di- minished in insulin resistance without affecting lipid levels [80]. Thus, LRP-1 is a plausible mechanism linking hyperinsulinemia with Aβ and LOAD. Soluble LRP (sLRP) facilitates the clearance of Aβ 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 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. 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 [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 hyperinsulinemiawas higher among persons with the

APOE-ε4. 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 [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 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 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 in New York City found that T2D was related to

a higher risk of both amnestic and non-amnestic MCI,

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

First author, Year of

Setting

Findings

Publication Leibson, 1997 [159]

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): 1.34–2.05), RR relating

T2D with AD was 2.27 for men (95% CI:1.55–3.31) and 1.37 for 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 was

2.62

(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 dementia highest in persons treated with insulin (RR 4.3; 95% CI: 1.7–

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.

10.5]).

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 Ag- ing Study, Hawaii, United States. T2D was ascertained 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 had an RR of 5.5 (CI 2.2–13.7) for AD compared with those with neither risk factor.

Arvanitakis, 2004 [162]

824 persons older than 55 years from the Re-

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

ligious Orders Study in the United States

1.10–2.47).

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: 1.8–3.2).

Schnaider-Beeri,

1,892 male civil servants aged 40 to 65 at

OR relating T2D at midlife with dementia 30 years later was

2004 [163]

time of T2D ascertainment in Israel

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 or-

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

ganization in California, United States, who were between the ages of 40 and 44 at the time of T2D ascertainment

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 (1.04–2.67) for dementia and 1.77 (1.06–2.97) for AD.

Irie, 2008 [167]

2547 persons 65 years and from the Cardio-

RR for AD 1.42 (95% CI: 1.02–1.97) but was 4.53 (95% CI:

vascular Health Study in the United States.

2.47–8.30) when the APOE-ε4 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 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 been demonstrated 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 no intervention in 522 middle aged persons with over- weight or obesity and glucose intolerance [127]. The lifestyle intervention consisted of counseling to de- crease weight, decreased intake of total fats and saturat- ed fats, increased intake of fiber, and increased 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

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 re- mained 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 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 participants with 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 attention at 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 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 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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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 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 increased intesti- 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 it clearly 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 acarbose in 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, and lipids, 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 and Telemedicine Study (IDEATel) [156], a randomized tri- al of telemedicine versus 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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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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