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Figure 1.
Cumulative incidence of Alzheimer disease in entire sample: comparison of groups with and without diabetes mellitus (DM), adjusted for age and sex.

Cumulative incidence of Alzheimer disease in entire sample: comparison of groups with and without diabetes mellitus (DM), adjusted for age and sex.

Figure 2.
Cumulative incidence of Alzheimer disease in low-risk group: comparison of persons with and without diabetes mellitus (DM), adjusted for age and sex.

Cumulative incidence of Alzheimer disease in low-risk group: comparison of persons with and without diabetes mellitus (DM), adjusted for age and sex.

Table 1. 
Characteristics of Study Sample at Baseline (16th Biennial) Examination*
Characteristics of Study Sample at Baseline (16th Biennial) Examination*
Table 2. 
Multivariable Cox Proportional Hazards Models Examining the Relation Between Diabetes and the Risk of All-Cause Dementia, Alzheimer Disease, and Vascular Dementia Using Standard and Time-Dependent Cox Models
Multivariable Cox Proportional Hazards Models Examining the Relation Between Diabetes and the Risk of All-Cause Dementia, Alzheimer Disease, and Vascular Dementia Using Standard and Time-Dependent Cox Models
1.
Arvanitakis  ZWilson  RSBienias  JLEvans  DABennett  DA Diabetes mellitus and risk of Alzheimer disease and decline in cognitive function. Arch Neurol 2004;61661- 666
PubMedArticle
2.
Elias  PKElias  MFD'Agostino  RB  et al.  NIDDM and blood pressure as risk factors for poor cognitive performance: The Framingham Study. Diabetes Care 1997;201388- 1395
PubMedArticle
3.
Fontbonne  ABerr  CDucimetiere  PAlperovitch  A Changes in cognitive abilities over a 4-year period are unfavorably affected in elderly diabetic subjects: results of the Epidemiology of Vascular Aging Study. Diabetes Care 2001;24366- 370
PubMedArticle
4.
Gregg  EWYaffe  KCauley  JA  et al.  Is diabetes associated with cognitive impairment and cognitive decline among older women? Study of Osteoporotic Fractures Research Group. Arch Intern Med 2000;160174- 180
PubMedArticle
5.
Knopman  DBoland  LLMosley  T  et al.  Cardiovascular risk factors and cognitive decline in middle-aged adults. Neurology 2001;5642- 48
PubMedArticle
6.
Yaffe  KBlackwell  TKanaya  AMDavidowitz  NBarrett-Connor  EKrueger  K Diabetes, impaired fasting glucose, and development of cognitive impairment in older women. Neurology 2004;63658- 663
PubMedArticle
7.
Logroscino  GKang  JHGrodstein  F Prospective study of type 2 diabetes and cognitive decline in women aged 70-81 years. BMJ 2004;328548
PubMedArticle
8.
Elias  MFElias  PKSullivan  LMWolf  PAD'Agostino  RB Obesity, diabetes and cognitive deficit: The Framingham Heart Study. Neurobiol Aging 2005;26(Suppl 1)11- 16
PubMedArticle
9.
Araki  YNomura  MTanaka  H  et al.  MRI of the brain in diabetes mellitus. Neuroradiology 1994;36101- 103
PubMedArticle
10.
den Heijer  TVermeer  SEvan Dijk  EJ  et al.  Type 2 diabetes and atrophy of medial temporal lobe structures on brain MRI. Diabetologia 2003;461604- 1610
PubMedArticle
11.
Schmidt  RLauner  LJNilsson  LG  et al.  Magnetic resonance imaging of the brain in diabetes: the Cardiovascular Determinants of Dementia (CASCADE) Study. Diabetes 2004;53687- 692
PubMedArticle
12.
Schnaider Beeri  MGoldbourt  USilverman  JM  et al.  Diabetes mellitus in midlife and the risk of dementia three decades later. Neurology 2004;631902- 1907
PubMedArticle
13.
Xu  WLQiu  CXWahlin  AWinblad  BFratiglioni  L Diabetes mellitus and risk of dementia in the Kungsholmen project: a 6-year follow-up study. Neurology 2004;631181- 1186
PubMedArticle
14.
Hassing  LBJohansson  BNilsson  SE  et al.  Diabetes mellitus is a risk factor for vascular dementia, but not for Alzheimer's disease: a population-based study of the oldest old. Int Psychogeriatr 2002;14239- 248
PubMedArticle
15.
Luchsinger  JATang  MXStern  YShea  SMayeux  R Diabetes mellitus and risk of Alzheimer's disease and dementia with stroke in a multiethnic cohort. Am J Epidemiol 2001;154635- 641
PubMedArticle
16.
Haan  MNMungas  DMGonzalez  HMOrtiz  TAAcharya  AJagust  WJ Prevalence of dementia in older latinos: the influence of type 2 diabetes mellitus, stroke and genetic factors. J Am Geriatr Soc 2003;51169- 177
PubMedArticle
17.
Leibson  CLRocca  WAHanson  VA  et al.  Risk of dementia among persons with diabetes mellitus: a population-based cohort study. Am J Epidemiol 1997;145301- 308
PubMedArticle
18.
Ott  AStolk  RPvan Harskamp  FPols  HAHofman  ABreteler  MM Diabetes mellitus and the risk of dementia: The Rotterdam Study. Neurology 1999;531937- 1942
PubMedArticle
19.
Peila  RRodriguez  BLLauner  LJ Type 2 diabetes, APOE gene, and the risk for dementia and related pathologies: The Honolulu-Asia Aging Study. Diabetes 2002;511256- 1262
PubMedArticle
20.
Brayne  CGill  CHuppert  FA  et al.  Vascular risks and incident dementia: results from a cohort study of the very old. Dement Geriatr Cogn Disord 1998;9175- 180
PubMedArticle
21.
MacKnight  CRockwood  KAwalt  EMcDowell  I Diabetes mellitus and the risk of dementia, Alzheimer's disease and vascular cognitive impairment in the Canadian Study of Health and Aging. Dement Geriatr Cogn Disord 2002;1477- 83
PubMedArticle
22.
Yoshitake  TKiyohara  YKato  I  et al.  Incidence and risk factors of vascular dementia and Alzheimer's disease in a defined elderly Japanese population: the Hisayama Study. Neurology 1995;451161- 1168
PubMedArticle
23.
Ivan  CSSeshadri  SBeiser  A  et al.  Dementia after stroke: the Framingham Study. Stroke 2004;351264- 1268
PubMedArticle
24.
Kuusisto  JKoivisto  KMykkanen  L  et al.  Association between features of the insulin resistance syndrome and Alzheimer's disease independently of apolipoprotein E4 phenotype: cross sectional population based study. BMJ 1997;3151045- 1049
PubMedArticle
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Welty  FKLahoz  CTucker  KLOrdovas  JMWilson  PWSchaefer  EJ Frequency of ApoB and ApoE gene mutations as causes of hypobetalipoproteinemia in the Framingham offspring population. Arterioscler Thromb Vasc Biol 1998;181745- 1751
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PubMedArticle
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Original Contribution
November 2006

Diabetes Mellitus and Risk of Developing Alzheimer DiseaseResults From the Framingham Study

Author Affiliations

Author Affiliations: Department of Medicine, Morehouse School of Medicine, Atlanta, Ga (Dr Akomolafe); the Departments of Biostatistics (Dr Beiser), Medicine [Genetics Program] (Dr Farrer), and Neurology (Drs Au, Green, Wolf, and Seshadri), Schools of Public Health and Medicine, Boston University, Boston, Mass; the General Medicine Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston (Dr Meigs); and the National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Mass.

Arch Neurol. 2006;63(11):1551-1555. doi:10.1001/archneur.63.11.1551
Abstract

Background  Diabetes mellitus (DM) could increase the risk of Alzheimer disease (AD) through several biologically plausible pathways, but the relationship between DM and the development of AD remains uncertain.

Objective  To compare the risk of developing AD in subjects with and without DM.

Design  Prospective community-based cohort study.

Participants  Framingham Study Original cohort participants who were dementia free and attended the 16th biennial examination (n = 2210 persons, 1325 women; mean age, 70 years).

Main Outcome Measures  Relative risk of incident AD (criteria from the National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders Association) associated with baseline DM (casual plasma glucose ≥200 mg/dL [≥11.1 mmol/L] or use of insulin or a hypoglycemic drug) in overall group and within subgroups defined by apolipoprotein E genotype and plasma homocysteine levels; models were adjusted for age, sex, and cardiovascular risk factors.

Results  At baseline, 202 participants (9.1%) had DM. During the follow-up period (mean, 12.7 years; range, 1-20 years), 17 of 202 persons with DM (8.4%) and 220 of 2008 persons without DM (11.0%) developed AD, yielding a relative risk of 1.15 (95% confidence interval, 0.65-2.05). Among subjects without an apolipoprotein E ε4 allele or elevated plasma homocysteine levels, 44 of 684 persons (6.4%) developed AD; relative risk for AD comparing diabetic patients with nondiabetic patients was 2.98 (95% confidence interval, 1.06-8.39; P = .03). The effect was strongest in persons aged 75 years or older with a relative risk of 4.77 (95% confidence interval, 1.28-17.72; P = .02).

Conclusion  Diabetes mellitus did not increase the risk of incident AD in the Framingham cohort overall; however, DM may be a risk factor for AD in the absence of other known major AD risk factors.

Diabetes mellitus (DM) has been associated with cognitive decline,18 anatomical measures of brain aging (whole-brain atrophy and hippocampal atrophy),911 and with an increased risk of stroke and vascular dementia (VaD).1216 The relationship between DM and Alzheimer disease (AD) is less clear; while some prior studies did find an association,1,1720 others did not.13,14,21,22 The varying results may be due to differences in the age, ethnicity, sex, and risk factor profile of different study populations; variations in the study designs, criteria used to define DM, dementia, VaD, and AD; and varying lengths of follow-up. Prior studies relating DM to the risk of AD have either had a relatively short follow-up period of less than 6 years or substantial loss to follow-up.12

We had previously observed that the risk of developing dementia following stroke was greatest in younger, apolipoprotein E (APOE) ε4–negative participants, that is, in persons at the lowest a priori risk of developing dementia.23 Furthermore, insulin resistance increased the risk of developing AD only among persons who were APOE ε4 negative.24 We hypothesized that the association between DM and AD would also be best demonstrated in a long-term follow-up of subjects without other major known risk factors for AD (APOE ε4 genotype and an elevated plasma homocysteine [tHcy] level).

METHODS

Framingham Original cohort participants (n = 2611) were enrolled in a dementia-free cohort between 1976 and 1978, based on their performance on a standardized neuropsychological test battery,25 subsequent biennial Mini-Mental State Examinations,26 and, in persons suspected to have cognitive impairment, further evaluations by a neurologist. At the 16th biennial examination (1979-1982), 2210 participants (1325 women; mean age 70 ± 7.0 years) from this cohort remained free of dementia and attended the examination; they constituted our study sample. Informed consent was obtained from all participants using a consent form approved by the Institutional Review Board at the Boston University School of Medicine.

DIAGNOSIS OF INCIDENT DEMENTIA, AD, AND VaD

Methods used for dementia screening and follow-up have been previously described.27,28 Participants identified as demented met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria29 and had definite dementia (Clinical Dementia Rating scale score ≥1)30 for a period of 6 months or longer. Participants diagnosed with AD met National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders Association criteria for definite or probable AD,31 while those with VaD met Alzheimer Disease Diagnostic and Treatment Center criteria for probable VaD.32 Persons with more than 1 possible cause for their dementia were included only in the all-dementia analysis.

DIAGNOSIS OF DM

We defined DM as the documented use of insulin or an oral hypoglycemic drug or a casual (nonfasting) plasma glucose level greater than or equal to 200 mg/dL (11.1 mmol/L), recorded at the 16th biennial examination or at an earlier examination.33

DEFINITION OF COVARIATES

The APOE genotype data were available for only 1139 persons (51%), as other participants either died before DNA could be collected for genotyping, or they refused consent.34 Participants were dichotomized into those with and those without an APOE ε4 allele. Information on all other covariates—plasma tHcy levels (dichotomized as within or below the top age and sex quartile), educational status (dichotomized at high school completion), current cigarette smoking, alcohol intake (0, <2, or ≥2 drinks per day), systolic blood pressure, body mass index, baseline cardiovascular disease, and stroke—was available for most participants.

STATISTICAL ANALYSIS

In our primary analysis, the exposure variable was the presence or absence of DM at the 16th biennial examination, which we related to the subsequent development of all-cause dementia, AD, and VaD (until December 2003) using Cox proportional hazards regression models (age- and sex-adjusted, and multivariable models). Alzheimer disease and VaD were treated as competing risks. In subjects for whom APOE genotype data were available, we further adjusted for APOE ε4 status. We examined effect modification by age, sex, baseline blood pressure, diabetes treatment, a priori risk status, and availability of APOE ε4 genotyping by incorporating corresponding interaction terms in the analyses. We further estimated the risks of developing all dementia and AD within subgroups of subjects at a lower a priori risk of developing dementia and AD. In secondary analyses we modeled diabetes as a time-dependent covariate. All statistical analyses were performed using SAS software (SAS Institute, Cary, NC).

RESULTS

At baseline, 202 (9.1%) of the 2210 study participants had DM; 98 subjects (4.4%) had a documented blood glucose level greater than 198 mg/dL (11 mmol/L), and 176 subjects (8%) were receiving insulin or oral hypoglycemic drugs. Demographic and baseline characteristics of the diabetic and nondiabetic subjects are compared in Table 1.

During a 20-year follow-up period (range, 1-20 years; mean, 12.7 years), 319 of the 2210 participants became demented (237 had definite or probable AD; 32 had probable VaD). Low-risk subjects who did not have either a plasma tHcy level in the top quartile or an APOE ε4 gene had a relative risk (RR) for AD of 0.32 (95% confidence interval, 0.23-0.47; P<.001), and very low-risk subjects with these traits who were also aged less than 75 years had a RR for AD of 0.24 (95% confidence interval, 0.15-0.39; P<.001), compared with all subjects.

Using either the standard or the time-dependent Cox models, we found that overall, DM did not increase the risk of all-cause dementia and AD, but in the standard Cox models, there was an increased risk in the subgroup of low-risk and very low-risk subjects (Table 2). This difference in risk was seen throughout the period of follow-up (Figure 1 and Figure 2). We found effect modification by age (higher risk in younger subjects; P<.05) and a priori risk status, but did not find effect modification by sex, diabetes treatment, baseline blood pressure, or availability of APOE genotyping.

Our numbers are too small to permit a definitive conclusion regarding the risk of developing VaD.

COMMENT

Diabetes mellitus was not an independent risk factor for AD in the overall Framingham Study sample, but it was a strong independent risk factor for AD among persons at a relatively lower initial risk for developing the disease (those who were APOE ε4 negative and did not have a plasma tHcy level in the highest age- and sex-specific quartile), raising the RR for AD by 3- to 5- fold in this group. The RR was greatest in younger subjects (<75 years of age) in whom the population-attributable risk from DM was 25%. Our findings suggest that an influence of DM on AD risk may be evident in subgroups of study populations in which there is no evidence for an overall association between these traits.

The strengths of our study are its community-based sample, prospective study design, and the direct ascertainment of exposure and outcome status. Selection bias was minimized by population enrollment well before the onset of diabetes or dementia, and intensive, ongoing follow-up of survival and cognitive status. The ongoing determination of diabetic status at each biennial examination, starting well before the onset of dementia, minimized the possibility of an ascertainment bias. Finally, subjects were observed for up to 2 decades.

An important limitation is the predominantly white study population. Further, we used casual (nonfasting) rather than fasting blood glucose levels and hence, we may have misclassified patients with impaired glucose tolerance as nondiabetic, which would bias the results of our overall and subgroup analyses toward the null hypothesis, but would not explain our findings of increased risk in some subgroups.

Our findings are consistent with the results of several prior studies,13,14,17,21,22 which either did not show an association between DM and the subsequent risk of developing AD or described such an association only in specific subgroups (men, persons with systolic blood pressure >180 mm Hg, or APOE ε4 genotype positive) .13,17,19 They differ from the findings of a few large population-based studies that did report an overall association.1,18,20,35 One possible explanation for this discrepancy is variation in the definition and prevalence of DM between the studies.

We found that the RR of developing AD attributable to DM was highest in subjects without the 3 known AD risk factors: a tHcy level in the top quartile, an APOE ε4 gene, or age 75 years or older. No prior studies have addressed the risk in this specific subgroup, but a higher RR of AD associated with DM has been described in subjects younger than 75 years compared with subjects older than 85 years.18 The Kungsholmen project13 reported no interaction between DM and the APOE ε4 genotype, while the Honolulu-Asia Aging study19 observed a higher RR among diabetic patients with an APOE ε4 genotype. These differences could be due to chance or differences in ethnicity and sex distribution in the populations. Prior studies have suggested that the brains of AD subjects without an APOE ε4 gene may be more susceptible to the adverse effects of hyperinsulinemia; this provides a possible biological rationale for our epidemiological findings.36

There are several biologically plausible, nonvascular pathways that could mediate an association between DM and AD. Diabetes mellitus promotes the formation of advanced glycation end products,37 inflammation,38 and neurofibrillary tangle formations.39 Insulin resistance and the resulting hyperinsulinemia appear to increase the risk of AD.40 Finally, common genetic pathways may underlie the development of both DM and AD; as one example, mutations in the insulin-degrading enzyme that induce DM41 also impair the degradation of β-amyloid protein.42

Our findings emphasize the need to consider DM as a potential risk factor for cognitive impairment, dementia, and AD. The utility of cognitive testing and improved diabetic control in reducing the risk of AD in persons with diabetes need to be addressed in further studies.

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Article Information

Correspondence: Sudha Seshadri, MD, Department of Neurology, Boston University School of Medicine, 715 Albany St, B-608, Boston, MA 02118-2526 (suseshad@bu.edu).

Accepted for Publication: May 24, 2006.

Author Contributions: Drs Beiser and Seshadri had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Akomolafe, Beiser, Green, Wolf, and Seshadri. Acquisition of data: Beiser, Au, Wolf, and Seshadri. Analysis and interpretation of data: Beiser, Meigs, Green, Farrer, Wolf, and Seshadri. Drafting of the manuscript: Akomolafe, Green, and Seshadri. Critical revision of the manuscript for important intellectual content: Beiser, Meigs, Au, Green, Farrer, Wolf, and Seshadri. Statistical analysis: Beiser and Farrer. Obtained funding: Akomolafe, Meigs, and Wolf. Administrative, technical, and material support: Au, Farrer, Wolf, and Seshadri. Study supervision: Au, Green, Farrer, and Seshadri.

Financial Disclosure: None reported.

Funding/Support: Supported by the National Heart, Lung, and Blood Institute's Framingham Heart Study (NIH/NHLBI Contract #N01-HC-25195) and grants from the National Institute of Neurological Disorders and Stroke (5R01-NS17950), the National Institute of Aging (5R01-AG08122, 5R01-AG16495, 3R01-AG09029), and the Boston University Alzheimer Disease Center (P30 AG13846). Dr Meigs is supported by an American Diabetes Association Career Development Award.

References
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Arvanitakis  ZWilson  RSBienias  JLEvans  DABennett  DA Diabetes mellitus and risk of Alzheimer disease and decline in cognitive function. Arch Neurol 2004;61661- 666
PubMedArticle
2.
Elias  PKElias  MFD'Agostino  RB  et al.  NIDDM and blood pressure as risk factors for poor cognitive performance: The Framingham Study. Diabetes Care 1997;201388- 1395
PubMedArticle
3.
Fontbonne  ABerr  CDucimetiere  PAlperovitch  A Changes in cognitive abilities over a 4-year period are unfavorably affected in elderly diabetic subjects: results of the Epidemiology of Vascular Aging Study. Diabetes Care 2001;24366- 370
PubMedArticle
4.
Gregg  EWYaffe  KCauley  JA  et al.  Is diabetes associated with cognitive impairment and cognitive decline among older women? Study of Osteoporotic Fractures Research Group. Arch Intern Med 2000;160174- 180
PubMedArticle
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Knopman  DBoland  LLMosley  T  et al.  Cardiovascular risk factors and cognitive decline in middle-aged adults. Neurology 2001;5642- 48
PubMedArticle
6.
Yaffe  KBlackwell  TKanaya  AMDavidowitz  NBarrett-Connor  EKrueger  K Diabetes, impaired fasting glucose, and development of cognitive impairment in older women. Neurology 2004;63658- 663
PubMedArticle
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Logroscino  GKang  JHGrodstein  F Prospective study of type 2 diabetes and cognitive decline in women aged 70-81 years. BMJ 2004;328548
PubMedArticle
8.
Elias  MFElias  PKSullivan  LMWolf  PAD'Agostino  RB Obesity, diabetes and cognitive deficit: The Framingham Heart Study. Neurobiol Aging 2005;26(Suppl 1)11- 16
PubMedArticle
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Araki  YNomura  MTanaka  H  et al.  MRI of the brain in diabetes mellitus. Neuroradiology 1994;36101- 103
PubMedArticle
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den Heijer  TVermeer  SEvan Dijk  EJ  et al.  Type 2 diabetes and atrophy of medial temporal lobe structures on brain MRI. Diabetologia 2003;461604- 1610
PubMedArticle
11.
Schmidt  RLauner  LJNilsson  LG  et al.  Magnetic resonance imaging of the brain in diabetes: the Cardiovascular Determinants of Dementia (CASCADE) Study. Diabetes 2004;53687- 692
PubMedArticle
12.
Schnaider Beeri  MGoldbourt  USilverman  JM  et al.  Diabetes mellitus in midlife and the risk of dementia three decades later. Neurology 2004;631902- 1907
PubMedArticle
13.
Xu  WLQiu  CXWahlin  AWinblad  BFratiglioni  L Diabetes mellitus and risk of dementia in the Kungsholmen project: a 6-year follow-up study. Neurology 2004;631181- 1186
PubMedArticle
14.
Hassing  LBJohansson  BNilsson  SE  et al.  Diabetes mellitus is a risk factor for vascular dementia, but not for Alzheimer's disease: a population-based study of the oldest old. Int Psychogeriatr 2002;14239- 248
PubMedArticle
15.
Luchsinger  JATang  MXStern  YShea  SMayeux  R Diabetes mellitus and risk of Alzheimer's disease and dementia with stroke in a multiethnic cohort. Am J Epidemiol 2001;154635- 641
PubMedArticle
16.
Haan  MNMungas  DMGonzalez  HMOrtiz  TAAcharya  AJagust  WJ Prevalence of dementia in older latinos: the influence of type 2 diabetes mellitus, stroke and genetic factors. J Am Geriatr Soc 2003;51169- 177
PubMedArticle
17.
Leibson  CLRocca  WAHanson  VA  et al.  Risk of dementia among persons with diabetes mellitus: a population-based cohort study. Am J Epidemiol 1997;145301- 308
PubMedArticle
18.
Ott  AStolk  RPvan Harskamp  FPols  HAHofman  ABreteler  MM Diabetes mellitus and the risk of dementia: The Rotterdam Study. Neurology 1999;531937- 1942
PubMedArticle
19.
Peila  RRodriguez  BLLauner  LJ Type 2 diabetes, APOE gene, and the risk for dementia and related pathologies: The Honolulu-Asia Aging Study. Diabetes 2002;511256- 1262
PubMedArticle
20.
Brayne  CGill  CHuppert  FA  et al.  Vascular risks and incident dementia: results from a cohort study of the very old. Dement Geriatr Cogn Disord 1998;9175- 180
PubMedArticle
21.
MacKnight  CRockwood  KAwalt  EMcDowell  I Diabetes mellitus and the risk of dementia, Alzheimer's disease and vascular cognitive impairment in the Canadian Study of Health and Aging. Dement Geriatr Cogn Disord 2002;1477- 83
PubMedArticle
22.
Yoshitake  TKiyohara  YKato  I  et al.  Incidence and risk factors of vascular dementia and Alzheimer's disease in a defined elderly Japanese population: the Hisayama Study. Neurology 1995;451161- 1168
PubMedArticle
23.
Ivan  CSSeshadri  SBeiser  A  et al.  Dementia after stroke: the Framingham Study. Stroke 2004;351264- 1268
PubMedArticle
24.
Kuusisto  JKoivisto  KMykkanen  L  et al.  Association between features of the insulin resistance syndrome and Alzheimer's disease independently of apolipoprotein E4 phenotype: cross sectional population based study. BMJ 1997;3151045- 1049
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