Elsevier

The Lancet Neurology

Volume 5, Issue 1, January 2006, Pages 64-74
The Lancet Neurology

Review
Risk of dementia in diabetes mellitus: a systematic review

https://doi.org/10.1016/S1474-4422(05)70284-2Get rights and content

Summary

The relation between diabetes and major types of dementia is controversial. This systematic review examines the incidence of dementia in people with diabetes mellitus. We identified 14 eligible longitudinal population-based studies of variable methodological quality. The incidence of “any dementia” was higher in individuals with diabetes than in those without diabetes in seven of ten studies reporting this aggregate outcome. This high risk included both Alzheimer's disease and vascular dementia (eight of 13 studies and six of nine studies respectively). Detailed data on modulating and mediating effects of glycaemic control, microvascular complications, and comorbidity (eg, hypertension and stroke) were generally absent. The findings of mechanistic studies suggest that vascular disease and alterations in glucose, insulin, and amyloid metabolism underlie the pathophysiology, but which of these mechanisms are clinically relevant is unclear. Further high quality studies need to be initiated, with objective diabetes assessment, together with reliable methods to establish the contribution of vascular disease and other comorbidity to dementia.

Introduction

Diabetes mellitus is associated with changes in cognition. In type 1 diabetes mellitus this association is shown by a mild to moderate slowing of mental speed and a diminished mental flexibility.1 In type 2 diabetes cognitive changes mainly affect learning and memory, mental flexibility, and mental speed.2, 3, 4 Several large longitudinal population-based studies have shown that the rate of cognitive decline is accelerated in elderly people with type 2 diabetes.5 The determinants of this accelerated cognitive decline, however, are less clear;5 some researchers suggest that hypertension could be an important mediator,6 whereas others have found associations with glycaemic control.7

Although the association between diabetes and these modest changes in cognition is now well established, the relation between diabetes and dementia is an area of controversy. Early studies that reported a low rate of diabetes in patients with Alzheimer's disease,8, 9, 10 suggested that diabetes and Alzheimer's disease might not coexist.9 However, a more recent study suggested that type 2 diabetes or impaired fasting glucose might be present in up to 80% of patients with Alzheimer's disease.11 These opposing results clearly indicate that studies of the prevalence of diabetes in people with established dementia are unlikely to provide reliable data for the risk of dementia in individuals with diabetes. These differing outcomes may be the result of methodological issues, such as survival bias of non-diabetic patients with Alzheimer's disease and the possible effects of Alzheimer's disease itself on glucose metabolism,12 which might obscure the relation with diabetes in more advanced cases of dementia. Population-based studies that compare the incidence of dementia between patients with and without diabetes provide more reliable risk estimates than studies on patients with established dementia.

Both the absolute and relative numbers of elderly people who are affected by diabetes are expected to increase over the next few decades.13 Better insight into the strength and the nature of the association between diabetes and dementia is therefore of great importance.

In this article, we systematically review studies on the incidence of dementia in patients with diabetes mellitus to determine the strength of the association between diabetes and dementia. We also examined the extent to which researchers investigated potential modulators and mediators of the risk of dementia in people with diabetes. We discuss underlying mechanisms and relevant neuropathological and neuroradiological studies.

Section snippets

Identification of studies

Studies were identified by searches of MEDLINE (1966 to August, 2005) and EMBASE (1966 to August, 2005) with the search terms “diabet* AND Alzheim* OR dement*”. Searches were restricted to papers published in English and the Embase search was restricted to “human studies”. The bibliographies of relevant original and review articles were screened. This systematic review aimed to include all published studies that provide an estimate of the incidence of dementia among patients with diabetes

Study populations

The 14 study populations included participants of different ethnic origins: white, Hispanic, black, and, Asian. Further demographic details are presented in table 1. Most studies included both individuals living in institutions and those living at home in their baseline study sample. Recruitment varied among the studies from sampling within religious orders to true population sampling. The Rochester sample simply used the population denominator and the medical records associated with that

Discussion

This systematic review of population-based studies brings together the evidence that the risk of dementia is, in general, increased in patients with diabetes mellitus. This increased risk seems to include both Alzheimer's disease and vascular dementia—although the limitations of clinical diagnostic criteria in the classification of dementia by pathological subtype should be considered, especially in a complex disorder such as diabetes. Therefore, rather than focusing the discussion on which

Conclusion

There is convincing evidence that shows an increased risk of dementia in people with diabetes, but there are few detailed epidemiological data for risk factors. There are mechanistic studies that provide pathophysiological leads, but do not indicate which of these leads are clinically relevant. This gap in evidence between epidemiological and mechanistic studies needs to be closed. The risk factors and mechanisms that drive the association between diabetes and accelerated cognitive decline and

References (94)

  • JC de la Torre

    Critically attained threshold of cerebral hypoperfusion: the CATCH hypothesis of Alzheimer's pathogenesis

    Neurobiol Aging

    (2000)
  • K Gerozissis

    Brain insulin and feeding: a bi-directional communication

    Eur J Pharmacol

    (2004)
  • WA Banks

    The source of cerebral insulin

    Eur J Pharmacol

    (2004)
  • CA Bondy et al.

    Signaling by insulin-like growth factor 1 in brain

    Eur J Pharmacol

    (2004)
  • W Zhao et al.

    Role of insulin and insulin receptor in learning and memory

    Mol Cell Endocrinol

    (2001)
  • A Caccamo et al.

    Age- and region-dependent alterations in Abeta-degrading enzymes: implications for Abeta-induced disorders

    Neurobiol Aging

    (2005)
  • S Craft et al.

    Insulin and neurodegenerative disease: shared and specific mechanisms

    Lancet Neurol

    (2004)
  • L Gasparini et al.

    Potential roles of insulin and IGF-1 in Alzheimer's disease

    Trends Neurosci

    (2003)
  • DG Cook et al.

    Reduced hippocampal insulin-degrading enzyme in late-onset Alzheimer's disease is associated with the apolipoprotein E-epsilon4 allele

    Am J Pathol

    (2003)
  • AMA Brands et al.

    The effects of Type 1 diabetes on cognitive performance: a meta-analysis

    Diabetes Care

    (2005)
  • N Awad et al.

    The relationship between impaired glucose tolerance, type 2 diabetes, and cognitive function

    J Clin Exp Neuropsychol

    (2004)
  • R Stewart et al.

    Type 2 diabetes mellitus, cognitive impairment and dementia

    Diabet Med

    (1999)
  • MWJ Strachan et al.

    Is type II diabetes associated with an increased risk of cognitive dysfunction? A critical review of published studies

    Diabetes Care

    (1997)
  • LB Hassing et al.

    Comorbid type 2 diabetes mellitus and hypertension exacerbates cognitive decline: evidence from a longitudinal study

    Age Ageing

    (2004)
  • AM Kanaya et al.

    Change in cognitive function by glucose tolerance status in older adults: a 4-year prospective study of the Rancho Bernardo study cohort

    Arch Intern Med

    (2004)
  • KA Nielson et al.

    Apolipoprotein-E genotyping of diabetic dementia patients: is diabetes rare in Alzheimer's disease?

    J Am Geriatr Soc

    (1996)
  • G Bucht et al.

    Changes in blood glucose and insulin secretion in patients with senile dementia of Alzheimer type

    Acta Med Scand

    (1983)
  • GP Wolf-Klein et al.

    Are Alzheimer patients healthier?

    J Am Geriatr Soc

    (1988)
  • J Janson et al.

    Increased risk of type 2 diabetes in Alzheimer disease

    Diabetes

    (2004)
  • P Zimmet et al.

    Global and societal implications of the diabetes epidemic

    Nature

    (2001)
  • R Katzman et al.

    Development of dementing illnesses in an 80-year-old volunteer cohort

    Ann Neurol

    (1989)
  • T Yoshitake et al.

    Incidence and risk factors of vascular dementia and Alzheimer's disease in a defined elderly Japanese population: the Hisayama Study

    Neurology

    (1995)
  • CL Leibson et al.

    Risk of dementia among persons with diabetes mellitus: a population-based cohort study

    Am J Epidemiol

    (1997)
  • C Brayne et al.

    Vascular risks and incident dementia: results from a cohort study of the very old

    Dement Geriatr Cogn Disord

    (1998)
  • A Ott et al.

    Diabetes mellitus and the risk of dementia: the Rotterdam Study

    Neurology

    (1999)
  • JD Curb et al.

    Longitudinal association of vascular and Alzheimer's dementias, diabetes, and glucose tolerance

    Neurology

    (1999)
  • JA Luchsinger et al.

    Diabetes mellitus and risk of Alzheimer's disease and dementia with stroke in a multiethnic cohort

    Am J Epidemiol

    (2001)
  • LB Hassing 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)
  • R Peila et al.

    Type 2 diabetes, APOE gene, and the risk for dementia and related pathologies: the Honolulu-Asia Aging Study

    Diabetes

    (2002)
  • C MacKnight et al.

    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)
  • M Yamada et al.

    Association between dementia and midlife risk factors: the Radiation Effects Research Foundation Adult Health Study

    J Am Geriatr Soc

    (2003)
  • Z Arvanitakis et al.

    Diabetes mellitus and risk of Alzheimer disease and decline in cognitive function

    Arch Neurol

    (2004)
  • M Schnaider Beeri et al.

    Diabetes mellitus in midlife and the risk of dementia three decades later

    Neurology

    (2004)
  • WL Xu et al.

    Diabetes mellitus and risk of dementia in the Kungsholmen project: a 6-year follow-up study

    Neurology

    (2004)
  • JA Luchsinger et al.

    Aggregation of vascular risk factors and risk of incident Alzheimer disease

    Neurology

    (2005)
  • RA Whitmer et al.

    Midlife cardiovascular risk factors and risk of dementia in late life

    Neurology

    (2005)
  • R Hebert et al.

    Vascular dementia: incidence and risk factors in the Canadian Study of Health and Aging

    Stroke

    (2000)
  • Cited by (1717)

    View all citing articles on Scopus
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