We performed a systematic review and meta-analysis to explore whether type 2 diabetes mellitus (T2DM) increases the risk of Alzheimer's disease (AD). We also reviewed interactions with smoking, hypertension, and apolipoprotein E ɛ4. Using a series of databases (MEDLINE, EMBASE, PubMed, Current Contents Connect, and Google Scholar), we identified a total of 15 epidemiologic studies. Fourteen studies reported positive associations, of which 9 were statistically significant. Risk estimates ranged from 0.83 to 2.45. The pooled adjusted risk ratio was 1.57 (95% confidence interval: 1.41, 1.75), with a population-attributable risk of 8%. Smoking and hypertension, when comorbid with T2DM, had odds of 14 and 3, respectively. Of the 5 studies that investigated the interaction between T2DM and apolipoprotein E ɛ4, 4 showed positive associations, of which 3 were significant, with odds ranging from 2.4 to 4.99. The pooled adjusted risk ratio was 2.91 (95% confidence interval: 1.51, 5.61). Risk estimates were presented in the context of a key confounder-cerebral infarcts-which are more common in those with T2DM and might contribute to the manifestation of clinical AD. We provide evidence from clinico-neuropathologic studies that demonstrates the following: First, cerebral infarcts are more common than AD-type pathology in those with T2DM and dementia. Second, those with dementia at postmortem are more likely to have both AD-type and cerebrovascular pathologies. Finally, cerebral infarcts reduce the number of AD lesions required for the manifestation of clinical dementia, but they do not appear to interact synergistically with AD-type pathology. Therefore, the increased risk of clinically diagnosed AD seems to be mediated through cerebrovascular pathology.

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