Type 2 Diabetes as a Risk Factor for Alzheimer's Disease: The Confounders, Interactions, and Neuropathology Associated With This Relationship

Abstract

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.

Metabolic Risk Factors of Sporadic Alzheimer's Disease: Implications in the Pathology, Pathogenesis and Treatment

“…A mean follow-up study of 5.5 years for a population of 1138 persons has shown that diabetes is a strong risk factor for AD (hazard ratio 2.4) and the risk is further augmented when other risk factors like hypertension, heart disease and smoking are simultaneously present [86]. Several meta-analysis studies from published literature have estimated an aggregated relative risk of approximately 1.5 linking type 2 diabetes with AD, and the relative risk increases considerably by the presence of hypertension, smoking and APOE4 positivity [87,88,89,90]. A population based cross-sectional study has also shown the significant association of hyperglycemia and hyperinsulinemia with AD independent of APOE4 status [91].…”

“…Neuropathological autopsy studies do not support that type 2 diabetes predisposes to development of AD pathology in the brain of aged persons when compared to age-matched controls [95]. Several epidemiological studies also have examined a proportion of their study cohorts at autopsy for neuropathological changes typical of AD and concluded that type 2 diabetes does not promote AD pathology in the brain and instead vascular pathologies in brain are more commonly associated with type 2 diabetes [89,96]. While the controversy is persisting between epidemiological findings and neuropathological observations in relating type 2 with AD, in experimental AD research insulin and insulin resistance have been linked to AD pathogenesis in multiple ways.…”

The diabetic brain and cognition

“…Some autopsy studies stated that patients with DM have significantly less AD pathology but more frequent cerebrovascular lesions including microvascular changes (Alafuzoff et al 2009;Beeri et al 2005;Nelson et al 2009;Ahtiluoto et al 2010) or both types of cerebral pathology (Alafuzoff et al 2009;Vagelatos and Eslick 2013;Ahtiluoto et al 2010;Takeda et al 2011;Verdile et al 2015), and white matter lesions (Jellinger 2015a, b). The increased risk of cognitive decline in elderly subjects with DM is due to dual pathology, involving both the CVD and cortical atrophy (Biessels et al 2006a, b;Umegaki 2012).…”

“…A causative association between diabetes mellitus (DM) and cognitive impairment has been suggested based on clinical, epidemiological, and experimental studies (Alafuzoff et al 2009;Bitel et al 2012;Vagelatos and Eslick 2013;Carvalho et al 2015;Feinkohl et al 2015;Jellinger 2015a). In fact, recent studies demonstrate a pathophysiological link between diabetes mellitus type II (T2DM) and cognitive decline (Jellinger 2015b).…”

Dieta mediterránea y sus efectos benéficos en la prevención de la enfermedad de Alzheimer

“…Los factores modificables engloban a las enfermedades cardio-metabólicas como la diabetes mellitus tipo 2 (DM II), el síndrome metabólico (SM), dislipidemia, hipertensión arterial y la obesidad, ésta última relacionada con el sedentarismo, falta de actividad física y una dieta no equilibrada [14][15][16] .…”