Diabetes Mellitus Increases Risk of Incident Dementia in APOE ϵ4 Carriers: A Meta-Analysis

Background: Dementia is a devastating condition for older adults, with both modifiable (e.g., diabetes mellitus) and unmodifiable risk factors (e.g., APOE ϵ4 allele). It remains unclear how, and to what extent, diabetes impacts dementia risk via both cerebrovascular and amyloid-β pathways. Objective: We conducted a quantitative meta-analysis to investigate the contribution of diabetes to incident dementia risk in people with ϵ4 and, based on the vascular-related neuropathology of diabetes, whether the combination of these factors increases risk for vascular dementia versus Alzheimer's disease (AD). Methods: Systematic literature searches were conducted using EMBASE, MEDLINE, PsycINFO, and CINAHL databases. Pooled relative risk (RR) estimates were calculated using a random effects model, and subgroup analyses conducted across dementia subtypes. Results: Twelve studies were included, with a total of 16,200 participants. Considered concurrently, diabetes increased incident dementia risk an additional 35% for those with ϵ4 (RR=1.35, 95% CI=1.13-1.63). Similar patterns were observed for AD and vascular dementia. Conclusion: Interventions to prevent co-morbid diabetes, and diabetes-related complications and neuropathological changes, may be one way of modifying dementia risk in the vulnerable ϵ4 population.