Causal pathways linking type 2 diabetes and glycemic traits to cerebrovascular outcomes: a comprehensive Mendelian randomization analysis

Type 2 diabetes (T2D) and impaired glycemic traits demonstrate well-established epidemiological associations with dementia and cerebrovascular disease. However, the nature of these relationships—whether causal or confounded—remains incompletely elucidated, limiting targeted prevention strategies.

This investigation employed multivariable Mendelian randomization to: (1) determine the causal effects of T2D and glycemic traits on dementia subtypes and cerebrovascular outcomes, and (2) delineate the potential mediating role of cerebrovascular injury in the diabetes-dementia pathway.

We implemented a two-sample MR framework utilizing genetic instruments from genome-wide association studies of European-ancestry populations for T2D, hemoglobin A1c (HbA1c), fasting glucose, fasting insulin, and 2-hour glucose. Primary analyses employed inverse-variance weighted multivariable MR, with comprehensive sensitivity analyses including MR-Egger and weighted median methods. Outcome measures encompassed all-cause dementia, Alzheimer's disease, vascular dementia, cerebrospinal fluid biomarkers (amyloid-β₁₋₄₂, phosphorylated tau, total tau), cerebral white matter hyperintensity volume, and ischemic stroke subtypes.

Genetic predisposition to T2D demonstrated robust causal effects on ischemic stroke (OR 1.14, 95% CI 1.11-1.17; p<0.001) and lacunar stroke (OR 1.15, 95% CI 1.09-1.22; p<0.001), with consistent results across sensitivity analyses. HbA1c exhibited significant causal association with Alzheimer's disease (OR 1.39, 95% CI 1.03-1.66; p=0.032). Fasting glucose (OR 1.23, 95% CI 1.03-1.47; p=0.021) and fasting insulin (OR 1.46, 95% CI 1.05-2.02; p=0.024) demonstrated causal effects on ischemic stroke, while 2-hour glucose predicted lacunar stroke risk (OR 1.24, 95% CI 1.01-1.52; p=0.038). Notably, no direct causal effects were observed between T2D and dementia outcomes after accounting for cerebrovascular mediators.

This genetic evidence suggests that the relationship between diabetes and cognitive impairment operates predominantly through cerebrovascular pathways rather than direct neurodegenerative mechanisms. These findings underscore the critical importance of glycemic control and vascular risk factor management in preserving brain health, positioning cerebrovascular protection as a key strategic target for dementia prevention in diabetic populations.