Modifiable and clinically actionable exposures for vascular dementia: a structured evidence synthesis of Mendelian randomization studies.

backgroundVascular dementia (VaD) imposes a substantial global burden, yet prioritizing modifiable or clinically actionable exposures remains challenging due to confounding and reverse causation in observational studies. Mendelian randomization (MR) offers a genetic approach to strengthen causal inference, though current findings remain dispersed and difficult to interpret due to methodological heterogeneity. MAIN BODY: This structured evidence synthesis reviewed published primary MR studies evaluating modifiable or clinically actionable exposures relevant to VaD. We evaluated the interpretability and consistency of reported associations using a pragmatic evidence-prioritization framework (Tiers 1-3) that considers cross-estimator consistency, sensitivity analyses, and instrument strength to prioritize MR signals for further validation. The updated synthesis included 74 eligible primary MR studies, yielding 1002 method-specific MR estimates across multiple exposure domains. Higher-priority MR evidence was observed for cerebrovascular events, diabetes and hyperglycaemia, selected inflammatory and iron-handling markers, and neuropsychiatric traits including major depressive disorder and hearing loss. In contrast, MR evidence for several traditional risk factors, such as specific lipid fractions and blood pressure, was classified as Tier 2 or 3 due to inconsistent findings or heterogeneity, suggesting complex non-linear or time-dependent effects that differ from observational associations. SHORT

conclusionBy mapping heterogeneous MR findings onto an evidence-informed prioritization framework, this structured evidence synthesis distinguishes higher-priority MR signals from associations requiring further replication or mechanistic validation. This framework helps guide the prioritization of clinically relevant candidate signals for future mechanistic studies and informs the design of prevention strategies and clinical trials in vascular dementia.