Evidence for Causal Links Between Known Modifiable Risk Factors and Dementia: A Systematic Review of Mendelian
Roopal Desai1, Amber John1, Emma Anderson2
1ADAPT Lab, Research Department of Clinical Educational and Health Psychology, University College London, London, UK.
European Journal of Neurology
|December 4, 2025
Summary
Mendelian randomization studies show limited evidence for most dementia risk factors. However, probable causal links exist for lower educational attainment and type 2 diabetes, with smoking showing a protective effect.
Area of Science:
- Neuroscience
- Genetics
- Epidemiology
Background:
- Dementia is a growing global health concern.
- Identifying modifiable risk factors is crucial for prevention.
- Mendelian randomization (MR) offers a powerful tool to investigate causality.
Purpose of the Study:
- To systematically review MR evidence linking modifiable risk factors to dementia.
- To assess the strength of evidence for 12 risk factors identified by the Lancet Commission.
Main Methods:
- Comprehensive search of five databases up to April 2024.
- Categorization of MR analyses (robust, probable, suggestive, insufficient).
- Separate synthesis of clinically diagnosed dementia and proxy outcomes.
Main Results:
- 47 studies included, evaluating 240 MR associations.
- Insufficient evidence for causality in over 73% of analyses.
- Probable evidence for protective educational attainment and risk from type 2 diabetes; smoking showed probable protective association.
Conclusions:
- MR evidence for most dementia risk factors is insufficient or inconclusive.
- Lower educational attainment and type 2 diabetes show the most consistent causal support.
- Null findings require cautious interpretation due to methodological limitations.
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