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Evaluating the Bidirectional Causal Effects of Alzheimer’s Disease Across Multiple Conditions: A Systematic Review and Meta-Analysis of Mendelian Randomization Studies

Haoning Zhu,Huitong Ni,Qiuling Yang,Jiaqi Ni,Jianguang Ji,Shu Yang,Fu Peng

Published 2025 in International Journal of Molecular Sciences

ABSTRACT

This study systematically evaluates and meta-analyzes Mendelian randomization studies on the bidirectional causal relationship between Alzheimer’s disease (AD) and systemic diseases. We searched five databases, assessed study quality, and extracted data. Diseases were classified using ICD-11, and the meta-analysis was performed with RevMan 5.4. A total of 56 studies identified genetic links between AD susceptibility and systemic diseases. Notably, genetic proxies for hip osteoarthritis (OR = 0.80; p = 0.007) and rheumatoid arthritis (OR = 0.97; p = 0.004) were inversely associated with AD risk, while gout (OR = 1.02; p = 0.049) showed a positive association. Genetic liability to depression (OR = 1.03; p = 0.001) elevated AD risk, and AD genetic risk increased susceptibility to delirium (OR = 1.32; p = 0.0005). Cardiovascular traits, including coronary artery disease (OR = 1.07; p = 0.021) and hypertension (OR = 4.30; p = 0.044), were causally linked to a higher AD risk. Other conditions, such as insomnia, chronic periodontitis, migraine, and certain cancers, exhibited significant genetic correlations. Intriguingly, herpes zoster (OR = 0.87; p = 0.005) and cataracts (OR = 0.96; p = 0.012) demonstrated inverse genetic associations with AD. These findings suggest potential therapeutic targets and preventive strategies, emphasizing the need to address comorbid systemic diseases to reduce AD risk and progression.

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