A Causal Association Between Drug Use and Cognitive Impairment: A Two-Sample Mendelian Randomization Study

Area of Science:

• Pharmacogenomics
• Neurodegenerative Diseases
• Epidemiology

Background:

• Observational studies suggest a link between drug use and cognitive impairment.
• Investigating causal relationships requires robust methodologies beyond observational data.

Purpose of the Study:

• To investigate the potential causal relationship between the use of specific drugs and the risk of developing different types of dementia.
• To leverage genetic data for a Mendelian randomization approach to infer causality.

Main Methods:

• Utilized two-sample Mendelian randomization (MR) with genome-wide association study (GWAS) summary data from European ancestry populations.
• Employed inverse-variance weighted (IVW) methods for primary analysis, validated by MR Egger, weighted median, and weighted mode methods.
• Assessed pleiotropy, heterogeneity, and outlier effects using MR Egger, MR-PRESSO, Cochran's Q test, and leave-one-out analyses; calculated statistical power using mRnd.

Main Results:

• Antithrombotic agents, HMG CoA reductase inhibitors (statins), and salicylates were associated with increased dementia with Lewy bodies (DLB) risk.
• Diuretics and calcium channel blockers showed potential links to vascular dementia; thyroid preparations, diuretics, and immunosuppressants were associated with frontotemporal dementia.
• HMG CoA reductase inhibitors were also linked to dementia in Alzheimer's disease, and antihistamines showed effects on cognitive performance; results were generally robust to pleiotropy and heterogeneity but had limited statistical power.

Conclusions:

• Specific drug classes, including antithrombotic agents, statins, and diuretics, may have a causal impact on dementia development.
• Findings suggest a potential drug-induced component to dementia risk, warranting cautious interpretation due to statistical power limitations.
• Larger, well-designed MR studies are recommended to further elucidate the causal status of these drug-dementia associations.