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

## TL;DR

This study finds genetic evidence suggesting that certain drugs may increase the risk of specific types of dementia.

## Contribution

The novel use of two-sample Mendelian randomization provides causal insights into drug-dementia associations.

## Key findings

- Antithrombotic agents and HMG CoA reductase inhibitors are linked to dementia with Lewy bodies.
- Diuretics and calcium channel blockers may increase vascular dementia risk.
- Antihistamines show a causal effect on cognitive performance.

## Abstract

Observational studies have suggested a link between certain drugs and cognitive impairment. In this study, a two‐sample Mendelian randomization (MR) approach was used to investigate the causal relationship between drug use and different types of dementia.

We utilized summary data from genome‐wide association studies (GWAS) with populations of European ancestry. The primary analysis was conducted using inverse‐variance weighted (IVW) methods; MR Egger, weighted median, and weighted model methods were used to validate the results. Horizontal pleiotropy and outlier detection were assessed via MR Egger and MR‐PRESSO, respectively; Cochran's Q test evaluated heterogeneity, whereas leave‐one‐out analyses were used to evaluate the presence of predominant instrumental variables (IVs). Statistical power was calculated using the online tool mRnd to assess the robustness of MR estimates.

The IVW analysis indicated that antithrombotic agents (odds ratio [OR] = 2.12, 95% confidence interval [CI] = 1.03–4.34, p = 0.04), HMG CoA reductase inhibitors (OR = 1.36, 95% CI = 1.07–1.72, p = 0.01), and salicylic acid and derivatives (OR = 2.77, 95% CI = 1.44–5.32, p = 0.002) are a strong risk factor for dementia with Lewy bodies (DLB); diuretics (OR = 1.13, 95% CI = 1–1.27, p = 0.047) and calcium channel blockers (OR = 1.16, 95% CI = 1.04–1.29, p = 0.007) might be a risk factor for vascular dementia; thyroid preparations (OR = 1.03, 95% CI = 1.01–1.06, p = 0.01), diuretics (OR = 1.06, 95% CI = 1.02–1.11, p = 0.004), and immunosuppressants (OR = 1.07, 95% CI = 1.01–1.12, p = 0.001), are a risk factor for frontotemporal dementia; HMG CoA reductase inhibitors is a risk factor for dementia in Alzheimer disease (OR = 1.32, 95% CI = 1.05–1.65, p = 0.01). Moreover, antihistamines for systemic use showed some causal effect on cognitive performance (p < 0.05). The MR‐Egger regression indicated that results were unaffected by horizontal pleiotropy. Moreover, no heterogeneity was detected. However, power analyses revealed that several associations had relatively low statistical power, suggesting that these findings should be interpreted with caution.

Our findings suggest that certain drugs may causally affect dementia. Larger, well‐designed MR studies may help establish the causal status of these dementia risk factors.

The schematic diagram illustrates the overall design of this two‐sample Mendelian randomization (MR) study investigating the causal association between drug use and cognitive impairment. Genetic variants significantly associated with drug use were selected as instrumental variables from large‐scale GWAS datasets. These variants were then used to estimate their causal effects on cognitive impairment through multiple MR analytical methods. The findings provide genetic evidence supporting a potential causal relationship between specific drug use and cognitive impairment risk.