Association of antihypertensive drug target genes with alzheimer's disease: a mendelian randomization study

Background: Epidemiological and genetic studies have elucidated associations between antihypertensive medication and Alzheimer's disease (AD), with the directionality of these associations varying upon the specific class of antihypertensive agents.

Methods: Genetic instruments for the expression of antihypertensive drug target genes were identified using expression quantitative trait loci (eQTL) in blood, which are associated with systolic blood pressure (SBP). Exposure was derived from existing eQTL data in blood from the eQTLGen consortium and in the brain from the PsychENCODE and subsequently replicated in GTEx V8 and BrainMeta V2. We performed two-sample Mendelian randomization (MR) to estimate the potential effect of different antihypertensive drug classes on AD using summary statistics from a meta-analysis (111,326 cases and 677,663 controls) and further replicated in FinnGen cohorts (9301 cases and 367,976 controls). The reverse causality detection, assessing horizontal pleiotropy, Bayesian co-localization, phenotype scanning, and protein quantitative trait loci (pQTL) analysis were implemented to consolidate the MR findings further.

Results: A 1-standard deviation (SD) lower expression of the angiotensin-converting enzyme (ACE) gene in blood was associated with a lower SBP of 3.92 (95% confidence interval (CI), 2.69-5.15) mmHg but an increased risk of AD (odds ratio (OR), 2.46; 95% CI, 1.82-3.33). A similar direction of association was also observed between ACE expression in prefrontal cortex (OR, 1.19; 95% CI, 1.10-1.28), frontal cortex (OR, 1.19; 95% CI, 1.11-1.27), cerebellum (OR, 1.13; 95% CI, 1.09-1.17), cortex (OR, 1.59; 95% CI, 1.33-1.28) and ACE protein levels in plasma (OR, 1.13; 95% CI, 1.09-1.17) and AD risk. Colocalization supports these results. Similar results were found in external validation. We found no evidence for an association between genetically estimated blood pressure (BP) and AD risk.

Conclusions: There findings suggest an adverse association of lower ACE messenger RNA and protein levels with an elevated risk of AD, irrespective of its BP-lowering effects. These findings warrant greater pharmacovigilance and further investigation into the effect of ACE inhibitors, particularly those that are centrally acting, on neurodegenerative symptoms in patients with AD.