A drug-target Mendelian randomization (MR) analysis indicated adverse neurocognitive effects related to statins but not proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition. Data were from a combined sample of ∼740,000 participants in predominantly European ancestry-based genome-wide association cohort studies. There was a neutral cognitive profile related to genetic PCSK9 inhibition, with no significant effects on cognitive and memory performance, or cortical surface area. Conversely, there were several adverse associations for 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) inhibition with lowered cognitive performance (beta: –0.082; P = 0.03), reaction time (beta = 0.00064; P = 0.0002), and cortical surface area (beta = –0.18; P = 0.03). Neither PCSK9 nor HMGCR inhibition impacted biomarkers of Alzheimer’s disease progression or Lewy body dementia risk. Consistency of findings across MR methods accommodating different assumptions about genetic pleiotropy strengthens causal inference. The findings provide genetic evidence for alleviating ongoing concern regarding the neurocognitive safety of PCSK9 inhibitors. The slight adverse effects of HMGCR inhibition on neurocognition do not outweigh the cardiovascular benefits of statin use. Source:https://www.jacc.org/
