Although proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition and statin-based lipid-lowering medication are effective methods for lowering the risk of cardiovascular disease, worries regarding potential long-term negative neurocognitive consequences persist. For a genetics-based study, researchers sought to assess the effects of long-term statin usage and PCSK9 inhibition on neurocognitive outcomes.

They performed drug-target Mendelian randomization and extracted single-nucleotide polymorphisms in 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) and PCSK9 from primarily European ancestry-based genome-wide association studies summary-level statistics of low-density lipoprotein cholesterol. They then proxied the potential neurocognitive impact of drug-based PCSK9 and HMGCR inhibition using a range of outcomes to capture the complex facets of cognition and dementia.

They found a neutral cognitive profile associated with genetic PCSK9 inhibition, with no significant impacts on cognitive function, memory function, or cortical surface area, using data from a pooled sample of about ∼740,000 persons. Contrarily, we found a number of negative correlations between HMGCR inhibition and worse cognition (beta: -0.082; 95% CI: -0.16 to -0.0080; P=0.03), reaction time (beta: 0.00064; 95% CI: 0.00030-0.00098; P=0.0002), and cortical surface area (beta: -0.18; 95% CI: -0.35 to -0.014 P=0.03). Inhibition of PCSK9 or HMGCR had no effect on risk factors for Lewy body dementia or the course of Alzheimer’s disease. Strengthening causal inference was the consistency of results across Mendelian randomization approaches tolerating various genetic pleiotropy assumptions.

They searched for genetic evidence of a negative PCSK9-related impact using a wide variety of cognitive function and dementia endpoints but were unable to locate any, indicating a neutral cognitive profile. The cardiovascular advantages of using statins may well exceed the negative neurocognitive effects we saw with HMGCR inhibition, but they nevertheless may call for pharmacovigilance.