Abstract
Background
Proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors are potent lipid-lowering therapies, however, concerns regarding their neurocognitive safety persist because of conflicting evidence.Methods
We applied an integrated approach combining real-world pharmacovigilance, genetic epidemiology, and preclinical models. Disproportionality analysis was performed using the FDA Adverse Event Reporting System (FAERS) data to assess cognitive adverse events. Two-sample Mendelian randomization (MR) was used to assess the causal effects of apolipoprotein B (ApoB) lowering and PCSK9 inhibition on Alzheimer's disease (AD) using UK Biobank and FinnGen data, with a factorial MR design to evaluate interactions stratified by ApoB and PCSK9 polygenic risk. Preclinically, hepatocyte-specific knockout and pharmacological inhibition of PCSK9 in AD-transgenic mice were assessed through cognitive testing and neuropathological assessment.Results
FAERS analysis showed no increased reporting signal for cognitive adverse events with PCSK9 inhibitors. For AD, the ROR was below unity (ROR = 0.62, 95% CI 0.45-0.87), whereas no statistically significant signal was observed for dementia (ROR = 0.92, 95% CI 0.79-1.08). In contrast, statins showed significant disproportionality signals for AD (ROR = 2.86, 95% CI 2.51-3.26) and dementia (ROR = 1.51, 95% CI 1.36-1.67). MR analysis revealed no causal association between genetically proxied PCSK9 inhibition and AD risk (OR = 1.00, 95% CI 0.93-1.07), or between ApoB and AD risk (OR = 0.79, 95% CI 0.56-1.11). In AD-transgenic mice, PCSK9 knockout reduced low-density lipoprotein-cholesterol by 54% without impairing cognition or neuronal integrity, or increasing amyloid-β plaques and astrocytes. Pharmacological inhibition of PCSK9 similarly showed no cognitive deficits.Conclusions
Integrated evidence from pharmacovigilance, genetic epidemiology, and preclinical models robustly supports the neurocognitive safety of PCSK9 inhibitors, including in individuals with high ApoB levels. These findings affirm their long-term neurocognitive safety profile in the management of atherosclerotic cardiovascular disease.