PCSK9 inhibitors do not increase cognitive risk

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.