PCSK9 Inhibitors Do Not Increase Cognitive Risk

Background Proprotein convertase subtilisin–kexin type 9 (PCSK9) inhibitors are potent lipid-lowering therapies, yet concerns regarding their neurocognitive safety persist amidst conflicting evidence. Methods We applied an integrated approach combining real-world pharmacovigilance, genetic epidemiology, and preclinical models. Disproportionality analysis was performed using FDA Adverse Event Reporting System (FAERS) data to assess cognitive adverse events. Two-sample Mendelian randomization (MR) was used to analyze the causal effects of apolipoprotein B (ApoB)-lowering and PCSK9 inhibition on Alzheimer’s disease (AD) via UK Biobank/FinnGen data, with a factorial MR design to evaluate interactions stratified by ApoB/PCSK9 polygenic risk. Preclinically, hepatocyte-specific knockout and pharmacological inhibition of PCSK9 in AD-transgenic mice were assessed through cognitive testing and neuropathological evaluations. Results No increased risk signal for cognitive events was identified with PCSK9 inhibitors in FAERS analysis (AD Reporting Odds Ratio [ROR] = 0.62, 95% CI 0.45–0.87; dementia ROR = 0.92, 0.79–1.08), unlike statins which showed a significant signal (AD ROR = 2.86). MR analysis revealed no causal association between PCSK9 inhibition (OR = 1.00, 0.93–1.07) or its ApoB-lowering effects (OR = 0.79, 0.56–1.11) and AD. In AD-transgenic mice, PCSK9 knockout reduced low-density lipoprotein-cholesterol by 54% without impairing cognition or neuron 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.