PCSK9 inhibitor use and risk of dementia and neurodegenerative diseases in adults aged 50 Years and older: a global electronic health record study

Background Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors achieve profound lipid lowering, yet their long-term neurocognitive effects remain uncertain. Evidence from randomized trials is limited by short follow-up and lack of dedicated neurodegenerative endpoints. Methods We performed a retrospective target trial emulation using the TriNetX Global Collaborative Network. Adults aged ≥50 years with hyperlipidemia initiating PCSK9 inhibitors or comparator lipid-lowering therapies between 2015 and 2024 were included. Active-comparator cohorts were constructed against statins, ezetimibe, and fenofibrate or cholestyramine with mutual exclusion of prior exposure. Propensity score matching at a 1:1 ratio balanced demographics, body mass index, socioeconomic indicators, healthcare utilization, and cardiometabolic comorbidities. Outcomes included incident all-cause dementia, Alzheimer’s disease, vascular dementia, Parkinson’s disease, and other neurodegenerative disorders. Sensitivity analyses incorporated lag periods, varying follow-up durations, alternative matching strategies, and intention-to-treat analyses. Cross-dataset validation was additionally conducted using the US Collaborative Network to assess reproducibility under independent data settings. Hazard ratio along with 95% confidence interval were evaluated in each analysis. Results Among 31,604 matched PCSK9 inhibitor–statin pairs, PCSK9 inhibitor use was associated with lower risks of all-cause dementia (HR 0.454; 95% CI 0.394–0.522), Alzheimer’s disease (HR 0.553; 95% CI 0.433–0.705), vascular dementia (HR 0.536; 95% CI 0.402–0.714), Parkinson’s disease (HR 0.686; 95% CI 0.544–0.865), and other neurodegenerative disorders (HR 0.730; 95% CI 0.645–0.825). Results were consistent across comparator therapies, cross-dataset validation and sensitivity analyses. Conclusion PCSK9 inhibitor use was associated with lower observed risks of neurodegenerative outcomes across multiple analyses and datasets. These findings support a potential association but do not establish causality and require confirmation in prospective trials.