ArticleFrontiers in pharmacology2026
PCSK9 inhibitor use and risk of dementia and neurodegenerative diseases in adults aged 50 Years and older: a global electronic health record study.
Article in Frontiers in pharmacology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
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.
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