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Peer-reviewedCC BY 4.0Frontiers in Pharmacology

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

  • Shuo-Yan Gau1,2,3
  • Shao-Wei Lo4
  • Christine Hsu5
  • Yung-Fang Tu6
  • Yu-Jung Su7
  • Chien-Chin Chen8,9,10,11
  • Meng-Che Wu12,13,14
  • Yasue Mitsukura15
  • Hui-Chin Chang12,16,17
17 affiliations
  1. 1Institute of Allergology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin
  2. 2Department of Medical Education, Ditmanson Medical Foundation Chia-Yi Christian Hospital
  3. 3Department and Graduate Institute of Business Administration, National Taiwan University
  4. 4Department of Internal Medicine, Cleveland Clinic Foundation
  5. 5Department of Medicine, Monmouth Medical Center, Robert Wood Johnson/Barnabas Healthcare System
  6. 6Department of Biostatistics, Harvard T.H. Chan School of Public Health
  7. 7Orthopedics Department, Chi-Mei Medical Center
  8. 8Department of Pathology, Ditmanson Medical Foundation Chia-Yi Christian Hospital
  9. 9Department of Cosmetic Science, Chia Nan University of Pharmacy and Science
  10. 10Ph.D. Program in Translational Medicine, Rong Hsing Research Center for Translational Medicine, National Chung Hsing University
  11. 11Department of Biotechnology and Bioindustry Sciences, College of Bioscience and Biotechnology, National Cheng Kung University
  12. 12School of Medicine, Chung Shan Medical University
  13. 13Division of Pediatric Gastroenterology, Children’s Medical Center, Taichung Veterans General Hospital
  14. 14Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University
  15. 15Department of Neuropsychiatry, Faculty of Science and Technology, Keio University School of Medicine, Keio University
  16. 16Evidence-based Medicine Center, Chung Shan Medical University Hospital
  17. 17Library, Chung Shan Medical University Hospital
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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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Cite

BibTeXRIS
BibTeX
@article{gau2026pcsk9,
  title = {{PCSK9 inhibitor use and risk of dementia and neurodegenerative diseases in adults aged 50 Years and older: a global electronic health record study}},
  author = {Shuo-Yan Gau and Shao-Wei Lo and Christine Hsu and Yung-Fang Tu and Yu-Jung Su and Chien-Chin Chen and Meng-Che Wu and Yasue Mitsukura and Hui-Chin Chang},
  journal = {Frontiers in Pharmacology},
  year = {2026},
  month = oct,
  doi = {10.3389/fphar.2026.1942691},
  url = {https://www.frontiersin.org/articles/10.3389/fphar.2026.1942691/full},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - PCSK9 inhibitor use and risk of dementia and neurodegenerative diseases in adults aged 50 Years and older: a global electronic health record study
AU  - Shuo-Yan Gau
AU  - Shao-Wei Lo
AU  - Christine Hsu
AU  - Yung-Fang Tu
AU  - Yu-Jung Su
AU  - Chien-Chin Chen
AU  - Meng-Che Wu
AU  - Yasue Mitsukura
AU  - Hui-Chin Chang
PY  - 2026
DA  - 2026/10/29
JO  - Frontiers in Pharmacology
DO  - 10.3389/fphar.2026.1942691
UR  - https://www.frontiersin.org/articles/10.3389/fphar.2026.1942691/full
AB  - 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.
SN  - 1663-9812
ER  -