{
  "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.\n\nMethods: 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.\n\nResults: 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.\n\nConclusion: 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.",
  "abstract_shown": true,
  "affiliations": [
    "Institute of Allergology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin",
    "Department of Medical Education, Ditmanson Medical Foundation Chia-Yi Christian Hospital",
    "Department and Graduate Institute of Business Administration, National Taiwan University",
    "Department of Internal Medicine, Cleveland Clinic Foundation",
    "Department of Medicine, Monmouth Medical Center, Robert Wood Johnson/Barnabas Healthcare System",
    "Department of Biostatistics, Harvard T.H. Chan School of Public Health",
    "Orthopedics Department, Chi-Mei Medical Center",
    "Department of Pathology, Ditmanson Medical Foundation Chia-Yi Christian Hospital",
    "Department of Cosmetic Science, Chia Nan University of Pharmacy and Science",
    "Ph.D. Program in Translational Medicine, Rong Hsing Research Center for Translational Medicine, National Chung Hsing University",
    "Department of Biotechnology and Bioindustry Sciences, College of Bioscience and Biotechnology, National Cheng Kung University",
    "School of Medicine, Chung Shan Medical University",
    "Division of Pediatric Gastroenterology, Children’s Medical Center, Taichung Veterans General Hospital",
    "Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University",
    "Department of Neuropsychiatry, Faculty of Science and Technology, Keio University School of Medicine, Keio University",
    "Evidence-based Medicine Center, Chung Shan Medical University Hospital",
    "Library, Chung Shan Medical University Hospital"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 9,
  "authors": [
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Shuo-Yan Gau"
    },
    {
      "affs": [
        3
      ],
      "name": "Shao-Wei Lo"
    },
    {
      "affs": [
        4
      ],
      "name": "Christine Hsu"
    },
    {
      "affs": [
        5
      ],
      "name": "Yung-Fang Tu"
    },
    {
      "affs": [
        6
      ],
      "name": "Yu-Jung Su"
    },
    {
      "affs": [
        7,
        8,
        9,
        10
      ],
      "name": "Chien-Chin Chen"
    },
    {
      "affs": [
        11,
        12,
        13
      ],
      "name": "Meng-Che Wu"
    },
    {
      "affs": [
        14
      ],
      "name": "Yasue Mitsukura"
    },
    {
      "affs": [
        11,
        15,
        16
      ],
      "name": "Hui-Chin Chang"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/0yc491n181dfx.bib",
  "cited_by": 0,
  "doi": "10.3389/fphar.2026.1942691",
  "fulltext_url": null,
  "id": "0yc491n181dfx",
  "issns": [
    "1663-9812"
  ],
  "landing_url": "https://www.frontiersin.org/articles/10.3389/fphar.2026.1942691/full",
  "language": null,
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [],
  "openalex": null,
  "pdf_url": null,
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-29",
  "publisher": "Frontiers Media SA",
  "ris": "https://research.draconitic.com/paper/0yc491n181dfx.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:20:06Z",
      "native_id": "10.3389/fphar.2026.1942691",
      "source": "crossref",
      "url": "https://www.frontiersin.org/articles/10.3389/fphar.2026.1942691/full"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "issn:1663-9812",
      "subfield": "pharmacology-toxicology"
    }
  ],
  "title": "PCSK9 inhibitor use and risk of dementia and neurodegenerative diseases in adults aged 50 Years and older: a global electronic health record study",
  "title_text": "PCSK9 inhibitor use and risk of dementia and neurodegenerative diseases in adults aged 50 Years and older: a global electronic health record study",
  "type": "peer-reviewed",
  "updated_at": "2026-10-31T00:21:07Z",
  "url": "https://research.draconitic.com/paper/0yc491n181dfx",
  "venue": "Frontiers in Pharmacology",
  "versions": []
}