{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T18:04:15Z","timestamp":1788026655908,"version":"build-2784847793"},"reference-count":80,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,12,2]],"date-time":"2025-12-02T00:00:00Z","timestamp":1764633600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Directorate of Research and Development, Universitas Indonesia","award":["NKB-175\/UN2.RST\/HKP.05.00\/2024"],"award-info":[{"award-number":["NKB-175\/UN2.RST\/HKP.05.00\/2024"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Life"],"abstract":"<jats:p>Alzheimer\u2019s disease (AD) is increasingly associated with alterations in cholesterol metabolism. Proprotein convertase subtilisin\/kexin type 9 (PCSK9), an enzyme regulating low-density lipoprotein receptor (LDLR) degradation, has been implicated in AD through mechanisms involving amyloid-\u03b2 (A\u03b2) processing, tau phosphorylation, and synaptic dysfunction. This review aimed to evaluate clinical, genetic, and experimental evidence regarding the role of PCSK9 in AD and its potential as a biomarker or therapeutic target. A systematic search was conducted in PubMed, Scopus, ScienceDirect, and Google Scholar (2020\u20132025) using predefined terms related to PCSK9 and Alzheimer\u2019s disease. Eligible studies included clinical, in vivo, and in vitro investigations reporting PCSK9 expression, regulation, or inhibition in relation to AD pathology. Due to methodological heterogeneity, a narrative synthesis was performed. Forty-two studies met inclusion criteria. Preclinical findings consistently showed that elevated PCSK9 may indirectly promote A\u03b2 accumulation, tau hyperphosphorylation, neuroinflammation, and cognitive decline, while genetic deletion or pharmacological inhibition of PCSK9 mitigates these effects. Clinical evidence was variable: several studies identified increased PCSK9 levels in cerebrospinal fluid or brain tissue of AD patients, often correlating with tau markers, but large-scale genetic and Mendelian randomization studies did not confirm a causal association. PCSK9 inhibitors, widely used in cardiovascular therapy, demonstrated potent LDL-C reduction without cognitive adverse effects. Experimental data suggest that PCSK9 contributes to AD-related pathology, whereas human evidence indicates a modulatory or biomarker role rather than a causative one. Despite strong preclinical data, human genetics lacks causal evidence for PCSK9 in Alzheimer\u2019s. It may be a disease modifier or biomarker; its clinical relevance requires confirmation through longitudinal studies and CNS-penetrant therapies.<\/jats:p>","DOI":"10.3390\/life15121851","type":"journal-article","created":{"date-parts":[[2025,12,2]],"date-time":"2025-12-02T12:39:43Z","timestamp":1764679183000},"page":"1851","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["The Roles of PCSK9 in Alzheimer\u2019s Disease: A Systematic Review of Clinical, Genetic, and Preclinical Evidence"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6315-706X","authenticated-orcid":false,"given":"Vicko","family":"Suswidiantoro","sequence":"first","affiliation":[{"name":"Doctoral Programme, Faculty of Pharmacy, Universitas Indonesia, Kota Depok 16424, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1550-8627","authenticated-orcid":false,"given":"Meidi Utami","family":"Puteri","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmacology and Toxicology, Faculty of Pharmacy, Universitas Indonesia, Kota Depok 16424, Indonesia"},{"name":"National Metabolomics Collaborative Research Centre, Faculty of Pharmacy, Universitas Indonesia, Kota Depok 16424, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9905-2473","authenticated-orcid":false,"given":"Mitsuyasu","family":"Kato","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Universitas Indonesia, Kota Depok 16424, Indonesia"},{"name":"Department of Experimental Pathology, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Ibaraki, Japan"},{"name":"Division of Cell Dynamics, Transborder Medical Research Center, University of Tsukuba, Tsukuba 305-8575, Ibaraki, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0917-0538","authenticated-orcid":false,"given":"Donna Maretta","family":"Ariestanti","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Universitas Indonesia, Kota Depok 16424, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4138-615X","authenticated-orcid":false,"given":"Richard Johari","family":"James","sequence":"additional","affiliation":[{"name":"Integrative Pharmacogenomics Institute (iPROMISE), UiTM Selangor Branch, Puncak Alam Campus, Bandar Puncak Alam 42300, Selangor, Malaysia"},{"name":"Faculty of Pharmacy, UiTM Selangor Branch, Puncak Alam Campus, Bandar Puncak Alam 42300, Selangor, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6668-8915","authenticated-orcid":false,"given":"Fadlina Chany","family":"Saputri","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmacology and Toxicology, Faculty of Pharmacy, Universitas Indonesia, Kota Depok 16424, Indonesia"},{"name":"National Metabolomics Collaborative Research Centre, Faculty of Pharmacy, Universitas Indonesia, Kota Depok 16424, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1038\/nrn3012","article-title":"Linking lipids to Alzheimer\u2019s disease: Cholesterol and beyond","volume":"12","author":"Kim","year":"2011","journal-title":"Nat. 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