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We hypothesized that PCSK9 impacts on Alzheimer's disease (AD) risk in an\n                      <jats:italic>APOE<\/jats:italic>\n                      genotype dependent manner.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We used the Framingham Heart Study (FHS) Offspring cohort (Gen 2), with data on plasma PCSK9 protein concentration, as the baseline exposure for 1,704 study subjects. Using Cox regression models, the outcomes were incidents of AD or all\u2010cause dementia. Using another FHS dataset with 3,048 individuals with genetic data, we examined the association between PCSK9 genotypes and the incidence of AD\/dementia, stratifying the analysis based on\n                      <jats:italic>APOE<\/jats:italic>\n                      \u03b54 status. The Alzheimer's Disease Neuroimaging Initiative (ADNI) study was used to validate some of the main findings.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Higher plasma PCSK9 protein levels were associated with a lower risk of AD (HR [95%CI]: 0.74 [0.58, 0.94];\n                      <jats:italic>p<\/jats:italic>\n                      = 0.01) in\n                      <jats:italic>APOE<\/jats:italic>\n                      \u03b54 noncarriers; in contrast, PCSK9 levels were not significantly associated with AD risk in\n                      <jats:italic>APOE<\/jats:italic>\n                      \u03b54 carriers, after adjusting for common confounders, lipid profile, and lipid treatment. Using the three SNPs (rs502576, rs529787, rs676297) of the PCSK9 gene associated with PCSK9 levels in blood, we consistently found that the genotypes, which determine a low concentration of PCSK9, were associated with AD risk only in\n                      <jats:italic>APOE<\/jats:italic>\n                      \u03b54 noncarriers. These findings were validated by the ADNI study, which showed that the PCSK9 genotypes were associated with AD risk and with the AD biomarker\u2014a low concentration of A\u03b242 in CSF, only in APOE \u03b54 noncarriers.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Our study suggests that high blood PCSK9 levels are protective against AD risk in\n                      <jats:italic>APOE<\/jats:italic>\n                      \u03b54 noncarriers, potentially through mechanisms related to lipid metabolism. The findings may highlight the importance of considering\n                      <jats:italic>APOE<\/jats:italic>\n                      genotype when prescribing the drugs targeting PCSK9.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/hsr2.71810","type":"journal-article","created":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T04:57:17Z","timestamp":1771822637000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Blood PCSK9 Impacts Alzheimer's Disease Risk in an\n                    <i>APOE<\/i>\n                    Genotype\u2010Dependent Manner: A Prospective Cohort Study"],"prefix":"10.1002","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1852-3681","authenticated-orcid":false,"given":"Qiushan","family":"Tao","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Physiology &amp; Biophysics Boston University Chobanian &amp; Avedisian School of Medicine Boston Massachusetts USA"},{"name":"Department of Anatomy &amp; Neurobiology Boston University Chobanian &amp; Avedisian School of Medicine Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting Fang Alvin","family":"Ang","sequence":"additional","affiliation":[{"name":"Department of Anatomy &amp; Neurobiology Boston University Chobanian &amp; Avedisian School of Medicine Boston Massachusetts USA"},{"name":"Slone Epidemiology Center, School of Public Health Boston University Medical Campus (BUMC) Boston Massachusetts USA"},{"name":"Framingham Heart Study Boston University Chobanian &amp; Avedisian School of Medicine Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinghan","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Physiology &amp; Biophysics Boston University Chobanian &amp; Avedisian School of Medicine Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Indira Swetha","family":"Itchapurapu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Physiology &amp; Biophysics Boston University Chobanian &amp; Avedisian School of Medicine Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jesse","family":"Mez","sequence":"additional","affiliation":[{"name":"Framingham Heart Study Boston University Chobanian &amp; Avedisian School of Medicine Boston Massachusetts USA"},{"name":"Department of Neurology Boston University Chobanian &amp; Avedisian School of Medicine Boston Massachusetts USA"},{"name":"Alzheimer's Disease and CTE Centers, Boston University Chobanian &amp; Avedisian School of Medicine Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Alosco","sequence":"additional","affiliation":[{"name":"Department of Neurology Boston University Chobanian &amp; Avedisian School of Medicine Boston Massachusetts USA"},{"name":"Alzheimer's Disease and CTE Centers, Boston University Chobanian &amp; Avedisian School of Medicine Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rhoda","family":"Au","sequence":"additional","affiliation":[{"name":"Department of Anatomy &amp; Neurobiology Boston University Chobanian &amp; Avedisian School of Medicine Boston Massachusetts USA"},{"name":"Slone Epidemiology Center, School of Public Health Boston University Medical Campus (BUMC) Boston Massachusetts USA"},{"name":"Framingham Heart Study Boston University Chobanian &amp; Avedisian School of Medicine Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lindsay A.","family":"Farrer","sequence":"additional","affiliation":[{"name":"Framingham Heart Study Boston University Chobanian &amp; Avedisian School of Medicine Boston Massachusetts USA"},{"name":"Department of Medicine 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