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basis of sporadic early\u2010onset Alzheimer's disease (EOAD) remains largely unknown, prompting evaluation of late\u2010onset Alzheimer's disease (LOAD) polygenic risk in EOAD.<\/jats:p>\n <\/jats:sec>\n \n METHODS<\/jats:title>\n A LOAD polygenic score (PGS) was calculated in the Longitudinal Early\u2010onset Alzheimer's Disease Study (LEADS) and Alzheimer's Disease Neuroimaging Initiative (ADNI) study and tested for associations with AD risk, cognitive performance, and imaging and fluid biomarkers.<\/jats:p>\n <\/jats:sec>\n \n RESULTS<\/jats:title>\n \n Though PGS was elevated in LOAD and EOAD, it was not a significant predictor of EOAD adjusting for\n APOE<\/jats:italic>\n \u03b54 carrier status and was not associated with age of EOAD onset (\n p<\/jats:italic>\n \u00a0=\u00a00.106) or with cognitive performance (\n p<\/jats:italic>\n \u00a0=\u00a00.417). In LEADS, greater LOAD PGS was associated with differences in neuroimaging and fluid biomarkers, including elevated synaptosomal\u2010associated protein 25 (SNAP\u201025) (\n p<\/jats:italic>\n \u00a0=\u00a02.3\u00a0\u00d7\u00a010\n \u22125<\/jats:sup>\n ).\n <\/jats:p>\n <\/jats:sec>\n \n DISCUSSION<\/jats:title>\n While LOAD polygenic risk contributed minimally to EOAD onset and cognitive dysfunction, PGS association with fluid biomarkers in LEADS suggests a role for LOAD polygenic risk in EOAD pathophysiology.<\/jats:p>\n <\/jats:sec>\n \n Highlights<\/jats:title>\n \n \n \n \n LOAD PGSs were elevated in both LOAD and EOAD compared to controls; however, LOAD PGS did not significantly predict EOAD risk, age at onset, or cognitive performance independent of\n APOE<\/jats:italic>\n \u03b54 in the LEADS.\n <\/jats:p>\n <\/jats:list-item>\n \n Higher LOAD PGS was associated with lower amyloid PET Centiloids (less brain amyloid deposition) as well as lower CSF biomarker A\u03b242 in LEADS (proxy marker suggesting higher brain amyloid deposition) in LEADS; these contradictory findings support the need for larger studies to further investigate whether LOAD PGS is associated with increased amyloid deposition in EOAD.<\/jats:p>\n <\/jats:list-item>\n \n Higher LOAD PGS was also associated with higher levels of CSF synaptosomal\u2010associated protein 25 (SNAP\u201025), a key component of the SNARE complex, suggesting that LOAD genetic factors may contribute to dysregulation of synaptic transmission and\/or pathological protein aggregation in EOAD.<\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/alz.71066","type":"journal-article","created":{"date-parts":[[2026,1,14]],"date-time":"2026-01-14T14:21:59Z","timestamp":1768400519000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Alzheimer's disease polygenic risk in early\u2010 and late\u2010onset Alzheimer's disease"],"prefix":"10.1002","volume":"22","author":[{"given":"Julian V.","family":"Pentchev","sequence":"first","affiliation":[{"name":"Department of Neurology Indiana University School of Medicine Indianapolis USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Trever","family":"Jackson","sequence":"additional","affiliation":[{"name":"Department of Medical and Molecular Genetics Indiana University School of Medicine Indianapolis USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naazneen","family":"Khan","sequence":"additional","affiliation":[{"name":"Department of Neurology Indiana University School of Medicine Indianapolis USA"},{"name":"Indiana Alzheimer's Disease Research Center Indiana University School of Medicine Indianapolis USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thea J.","family":"Rosewood","sequence":"additional","affiliation":[{"name":"Indiana Alzheimer's Disease Research Center Indiana University School of Medicine Indianapolis USA"},{"name":"Department of Radiology and Imaging Sciences Indiana University School of Medicine Indianapolis USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yen\u2010Ning","family":"Huang","sequence":"additional","affiliation":[{"name":"Indiana Alzheimer's Disease Research Center Indiana University School of Medicine Indianapolis USA"},{"name":"Department of Radiology and Imaging Sciences Indiana University School of Medicine Indianapolis USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kwangsik","family":"Nho","sequence":"additional","affiliation":[{"name":"Indiana Alzheimer's Disease Research Center Indiana University School of Medicine Indianapolis USA"},{"name":"Department of Radiology and Imaging Sciences Indiana University School of Medicine Indianapolis USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew J.","family":"Saykin","sequence":"additional","affiliation":[{"name":"Department of Neurology Indiana University School of Medicine Indianapolis USA"},{"name":"Department of Medical and Molecular Genetics Indiana University School of Medicine Indianapolis USA"},{"name":"Indiana Alzheimer's Disease Research Center Indiana University School of Medicine Indianapolis USA"},{"name":"Department of Radiology and Imaging Sciences Indiana University School of Medicine Indianapolis USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ani","family":"Eloyan","sequence":"additional","affiliation":[{"name":"Center for Statistical Sciences Brown University Providence USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Taurone","sequence":"additional","affiliation":[{"name":"Center for Statistical Sciences Brown University Providence USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maryanne","family":"Thangarajah","sequence":"additional","affiliation":[{"name":"Center for Statistical Sciences Brown University Providence USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meghan","family":"Riddle","sequence":"additional","affiliation":[{"name":"Department of Neurology Alpert Medical School Brown University Providence USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven","family":"Salloway","sequence":"additional","affiliation":[{"name":"Department of Neurology Alpert Medical School Brown University Providence USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alireza","family":"Atri","sequence":"additional","affiliation":[{"name":"Banner Sun Health Research Institute Sun City USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lawrence S.","family":"Honig","sequence":"additional","affiliation":[{"name":"Department of Neurology Columbia University Irving Medical Center New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik C. 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