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Identifying novel loci may reveal disease mechanisms and therapeutic targets. We investigated genetic variants influencing age at onset in early onset families from the Long\u2010Life Family Study (LLFS).\n <\/jats:p>\n <\/jats:sec>\n \n METHODS<\/jats:title>\n Six families with at least two early onset cases (onset \u2264 65) were identified among 3476 LLFS participants. Genome\u2010wide linkage analysis of age at onset was followed by single nucleotide polymorphism association. Validation analyses were performed in nine independent cohorts, alongside blood and brain transcriptomic analyses.<\/jats:p>\n <\/jats:sec>\n \n RESULTS<\/jats:title>\n \n Three significant linkage regions were identified, including\n RBFOX1<\/jats:italic>\n (logarithm of the odds\u00a0=\u00a04.41).\n RBFOX1<\/jats:italic>\n variants were associated with age at onset and cognitive phenotypes. A consistent association of\n RBFOX1<\/jats:italic>\n was observed across validation cohorts. Blood transcriptomics revealed\n RBFOX1<\/jats:italic>\n overexpression was associated with an earlier onset.\n <\/jats:p>\n <\/jats:sec>\n \n DISCUSSION<\/jats:title>\n \n RBFOX1<\/jats:italic>\n may influence AD age of onset, nominating the gene as a potential therapeutic target for delaying or preventing dementia.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/alz.71188","type":"journal-article","created":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T03:36:41Z","timestamp":1771817801000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["RBFOX1<\/i>\n association with age at onset of Alzheimer's disease"],"prefix":"10.1002","volume":"22","author":[{"given":"Laura","family":"Xicota","sequence":"first","affiliation":[{"name":"Department of Neurology Columbia University Irving Medical Center New York New York USA"},{"name":"Gertrude H. 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