biostudies-literatureXicota LNational Institute on Aging (NIA)National CenterNCATS NIH HHSde Influencia Genetica en AlzheimerNIA NIH HHSAlzheimer's Association Zenith Fellows AwardNational Institute on Aging Alzheimer's Disease Family Based StudyPhenotype Harmonization ConsortiumBrightFocus FoundationEarly-Onset Alzheimer's Disease Whole-Genome Sequencing ProjectWashington Heights-Inwood Columbia Aging ProjectBright FocusAlzheimer's Disease Neuroimaging InitiativeWisconsin Registry for Alzheimer's Prevention (WRAP)Alzheimer's AssociationNIH HHSe71188https://www.ebi.ac.uk/biostudies/studies/S-EPMC12928012biostudies-literatureUnknown22(2)<h4>Introduction</h4>Genetic contributors to early onset Alzheimer's disease (AD) beyond APP and PSEN1/2 remain unknown. 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-Life Family Study (LLFS).<h4>Methods</h4>Six families with at least two early onset cases (onset ≤ 65) were identified among 3476 LLFS participants. Genome-wide 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.<h4>Results</h4>Three significant linkage regions were identified, including RBFOX1 (logarithm of the odds = 4.41). RBFOX1 variants were associated with age at onset and cognitive phenotypes. A consistent association of RBFOX1 was observed across validation cohorts. Blood transcriptomics revealed RBFOX1 overexpression was associated with an earlier onset.<h4>Discussion</h4>RBFOX1 may influence AD age of onset, nominating the gene as a potential therapeutic target for delaying or preventing dementia.Alzheimer's & dementia : the journal of the Alzheimer's AssociationRBFOX1 association with age at onset of Alzheimer's disease.PMC12928012ZEN-22-848604AG072474R01AG041797R56 AG051876U19 AG063893A2015633SUL1TR001873U01AG068057U24AG026395AG066107R01AG058918U01-AG023749U24AG074855R01AG059716U01-AG023744U01-AG023755R01AG067501U01-AG023712Xicota LZmuda JMMayeux RWojczynski MLong‐Life Family Study (LLFS), Estudio Familiar de Influencia Genetica en Alzheimer (EFIGA), and The National Institute on Aging Alzheimer's Disease Family Based Study (NIA‐LOAD FBS)Vardarajan BVFeitosa MFReyes-Dumeyer DHohman TJContreras AGCruchaga CAndersen SLCheng RBradley JCosentino SBarral SLee JHfalseRBFOX1 association with age at onset of Alzheimer's disease.<h4>Introduction</h4>Genetic contributors to early onset Alzheimer's disease (AD) beyond APP and PSEN1/2 remain unknown. 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-Life Family Study (LLFS).<h4>Methods</h4>Six families with at least two early onset cases (onset ≤ 65) were identified among 3476 LLFS participants. Genome-wide 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.<h4>Results</h4>Three significant linkage regions were identified, including RBFOX1 (logarithm of the odds = 4.41). RBFOX1 variants were associated with age at onset and cognitive phenotypes. A consistent association of RBFOX1 was observed across validation cohorts. Blood transcriptomics revealed RBFOX1 overexpression was associated with an earlier onset.<h4>Discussion</h4>RBFOX1 may influence AD age of onset, nominating the gene as a potential therapeutic target for delaying or preventing dementia.2026-01-01T00:00:00Z2026 Feb2026-07-09T12:15:57.215Z2026-07-09T11:15:07.536ZS-EPMC129280124172470610.1002/alz.71188