Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026
RBFOX1 association with age at onset of Alzheimer's disease.
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Xicota Laura, Cheng Rong, Andersen Stacy L, Zmuda Joseph M, Wojczynski Mary, Feitosa Mary F, Bradley Joseph, Cruchaga Carlos, Contreras Alex G, Hohman Timothy J, Reyes-Dumeyer Dolly, Vardarajan Badri V, Cosentino Stephanie, Mayeux Richard, Lee Joseph H, Barral Sandra, Long‐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)
Аннотация
INTRODUCTION: 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).
METHODS: 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.
RESULTS: 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.
DISCUSSION: RBFOX1 may influence AD age of onset, nominating the gene as a potential therapeutic target for delaying or preventing dementia.
METHODS: 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.
RESULTS: 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.
DISCUSSION: RBFOX1 may influence AD age of onset, nominating the gene as a potential therapeutic target for delaying or preventing dementia.