Genetic Associations with Age at Dementia Onset in thePSEN1 E280AColombian Kindred

AbstractINTRODUCTIONGenetic associations with Alzheimer’s disease (AD) age at onset (AAO) could reveal genetic variants with therapeutic applications. We present a large Colombian kindred with autosomal dominant AD (ADAD) as a unique opportunity to discover AAO genetic associations.METHODSA genetic association study was conducted for ADAD dementia AAO in 340 individuals with thePSEN1 E280Amutation via TOPMed array imputation. Replication was assessed in two ADAD cohorts, one sporadic EOAD study, and four late onset AD studies.RESULTS13 variants hadp<1×10−7orp<1×10−5with replication including three independent loci with candidate associations with clusterin including nearCLU. Other suggestive associations were identified in or nearHS3ST1, HSPG2, ACE, LRP1B, TSPAN10, andTSPAN14.DISCUSSIONVariants with suggestive associations with AAO were associated with biological processes including clusterin, heparin sulfate and amyloid processing. The detection of these effects in the presence of a strong mutation for ADAD reinforce their potentially impactful role.