Genetic Associations with Age at Dementia Onset in thePSEN1 E280AColombian Kindred

INTRODUCTION Genetic 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. METHODS A genetic association study was conducted for ADAD dementia AAO in 340 individuals with the PSEN1 E280A mutation via TOPMed array imputation. Replication was assessed in two ADAD cohorts, one sporadic EOAD study, and four late onset AD studies. RESULTS 13 variants had p <1×10 −7 or p <1×10 −5 with replication including three independent loci with candidate associations with clusterin including near CLU . Other suggestive associations were identified in or near HS3ST1, HSPG2, ACE, LRP1B, TSPAN10 , and TSPAN14 . DISCUSSION Variants 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.