Genetic associations with age at dementia onset in the PSEN1 E280A Colombian 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 to examine ADAD AAO in 340 individuals with the PSEN1 E280A mutation via TOPMed array imputation. Replication was assessed in two ADAD cohorts, one sporadic early-onset AD study and four late-onset AD studies. RESULTS: 13 variants had p<1x10(-7) or p<1x10(-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 reinforces their potentially impactful role.

Automated summary

This study conducted a genetic association study on 340 individuals with the PSEN1 E280A mutation and identified 13 genetic variants associated with the age at onset of Alzheimer's disease (AD). Three independent loci near CLU were found to have candidate associations with clusterin. Other suggestive associations were also observed near HS3ST1, HSPG2, ACE, LRP1B, TSPAN10, and TSPAN14. These findings suggest the potential role of these genetic variants in the development of AD.