Genetic associations with age at dementia onset in the PSEN1 E280A Colombian kindred

Jesse Nicholas Cochran, Juliana Acosta-Uribe, Bianca T. Esposito, Lucia Madrigal, David Aguillón, Margarita M. Giraldo, Jared W. Taylor, Joseph Bradley, Brian Fulton-Howard, Shea J. Andrews, Natalia Acosta-Baena, Diana Alzate, Gloria P. Garcia, Francisco Piedrahita, Hugo E. Lopez, Ashlyn G. Anderson, Ivan Rodriguez-Nunez, Kevin Roberts, I. Dominantly, Devin AbsherRichard M. Myers, Gary W. Beecham, Christiane Reitz, Lindsay F. Rizzardi, Maria Victoria Fernandez, Alison M. Goate, Carlos Cruchaga, Alan E. Renton, Francisco Lopera, Kenneth S. Kosik

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

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<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 reinforces their potentially impactful role.

Original languageEnglish
Pages (from-to)3835-3847
Number of pages13
JournalAlzheimer's and Dementia
Volume19
Issue number9
DOIs
StatePublished - Sep 2023

Keywords

  • AAO
  • ACE
  • AOO
  • Alzheimer
  • CLU
  • E280A
  • HS3ST1
  • HSPG2
  • LRP1B
  • PSEN1
  • SIAH3
  • TSPAN10
  • TSPAN14
  • ZC3H13
  • age of onset
  • amyloid
  • clusterin
  • heparin sulfate
  • tetraspanin

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