Polygenic Risk Score of Sporadic Late Onset Alzheimer Disease Reveals a Shared Architecture with the Familial and Early Onset Forms

Carlos Cruchaga; Jorge L. Del‐Aguila; Benjamin A. Saef; Kathleen Black; María Victoria Fernández; John Budde; Laura Ibáñez; Yuetiva K. Deming; Manav Kapoor; Giuseppe Tosto; Richard P Mayeux; David M. Holtzman; Anne M. Fagan; John C. Morris; Randall John Bateman; Alison Goate; Dominantly Inherited Alzheimer Network (DIAN); Disease Neuroimaging Initiative (ADNI); NIA‐LOAD family study; Oscar Harari

doi:10.1016/j.jalz.2017.08.013

GeneticsAlzheimer s & DementiaSep 21, 2017

Peer-reviewed journal article

Polygenic Risk Score of Sporadic Late Onset Alzheimer Disease Reveals a Shared Architecture with the Familial and Early Onset Forms

Carlos Cruchaga iD, Jorge L. Del‐Aguila iD, Benjamin A. Saef, Kathleen Black, María Victoria Fernández iD, John Budde iD, Laura Ibáñez iD, Yuetiva K. Deming iD, Manav Kapoor iD, Giuseppe Tosto iD, Richard P Mayeux iD, David M. Holtzman iD, Anne M. Fagan iD, John C. Morris iD, Randall John Bateman iD, Alison Goate iD, Dominantly Inherited Alzheimer Network (DIAN), Disease Neuroimaging Initiative (ADNI), NIA‐LOAD family study, Oscar Harari iD

Abstract

ObjectiveTo determine whether the genetic architecture of sporadic late-onset Alzheimers Disease (sLOAD) has an effect on familial late-onset AD (fLOAD), sporadic early-onset (sEOAD) and autosomal dominant early-onset (eADAD).\n\nMethodsPolygenic risk scores (PRS) were constructed using previously identified 21 genome-wide significant loci for LOAD risk.\n\nResultsWe found that there is an overlap in the genetic architecture among sEOAD, fLOAD, and sLOAD. sEOAD showed the highest odds for the PRS (OR=2.27; p=1.29x10-7), followed by fLOAD (OR=1.75; p=1.12x10-7) and sLOAD (OR=1.40; p=1.21x10-3). PRS is associated with cerebrospinal fluid ptau181-A{beta}42 on eADAD.\n\nConclusionOur analysis confirms that the genetic factors identified for sLOAD also modulate risk in fLOAD and sEOAD cohorts. Furthermore, our results suggest that the burden of these risk variants is associated with familial clustering and earlier-onset of AD. Although these variants are not associated with risk in the eADAD, they may be modulating age at onset.

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