Carlos Cruchaga1, Jorge L Del-Aguila2, Benjamin Saef2, Kathleen Black2, Maria Victoria Fernandez2, John Budde2, Laura Ibanez2, Yuetiva Deming2, Manav Kapoor3, Giuseppe Tosto4, Richard P Mayeux5, David M Holtzman6, Anne M Fagan6, John C Morris6, Randall J Bateman6, Alison M Goate3, Oscar Harari7. 1. Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA; Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA. 2. Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA. 3. Ronald M. Loeb Center for Alzheimer's Disease, Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA. 4. Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University College of Physicians and Surgeons, New York, NY, USA; Gertrude H. Sergievsky Center, Columbia University College of Physicians and Surgeons, New York, NY, USA; Department of Neurology, Columbia University College of Physicians and Surgeons, New York-Presbyterian Hospital, New York, NY, USA. 5. Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University College of Physicians and Surgeons, New York, NY, USA; Gertrude H. Sergievsky Center, Columbia University College of Physicians and Surgeons, New York, NY, USA; School of Medicine, Mother and Teacher Pontifical Catholic University, Santiago, Dominican Republic. 6. Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA; Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA; Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA. 7. Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA. Electronic address: harario@wustl.edu.
Abstract
OBJECTIVE: To determine whether the extent of overlap of the genetic architecture among the sporadic late-onset Alzheimer's Disease (sLOAD), familial late-onset AD (fLOAD), sporadic early-onset AD (sEOAD), and autosomal dominant early-onset AD (eADAD). METHODS: Polygenic risk scores (PRSs) were constructed using previously identified 21 genome-wide significant loci for LOAD risk. RESULTS: We found that there is an overlap in the genetic architecture among sEOAD, fLOAD, and sLOAD. The highest association of the PRS and risk (odds ratio [OR] = 2.27; P = 1.29 × 10-7) was observed in sEOAD, followed by fLOAD (OR = 1.75; P = 1.12 × 10-7) and sLOAD (OR = 1.40; P = 1.21 × 10-3). The PRS was associated with cerebrospinal fluid ptau181-Aβ42 on eADAD (P = 4.36 × 10-2). CONCLUSION: Our analysis confirms that the genetic factors identified for LOAD modulate risk in sLOAD and fLOAD and also sEOAD cohorts. Specifically, 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.
OBJECTIVE: To determine whether the extent of overlap of the genetic architecture among the sporadic late-onset Alzheimer's Disease (sLOAD), familial late-onset AD (fLOAD), sporadic early-onset AD (sEOAD), and autosomal dominant early-onset AD (eADAD). METHODS: Polygenic risk scores (PRSs) were constructed using previously identified 21 genome-wide significant loci for LOAD risk. RESULTS: We found that there is an overlap in the genetic architecture among sEOAD, fLOAD, and sLOAD. The highest association of the PRS and risk (odds ratio [OR] = 2.27; P = 1.29 × 10-7) was observed in sEOAD, followed by fLOAD (OR = 1.75; P = 1.12 × 10-7) and sLOAD (OR = 1.40; P = 1.21 × 10-3). The PRS was associated with cerebrospinal fluid ptau181-Aβ42 on eADAD (P = 4.36 × 10-2). CONCLUSION: Our analysis confirms that the genetic factors identified for LOAD modulate risk in sLOAD and fLOAD and also sEOAD cohorts. Specifically, 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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