@article{a66be552534449cfa36f42d1aa4d59ac,
title = "Polygenic risk score penetrance & recurrence risk in familial Alzheimer disease",
abstract = "Objective: To compute penetrance and recurrence risk using a genome-wide PRS (including and excluding the APOE region) in families with Alzheimer's disease. Methods: Genotypes from the National Institute on Aging Late-Onset Alzheimer's Disease Family-Based Study and a study of familial Alzheimer's disease in Caribbean Hispanics were used to compute PRS with and without variants in the 2 MB region flanking APOE. PRS was calculated in using clumping/thresholding and Bayesian methods and was assessed for association with Alzheimer's disease and age at onset. Penetrance and recurrence risk for carriers in highest and lowest PRS quintiles were compared separately within APOE-ε4 carriers and non-carriers. Results: PRS excluding the APOE region was strongly associated with clinical and neuropathological diagnosis of AD. PRS association with AD was similar in participants who did not carry an APOE-ε4 allele (OR = 1.74 [1.53–1.91]) compared with APOE-ε4 carriers (1.53 [1.4–1.68]). Compared to the lowest quintile, the highest PRS quintile had a 10% higher penetrance at age 70 (p = 0.0006) and a 20% higher penetrance at age 80 (p < 10e-05). Stratifying by APOE-ε4 allele, PRS in the highest quintile was significantly more penetrant than the lowest quintile, both, within APOE-ε4 carriers (14.5% higher at age 80, p = 0.002) and non-carriers (26% higher at 80, p < 10e-05). Recurrence risk for siblings conferred by a co-sibling in the highest PRS quintile increased from 4% between the ages of 65–74 years to 39% at age 85 and older. Interpretation: PRS can be used to estimate penetrance and recurrence risk in familial Alzheimer's disease among carriers and non-carries of APOE-ε4.",
author = "Min Qiao and Lee, {Annie J.} and Dolly Reyes-Dumeyer and Giuseppe Tosto and Kelley Faber and Alison Goate and Alan Renton and Michael Chao and Brad Boeve and Carlos Cruchaga and Margaret Pericak-Vance and Haines, {Jonathan L.} and Roger Rosenberg and Debby Tsuang and Sweet, {Robert A.} and Bennett, {David A.} and Wilson, {Robert S.} and Tatiana Foroud and Richard Mayeux and Vardarajan, {Badri N.}",
note = "Funding Information: Data collection and genetic analysis in the NIA‐LOAD study is supported by NIA grant 5U24AG056270. The Caribbean Hispanic cohort is comprised of two cohorts: Estudio Familiar de la Gen{\'e}tica de la Enfermedad de Alzheimer (EFIGA): Data collection in EFIGA was supported by grants funded by the National Institute on Aging (NIA) of the National Institutes of Health (NIH) (R37AG015473, RF1AG015473, R01AG067501). Washington Heights‐Inwood Columbia Aging Project (WHICAP): This project was supported by grants: R01AG037212, RF1AG054023, RF1AG066107, R01AG072474 from the National Institute on Aging (NIA) and by the National Center for Advancing Translational Sciences UL1TR001873 of the National Institutes of Health. Funding Information: Each co‐author's conflict of interest is listed below. M.Q, A.J.L, D.R.D, K.F and M.C. do not have any conflicts of interest. G.T., C.C., M.P.V, and R.S.W have grants from the NIH. A.G. has grants from the NIA/NIH and receives money from Athena Diagnostics for licensing of TDP43 mutations, and has consulted for UK Dementia Research Institute, UK VIB, Katholik University, Leuven, Belgium Center for Molecular Neurology, Antwerp, Belgium Queensland Brain Institute, Brisbane, Australia. A.R. has grants from the NIA/NIH, the Alzheimer's Association, and from the JPB Foundation. B.B. has grants from the NIH, receives royalties as a co‐editor of a textbook on dementia, and is on the Scientific Advisory Board (SAB) for the Tau Consortium. J.H.L has received consulting fee from University of Miami and University of Miami. He holds grants from NIH. R.R. has grants from the NIA/NIH and The Zale Foundation and receives license/royalty fees from Elsevier Publishing Inc., Springer Publishing Inc.; payments from Elsevier, Springer and Vitruvian, Inc., and The American Academy of Neurology; and he has a 2009 patent on an Amyloid Beta Gene vaccine. D.T. has grants from the NIA/NIH and receives consulting fees from Acadia Pharma and is on the SAB for the Lewy Body Association. R.A.S has grants from the NIA/NIH and National Institute of Mental Health of the NIH. D.A.B. is a part of AbbVie's data monitoring board, a consultant with Takeda Inc, Origent Inc and SBIR. He consults with Vigorous Minds (unpaid). He has received NIH funding is a member of professional societies including the National Academy of Sciences and has given grand rounds talks. T.F. has grants from the NIA/NIH, The Department of Defense, and the Michael J. Fox Foundation; is on the SAB for several academic institutions; and receives support from Northwestern University for Continuing Medical Education. R.M. has grants from the NIA/NIH and is on the SAB for the Rush Alzheimer's Disease Research Center. B.N.V has grants from the National Institute on Aging (NIA) of the National Institutes of Health and the Department of Defense and is a cancer bioinformatics consultant for Kodikaz Therapeutics. Publisher Copyright: {\textcopyright} 2023 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.",
year = "2023",
month = may,
doi = "10.1002/acn3.51757",
language = "English",
volume = "10",
pages = "744--756",
journal = "Annals of Clinical and Translational Neurology",
issn = "2328-9503",
publisher = "John Wiley & Sons Inc.",
number = "5",
}