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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 <jats:italic>APOE\u2010\u03b54<\/jats:italic> carriers and non\u2010carriers.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>PRS excluding the <jats:italic>APOE<\/jats:italic> region was strongly associated with clinical and neuropathological diagnosis of AD. PRS association with AD was similar in participants who did not carry an <jats:italic>APOE\u2010\u03b54<\/jats:italic> allele (OR\u00a0=\u00a01.74 [1.53\u20131.91]) compared with <jats:italic>APOE<\/jats:italic>\u2010\u03b54 carriers (1.53 [1.4\u20131.68]). Compared to the lowest quintile, the highest PRS quintile had a 10% higher penetrance at age 70 (<jats:italic>p<\/jats:italic>\u00a0=\u00a00.0006) and a 20% higher penetrance at age 80 (<jats:italic>p<\/jats:italic>\u2009&lt;\u200910e\u201005). Stratifying by <jats:italic>APOE\u2010\u03b54<\/jats:italic> allele, PRS in the highest quintile was significantly more penetrant than the lowest quintile, both, within <jats:italic>APOE\u2010\u03b54<\/jats:italic> carriers (14.5% higher at age 80, <jats:italic>p<\/jats:italic>\u00a0=\u00a00.002) and non\u2010carriers (26% higher at 80, <jats:italic>p<\/jats:italic>\u2009&lt;\u200910e\u201005). Recurrence risk for siblings conferred by a co\u2010sibling in the highest PRS quintile increased from 4% between the ages of 65\u201374\u2009years to 39% at age 85 and older.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>PRS can be used to estimate penetrance and recurrence risk in familial Alzheimer's disease among carriers and non\u2010carries of <jats:italic>APOE\u2010\u03b54.<\/jats:italic><\/jats:p><\/jats:sec>","DOI":"10.1002\/acn3.51757","type":"journal-article","created":{"date-parts":[[2023,3,22]],"date-time":"2023-03-22T14:30:59Z","timestamp":1679495459000},"page":"744-756","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Polygenic risk score penetrance &amp; recurrence risk in familial Alzheimer disease"],"prefix":"10.1002","volume":"10","author":[{"given":"Min","family":"Qiao","sequence":"first","affiliation":[{"name":"Department of Neurology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain and the Gertrude H. Sergievsky Center Columbia University and the New York Presbyterian Hospital  New York New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Annie J.","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Neurology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain and the Gertrude H. Sergievsky Center Columbia University and the New York Presbyterian Hospital  New York New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dolly","family":"Reyes\u2010Dumeyer","sequence":"additional","affiliation":[{"name":"Department of Neurology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain and the Gertrude H. Sergievsky Center Columbia University and the New York Presbyterian Hospital  New York New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giuseppe","family":"Tosto","sequence":"additional","affiliation":[{"name":"Department of Neurology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain and the Gertrude H. Sergievsky Center Columbia University and the New York Presbyterian Hospital  New York New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kelley","family":"Faber","sequence":"additional","affiliation":[{"name":"Department of Medical and Molecular Genetics, National Centralized Repository for Alzheimer's Disease and Related Dementias (NCRAD) Indiana University School of Medicine  Indianapolis Indiana USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alison","family":"Goate","sequence":"additional","affiliation":[{"name":"Department of Genetics &amp; Genomic Sciences, Ronald M. Loeb Center for Alzheimer's disease Icahn School of Medicine at Mount Sinai  New York New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alan","family":"Renton","sequence":"additional","affiliation":[{"name":"Department of Genetics &amp; Genomic Sciences, Ronald M. Loeb Center for Alzheimer's disease Icahn School of Medicine at Mount Sinai  New York New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Chao","sequence":"additional","affiliation":[{"name":"Department of Genetics &amp; Genomic Sciences, Ronald M. 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