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Most PRSs are constructed in European\u2010ancestry populations, limiting their use in other ethnicities. Here we constructed and validated a PRS for late\u2010onset Alzheimer's Disease (LOAD) in Caribbean Hispanics (CH).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We used a CH discovery (n\u00a0=\u00a04,312) and independent validation sample (n\u00a0=\u00a01,850) to construct an ancestry\u2010specific PRS (\u201cCH\u2010PRS\u201d) and evaluated its performance alone and with other predictors using the area under curve (AUC) and logistic regression (strength of association with LOAD and statistical significance). We tested if CH\u2010PRS predicted conversion to LOAD in a subsample with longitudinal data (n\u00a0=\u00a01,239). We also tested the CH\u2010PRS in an independent replication CH cohort (n\u00a0=\u00a0200) and brain autopsy cohort (n\u00a0=\u00a033). Finally, we tested the effect of ancestry on PRS by using European and African American discovery cohorts to construct alternative PRSs (\u201cEUR\u2010PRS\u201d, \u201cAA\u2010PRS\u201d).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The full model (LOAD ~ CH\u2010PRS\u2009+\u2009sex + age\u2009+\u00a0<jats:italic>APOE\u2010\u025b4)<\/jats:italic>, achieved an AUC\u00a0=\u00a074% (OR<jats:sub>CH\u2010PRS<\/jats:sub>\u00a0=\u20091.51 95%CI\u00a0=\u00a01.36\u20131.68), raising to &gt;75% in<jats:italic>APOE\u2010\u025b4<\/jats:italic>non\u2010carriers. CH\u2010PRS alone achieved an AUC\u00a0=\u00a072% in the autopsy cohort, raising to AUC\u00a0=\u00a083% in full model. Higher CH\u2010PRS was significantly associated with clinical LOAD in the replication CH cohort (OR\u00a0=\u00a01.61, 95%CI\u00a0=\u00a01.19\u20132.17) and significantly predicted conversion to LOAD (HR\u00a0=\u00a01.93, CI\u00a0=\u00a01.70\u20132.20) in the longitudinal subsample. EUR\u2010PRS and AA\u2010PRS reached lower prediction accuracy (AUC\u00a0=\u00a058% and 53%, respectively).<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>Enriching diversity in genetic studies is critical to provide an effective PRS in profiling LOAD risk across populations. ANN NEUROL 2021;90:366\u2013376<\/jats:p><\/jats:sec>","DOI":"10.1002\/ana.26131","type":"journal-article","created":{"date-parts":[[2021,5,26]],"date-time":"2021-05-26T17:53:18Z","timestamp":1622051598000},"page":"366-376","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["Polygenic Risk Score for Alzheimer's Disease in Caribbean Hispanics"],"prefix":"10.1002","volume":"90","author":[{"given":"Sanjeev","family":"Sariya","sequence":"first","affiliation":[{"name":"Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons Columbia University New York NY"},{"name":"The Gertrude H. 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