AbstractObjectiveTo compute penetrance and recurrence risk using a genome‐wide PRS (including and excluding theAPOEregion) in families with Alzheimer's disease.MethodsGenotypes 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 flankingAPOE. 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 withinAPOE‐ε4carriers and non‐carriers.ResultsPRS excluding theAPOEregion was strongly associated with clinical and neuropathological diagnosis of AD. PRS association with AD was similar in participants who did not carry anAPOE‐ε4allele (OR = 1.74 [1.53–1.91]) compared withAPOE‐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 byAPOE‐ε4allele, PRS in the highest quintile was significantly more penetrant than the lowest quintile, both, withinAPOE‐ε4carriers (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.InterpretationPRS can be used to estimate penetrance and recurrence risk in familial Alzheimer's disease among carriers and non‐carries ofAPOE‐ε4.