Objective: To investigate the association between a genetic risk score (GRS) and familial late-onset Alzheimer disease (LOAD) and its predictive value in families multiply affected by the disease. Methods: Using data from the National Institute on Aging Genetics Initiative for Late-Onset Alzheimer Disease (National Institute on Aging-Late-Onset Alzheimer's Disease Family Study), mixed regression models tested the association of familial LOAD with a GRS based on single nucleotide polymorphisms (SNPs) previously associated with LOAD. We modeled associations using unweighted and weighted scores with estimates derived from the literature. In secondary models, we adjusted subsequent models for presence of the APOE ϵ4 allele and further tested the interaction between APOE ϵ4 and the GRS. We constructed a similar GRS in a cohort of Caribbean Hispanic families multiply affected by LOAD by selecting the SNP with the strongest p value within the same regions. Results: In the NIA-LOAD families, the GRS was significantly associated with LOAD (odds ratio [OR] 1.29; 95% confidence interval 1.21-1.37). The results did not change after adjusting for APOE ϵ4. In Caribbean Hispanic families, the GRS also significantly predicted LOAD (OR 1.73; 1.57-1.93). Higher scores were associated with lower age at onset in both cohorts. Conclusions: High GRS increases the risk of familial LOAD and lowers the age at onset, regardless of ethnic group.