The design of this study has several strengths. First, because most families have a strong history of AD, the sample is likely enriched for a greater genetic contribution to risk. Second, family-based analysis is robust to population substructures such as slight differences in ethnicity. This family-based design has been previously used to test for association with event-related brain oscillations correlated with deficits in alcoholics and offspring who are at risk for AD, with genome-wide significant association (p = 4.7 × 10−10) of SNPs in KCNJ6 (Kang et al., 2012). We did not correct the significance threshold for the number of phenotypes analyzed; however, there was no indication of inflated association results, and the correlated phenotypes are all related to AD. A weakness of the study is the cross-sectional nature of the phenotypes employed. Thus a longitudinal investigation to follow-up on individuals in the low-risk and especially those in the moderate-risk classes who are not yet AD could provide insight as to clusters of individuals who change latent classes over time, and further evidence of the validity of employing homogenous phenotypes and suggest a genetic mechanism of liability.
