Multimodal Analysis of AD

The principal goal of this study is to identify novel genetic signatures associations with subtypes of Alzheimer’s disease (AD). Specifically, we aim to (a) identify subtypes of AD using phenotypic variables including age-of-onset, sex, years of education, clinical measurements, and neurocognitive measurements, and (b) identify novel genetic signatures that include rare variants, APOE status and/or polygenic risk scores (PRS), which are associated with these subtypes. Current knowledge from literature and databases will be utilized to perform feature engineering such as calculation of PRS and genomic-region-based-bins for rare variant burden. We will employ unsupervised learning such as community detection and clustering algorithms to identify subtypes of AD, and supervised learning such as decision tree and regularization algorithms to find genetic signatures that are associated with the subtypes. The identified genetic signatures will be evaluated using appropriate performance metrics for the predictive models used. As more phenotypic variables are made available, the models will be updated to refine the subtypes with better characterization. It is anticipated that the novel genetic signatures will yield insight into the etiologies of the heterogeneous Alzheimer’s disease, and therefore provide opportunities to develop personalized treatments.

Initially, we will use the NIAGADS data to generate preliminary data for grant submissions. After receiving award, the project would utilize the very valuable dataset fully.

Alzheimer’s disease (AD) is a heterogeneous condition and is high heritable (58-79% heritability for late-onset and >90% heritability for early-onset). We have yet to identify large proportion of genetic variants that either increase or decrease risk for different subtypes of AD such as early-onset or late-onset. In the proposed study, we plan to identify genetic signatures for the different subtypes of AD. Unraveling the heterogeneity of AD and its associated genetic signatures is critical for implementation of precision medicine to combat such a devastating disease.