Understanding the role of genetic admixture in Alzheimer's disease risk in Latino populations

We aim to evaluate the potential modification of AD risk and manifestation of AD phenotypes through varying patterns of admixture, local ancestry, and global ancestry proportions within and between Latíno populations. We aim to develop an ancestry informed risk model and report how consideration of local and global ancestry may influence estimated effects of known AD risk factors to influence AD risk and phenotypes. We will leverage this information to build improved PRS and compare local ancestry aware methods to other common methods for improving multi-ancestry portability of PRS scores.
Specifically our study aims to classify:
1. The risk of AD conferred by the local ancestry of genetic risk factors in admixed populations
2. Methods and computational pipeline for establishing an ancestry informed risk score for AD in admixed populations from the US and Latin America
3. How patterns of admixture across a genome influence AD risk and modify associations with common co-morbidities or AD risk in response to social determinants of health or heath and other non-genetic AD risk factors.
4. How local ancestry informed PRS compare to other common methods for PRS derivation in admixed populations (PRS-CSx for example, as well as PolyPred-S, SBayesRC, etc, and other to-be published methods) including PRS methods which leverage ADRD-relevant functional annotation and QTL resources, such as for transcriptome based risk scoring
Since we will be using multiple data sets and harmonization of those data might not be the most statistically appropriate route to answer the specific questions our project seeks to address, we will in some cases perform a meta-analysis. To complete a meta- analysis specific to each objective of this proposal, we will employ a meta-analysis framework that has utility in both multiethnic and ethnic-specific analysis. Additionally, where appropriate, we will use linear mixed effects models and linear regression models to measure associations/correlations of the variables we will examine in our investigation (e.g. associations/correlations of longitudinal or cross-sectional global cognition with gene expression).

AD disparities between populations are well documented and are influenced by both social determinants of health and the genetic architecture specific ethnic groups. Our research aims to build a comprehensive model that elucidates how AD risk is modified in response of varying patterns of admixture within and between Latino populations. This study will report how ancestry differentiated and specific genetic loci (in terms of both variant frequency and effect size) modify AD risk, if differential patterns of admixture influence AD risk in the context of global ancestry proportions, and whether the expressivity of AD phenotypes is modified by admixture patterns across the genome in Latíno populations. Furthermore, this study will determine whether non-genetic risk factors along in combination with environmental risk factors that may be specific to sub-populations of Latínos mediate risk for AD in response to differential patterns of admixture.