Prior research and the 2018 NIA-Alzheimer’s-Association framework emphasize that novel insights into the complex biology and heterogeneity of Alzheimer’s disease (AD) are needed to develop efficient interventions that can be tailored to persons’ unique risk profiles. These profiles are likely a result of an interplay of many genetic and non-genetic risk and protective factors for AD, including those of vascular origin, which are difficult to disentangle. Emerging evidence suggests also that ADs and vascular diseases tend to cluster together. This project addresses an objective of PAR-17-054 on disentangling heterogeneous interactions of genetic and AD/vascular risk factors in risk and resilience to AD, including age-specific effects, by leveraging existing resources and engaging in activities that will improve statistical power. Our approach, combining thorough methods of genome-wide association studies and the rigor of the candidate-like methods in large samples, is built on: (i) core principles of evolutionary biology in genetics of AD and other age-related traits characteristic of post-reproductive life, which deals with an inherent heterogeneity in genetic predisposition to such traits, (ii) insights from prior studies of such traits (including our own work), and (iii) promising results of our large-scale studies proving its significance, feasibility, and potential to substantially improve power using the existing resources. This research contributed to better understanding of weaknesses in the rigor of prior studies and provided compelling evidence that our approach is a natural and critical strategy to advance the progress in dissecting the inherently heterogeneous mechanisms of AD and vascular traits. The goal is to identify personalized (i.e., more homogeneous, group-specific) mono/polygenic profiles of risks and resilience to AD and vascular diseases in the disease-specific and pleiotropic contexts in prioritized loci leveraging information from the AD-centered pleiotropic meta-analysis planned in this project and previous analyses by our and other research groups, and identify the role of AD risk and other factors in these profiles. We will address the following specific aims: Aim 1. Identify specific and pleiotropic loci for AD and vascular traits from new analyses and the existing studies. Aim 2. Dissect heterogeneity leveraging the analysis of molecular signatures defined as differences in linkage disequilibrium structures in affected and unaffected subjects. Aim 3. Identify personalized genetic profiles of AD-specific and pleiotropic risks and resilience. Aim 4. Characterize the functional roles of SNPs from the identified mono/polygenic variants and biological roles of genes for these SNPs. Characterize transcription pathways for SNPs using individual-level gene expression and epigenetic data and summary statistics from the available expression and methylation quantitative trait loci studies.