ApoE2 and protective molecular signatures in Alzheimer’s disease and aging

Objective: to identify personalized polygenic profiles, comprised of the APOE e2 allele, other SNPs in the APOE region, and SNPs spread through the entire genome, with stronger protection in aging and Alzheimer’s Disease (AD) framework, and identify the role of AD risk factors in these profiles using ADSP and 10 more studies. Study design: Aim 1 will identify molecular signatures of aging-related traits (AD, cardiovascular diseases, longevity, etc.), defined as differences in linkage disequilibrium (LD) patterns between affected and unaffected subjects using methods of LD analysis. In Aim 2 we will dissect heterogeneity in the molecular signatures using methods of stratification analyses. We will examine the impact of age at onset, sex, race/ethnicity, Braak stage, AD risk factors (diabetes, lipids, hypertension, body mass index, education), and other factors. Aim 3 will identify personalized polygenic profiles of aging-related traits using traditional and advanced bio-demographic methods. In Aim 4 we will perform bioinformatics analysis and characterize transcription pathways using summary statistics and individual-level data from the expression quantitative trait loci studies. In some cases, we may need to pool several datasets to increase power of the analyses in a mega sample. This will be done by pooling individuals’ records for genotypes and selected phenotypes described above from different studies. This pooling will not create any additional risks to participants because neither genetic nor phenotypic information for the same individual will increase.
This research is consistent with data use restrictions for ADSP. We will not conduct non-genetic research, will not investigate individual pedigree structures, population origins, ancestry, individual participant genotypes, perceptions of racial/ethnic identity, variables that could be considered as stigmatizing an individual or group, or issues such as non-maternity. The research is designed to protect data confidentiality and follow local and institutional policies and procedures for data handling. The results of this research will be broadly shared with the scientific community.

Increasing population of the elderly individuals worldwide raises serious concerns about burden of geriatric conditions in future, especially Alzheimer’s disease, cardiovascular diseases, and other common aging-related diseases. These diseases can cluster in families suggesting that they can have genetic origin. Understanding their genetic origin could lead to breakthrough in preventing or curing such diseases. Despite continuing efforts, understanding their genetic basis remains very limited. Particular problem is to better understand genetic basis of Alzheimer’s disease, its relationship to other aging-related diseases, and identify genetic variants which could help protect against such diseases. This project focuses on identifying personalized polygenic profiles involving the Alzheimer’s disease protective genetic variant, so-called APOE e2 allele, which could strengthen protective effects against Alzheimer’s disease and investigate which factors can improve this protection. This research will facilitate the development of interventional strategies aiming to promote healthy aging.