Immunity in AD

Objective: The HLA region was previously identified in an Alzheimer’s GWAS study. The role of the adaptive immune system in Alzheimer’s is not well understood, despite emerging evidence suggesting infectious agents may be contributing to the disease.

Study design: Using the data requested from NIAGADS, we will attempt to remap the HLA region to produce a more better defined haplotypes for each sample. We will also look at other variants of interest associated with Alzheimer’s and/or the innate and adaptive immune system, to pursue hypotheses around how these two arms of the immune system may interact. We will also use these data to perform association testing, identifying variants associated with AD risk or infection and evaluating their sensitivity to covariates such as APOE genotype, sex, and ancestry.

Analysis plan: Data from NIAGADS with be downloaded to an AWS instance. Regions of interest, such as the HLA region on chromosome 6, will be extracted using samtools. Additional genotype data will be imputed using the Michigan Imputation Server and reference data selected to best match the ancestry(s) represented in the data. Association
testing will adjust for population structure and genetic relatedness. Variants of interest will be annotated using resources such as the Variant Effect Predictor and the Genotype-Tissue Expression project to facilitate the interpretation of association results. Pathway analyses may be used to better understand potential relationships between implicated genes and genes previously implicated in AD and related disorders. We will perform genome scans in large data sets representing diverse ancestries. We will use imputed genotype data within association signals to fine-map the location of variants associated with Alzheimer’s disease. Association testing across independent data sets will be used to replicate these signals. We will use variant annotation to describe the potential relationships between implicated variants and gene function, regulation, and pathways. This work will attempt to identify genes involved in the innate and adaptive immune responses in connection with AD.

We will be investigating the possible connections between genes in the immune system and Alzheimer's disease. We will be looking at both the innate and adaptive arms of the immune system. We will also include approaches that consider the potential role of pathogens in contributing to Alzheimer's etiology.