APOE*4 Risk-Modifying Genes and Drug Targets in Alzheimer's Disease through Cell-Type Specific Genomic Analyses.

Area of Science:

• Neurogenetics
• Genomics
• Alzheimer's Disease Pathogenesis

Background:

• Apolipoprotein E (APOE) *4 is the most significant genetic risk factor for late-onset Alzheimer's disease (AD).
• Previous genetic studies on AD have not fully explored cell-type-specific impacts or integrated multi-omics data.
• Identifying counteracting genes requires a cell-type-specific framework.

Purpose of the Study:

• To conduct a large-scale, APOE *4-stratified genome-wide association study (GWAS) for AD.
• To integrate GWAS findings with cell-type-specific multi-omics data to identify novel AD-associated genes.
• To prioritize druggable targets and explore compound repurposing for AD based on APOE *4 status.

Main Methods:

• Meta-analysis of large AD cohorts including UK Biobank, Alzheimer's Disease Genetics Consortium, and Alzheimer's Disease Sequencing Project.
• Integration of GWAS data with brain cell-type-specific gene expression data (snRNA-seq).
• Prioritization of genes and compounds using multi-omics data and drug databases.

Main Results:

• Identified 67 significant cell-type-gene pairs in APOE *4 non-carriers and 17 in carriers.
• Oligodendrocytes showed the highest proportion of APOE *4-associated genes.
• Several prioritized genes (e.g., TNS3, CISD1, SLC23A2, UBXN4) were druggable, with associated compounds like Hydrocortisone and Trolox implicated in neuroinflammation and oxidative stress.

Conclusions:

• This study identified APOE *4-stratified genes potentially causal for AD via cell-type-specific mechanisms.
• Prioritized genes and compounds offer potential therapeutic avenues for AD treatment tailored to APOE *4 status.
• Findings highlight oxidative stress and neuroinflammation as key targets in APOE *4-positive AD.