Poster M1 - Large-scale proteomics analysis of Alzheimer’s Disease plasma blood reveals sex and APOE specific signatures

Introduction: Age, sex, and APOE4 genotype are key non-modifiable risk factors for Alzheimer’s disease (AD), with APOE4 significantly increasing risk, especially in women. The APOE-sex (APOE-SX) interaction underscores the need for personalized AD treatments. We analyzed plasma blood proteomic data from the UK Biobank to identify sex and APOE-specific protein and pathway signatures.

Materials and

Methods: Plasma samples were analyzed for participants diagnosed with AD and controls. After propensity-score matching on age and education level, 199 AD cases (133 females, F; 66 males, M) and 199 controls (104 F, 95 M) from APOE3/3, 3/4 and 4/4 individuals were retained. Protein levels were normalized using z-scores. For each APOE-SX condition, differentially expressed proteins (DEPs, p-value < 0.05) between AD and controls were identified using linear regression with empirical Bayes estimators to calibrate the per-protein variance using information from all the proteins. Gene Set Enrichment Analysis (GSEA) was subsequently conducted using Gene Ontology Biological Processes (GO-BP) accounting for DEP fold change. Redundant GO-BP terms (adjusted p-values < 0.05) were removed by computing GO-BP semantic similarity (cut-off of 0.6). Comparison analyses were then conducted to identify common and unique DEPs and enriched GO-BPs across APOE-SX conditions.

Results, Conclusions, and Discussions: Across all APOE-SX conditions, F4/4 exhibited the greatest number of DEPs (n=741), while M-44 had the least fewest (n=102), compared to matched controls. Proteomic analysis revealed DEPs specific and common across all conditions. For example, CCL8, involved in immunoregulatory processes, was overexpressed only in females. GSEA revealed the highest numbers of AD-enriched pathways in APOE3/3 carriers (n=37-40 GO-BPs), whereas M3/4 and M4/4 exhibited the fewest (n=13 and 17). Both unique and common GO-BPs were found related to APOE-SX signatures, such as downregulated pathways related to protein kinase activity were specific to F4/4, while intracellular transport and receptor signaling common to F3/4, F4/4, and M4/4. Notably, no common DEPs or GO-BP terms were found across all APOE-SX conditions.

These findings suggest APOE-SX specific proteomic signatures and altered biological processes in AD, supporting the development of personalized therapeutics considering APOE-SX interaction.

Acknowledgements (Optional): This work was supported by NIA grant P01-AG026572 and Women’s Alzheimer’s Movement to RDB