Oral Presentation 28th Annual Lorne Proteomics Symposium 2023

A Multi-Omic Investigation into the Role of the APOE Genotype in Alzheimer’s Disease (#47)

Erin Baker 1 , Melanie Odenkirk 2 , Kristin Burnum-Johnson 3 , Blaine Roberts 4
  1. University of North Carolina at Chapel Hill, Chapel Hill, NORTH CAROLINA, United States
  2. Chemistry, University of Arizona, Tucson, AZ, United States
  3. Pacific Northwest National Laboratory, Richland, WA
  4. Biochemistry, Emory, Atlanta, GA, United States

Alzheimer’s disease (AD) is a progressively common neurodegenerative disease that affects 47 million people worldwide. Despite extensive efforts, AD neuropathology remains confounded as underlying factors such as age and the APOE allele type alter AD progression mechanisms and challenge the development of effective treatments and intervention strategies. To gain a better understanding of the neuropathology of AD, we evaluated molecular mechanisms reflective of APOE allele types in two brain regions. Thus, post-mortem cerebellum (CBM) and frontal cortex (FCX) brain tissue collected from 62 patients [29 healthy control (HC) and 33 AD] having ε2/ε3, ε3/ε3, ε3/ε4, or ε4/ε4 allele groups. Multi-omic evaluations of the proteins, lipids and metals for each brain tissue sample were conducted to holistically characterize the genotype differences. Bottom-up proteomic and lipidomic analyses were performed by coupling liquid chromatography, ion mobility spectrometry and mass spectrometry (LC-IMS-MS) measurements to provide confident peptide and lipid identifications, and 15 metals were assessed with ICP-MS. Evaluation of the multi-omic studies showed molecular changes in the AD and HC comparisons for the different allele types, reflecting distinct AD progression mechanisms. Namely, proteins that mapped to the KEGG Alzheimer’s pathway were dysregulated to the greatest degree for the ε3/ε4 allele group in the CBM and the ε3/ε3 group in the FCX. Conversely, the ε2/ε3 AD versus HC comparison was the least perturbed in both brain regions. Lipidomic analyses revealed heightened dysregulation in the FCX for the ε3/ε3 and ε3/ε4 allele types, while the ε2/ε3 AD group showed little dysregulation relative to the ε2/ε3 HC except for lysolipids within the CBM being significantly downregulated. Metallomics further elucidated Zn66, Cu63 and Fe56 all being upregulated in the FCX tissue for AD patients.