APOE genotype or presence of brain amyloid alters the plasma proteome in cognitively normal, elderly subjects

Background Processes that drive Alzheimer’s disease pathogenesis have long been considered to occur within the central nervous system, yet recent studies have bolstered the possibility that changes in the periphery may be relevant to the disease process. Accumulating evidence has suggested that proteins changing in the blood may be reliable indicators of disease within the brain. Recent advances in geroscience have identified potential mechanisms of blood-brain communication that modulate brain function in ways that could be harnessed for therapy. While blood-borne proteins associated with either youth or old age have been targeted to restore function to the aged brain, it remains unclear whether other dysfunctional systemic states can be exploited for similar benefits. Here we investigate whether APOE allelic variation or presence of brain amyloid are associated with distinct proteomic changes within the systemic environment and what molecular processes are associated with these changes. Methods Using the SOMAscan assay, we measured 1,305 plasma proteins from 53 homozygous APOE3 and APOE4 subjects (mean age = 68 years; minimum = 54 years) who exhibited no cognitive impairment, some of whom can be categorized as harboring cerebral amyloid based on cerebrospinal fluid Aβ42 measurements. Using the Dream R package for linear mixed effects modeling, we investigated possible contributions of either the APOE-ε4 allele or amyloid positivity to changes in the plasma proteome. Ontology-based pathway and module trait correlation analyses were performed to understand disrupted pathways that vary based on APOE genotype or amyloid positivity. Results We found that expression of the APOE-ε4 allele produced distinct changes in the composition of the plasma proteome. Using both pathway enrichment analysis and weighted gene co-expression network analysis, we found that plasma proteins associated with APOE4 expression were linked to pathways related to atherosclerosis, lipid transport, the extracellular matrix, and synaptogenesis signaling. Independent of APOE4 , we found that cognitively normal, amyloid-positive subjects exhibit distinct plasma proteome signatures associated with pathways previously linked to AD pathology, relative to amyloid-negative controls. Harboring brain amyloid was associated with plasma proteomic changes linked to dysfunction in blood-brain barrier and other neural cell types. Our results indicate that changes in the plasma proteome are related to possession of AD risk alleles, as well as the presence of amyloid pathology in subjects prior to the onset of symptoms. This work highlights the possibility that pathways in the systemic environment in certain risk contexts may be plausible targets to explore for modulating disease. ### Competing Interest Statement J.M.C. is listed as a co-inventor on patents for treating aging-associated conditions, including the use of young plasma administration (US10688130B2) or youth-associated protein TIMP2 (US10617744B2), the latter of which is licensed to Alkahest, Inc. The remaining authors have no actual or potential conflicts of interest to declare. * AD : Alzheimer’s disease APOE : apolipoprotein E BBB : blood-brain barrier CDR : clinical dementia rating CNS : central nervous system CRP : C-reactive protein CSF : cerebrospinal fluid DAVID : Database for Annotation, Visualization, and Integrated Discovery ECM : extracellular matrix IPA : Ingenuity Pathway Analysis SOMA : slow off-rate modified aptamers TOM : topological matrix overlap WGCNA : weighted gene co-expression analysis