An Old Pathway Learns Two New Tricks: Role of Complement in Postoperative Cognitive Dysfunction, and in Synaptic Damage in APOE4 carriers

Abstract

AbstractBackgroundGenetic studies in both mice and humans suggest a role for complement in Alzheimer's disease, but exactly how complement contributes to preclinical AD progression is unclear. It is also unclear to what extent complement may play a role in AD risk within APOE4 carriers, or in the pathophysiology of perioperative neurocognitive disorders in older adults.MethodWe developed a hybrid proteomics platform, which uses both LC‐MS/MS for unbiased discovery across the entire human proteome, as well as stable isotope labelled (SIL) peptides for complement proteins to precisely quantify complement protein‐derived peptides (as would normally be possible only in a targeted proteomics assay). This platform was then used to study proteins and pathways altered in the CSF of APOE4 carriers vs non‐carriers, in which the vast majority of both groups were amyloid negative. We also used this platform to study pre‐operative samples from patients who did and those who did not develop postoperative delirium. Generally Applicable Gene Set Enrichment (GAGE) analysis was used to study alterations within specific protein pathways in both APOE4 carriers, and in patients with postoperative cognitive dysfunction.ResultIn our unbiased data, we detected >9,000 different peptides from 884 different proteins in over 100 CSF samples from older adults with normal cognition, including over 200 different complement protein‐derived peptides. In the complement proteins for which we had SIL peptides, we found an average reduction of ∼8.4% ± 0.5% in the levels of more than 50 peptides from each protein in the classical, alternative and mannose binding lectin complement cascades in APOE4 homozygotes versus APOE4 non‐carriers; the odds of this happening by chance would be 1 out of 2 x10^15. We also found reductions in complement proteins (and a significant change in the complement pathway as a whole) at multiple time points before and after surgery in patients who developed postoperative cognitive dysfunction.ConclusionThese results suggest that CNS complement pathway activation may play a role in both postoperative cognitive dysfunction, and in APOE4‐induced brain damage even in the absence of amyloid pathology.