Proteomic signatures of corona and herpes viral antibodies identify IGDCC4 as a mediator of neurodegeneration.

Abstract

Mechanisms underlying the dynamic relationships of viral infections and neurodegeneration warrant examination. Using a community-based cohort of older adults, the current study characterized the neurocognitive (cognitive functioning, brain volumes, Alzheimer's disease positron emission tomography, and plasma biomarkers) and plasma proteomic (7268 proteins) profiles of four common coronavirus and six herpesvirus antibody titers. Genetic inference techniques demonstrated the associations between viral antibody titers and neurocognitive outcomes may be attributed to altered expression in a subset of mechanistically relevant proteins in plasma. One of these proteins, IGDCC4 (immunoglobulin superfamily deleted in colorectal cancer subclass member 4), was related to 20-year dementia risk, cognitive functioning, and amyloid-β positivity using data from two independent cohorts, while its plasma and intrathecal abundance were causally implicated in dementia risk and clinically relevant brain atrophy. Our findings illuminate the biological basis by which host immune responses to viruses may affect neurocognitive outcomes in older adults and identify IGDCC4 as an important molecular mediator of neurodegeneration.