CMV titer associations with cognition and the plasma proteome implicate FLT1 and neurovascular mechanisms as potential moderators

Immune processes play complex roles in Alzheimer’s disease and related dementias (ADRD), but it remains unclear whether host defenses against common microbes also contribute to ADRD, and what underlying mechanisms may account for these relationships. Using antibody and plasma proteomic data from the Monongahela-Youghiogheny Healthy Aging Team study (n = 1,003; mean age = 78.0 yrs; follow up 7.6 yrs), the present study detected accelerated decline across a variety of cognitive domains and altered plasma abundance of FLT1 (also known as Vascular Endothelial Growth Factor Receptor 1) among participants with elevated cytomegalovirus (CMV) titers. After analyses in the Baltimore Longitudinal Study of Aging (n = 323) and the UK Biobank (n = 956) revealed CMV titer associations with higher cross-sectional cognition and greater cognitive decline were moderated by plasma FLT1 abundance, we leveraged two-sample Mendelian Randomization to uncover causal roles for host immune responses to CMV, including limiting brain amyloidosis. Using multi-cohort proteomic signatures of CMV antibody levels and plasma FLT1, bioinformatic analyses suggested that host immune responses to CMV may impact neurologic health through alterations in lymphocytic immunoregulatory cascades, with circulating FLT1 abundance capturing the extent to which these effects may be transmitted across the blood–brain-barrier. In addition to detecting pleiotropic associations of CMV titers with neurocognitive outcomes, our findings highlight FLT1 as an important molecular moderator of these effects, and extend our understanding of the biological basis by which host immune responses to common microbes may contribute to ADRD.