Herpesvirus Exposure, Cognitive Decline and Alzheimer Disease in Older Adults: Insights from a Multi-Cohort Study Using a Novel Multiplex Sero-assay

Abstract Background Evidence increasingly supports the “infectious hypothesis” of Alzheimer Disease (AD) in older adults, proposing that common pathogens—particularly human herpesviruses—increase one's risk of AD. However, most studies have used medical records and clinically-diagnosed infections to test this association. To obtain a direct measure of viral exposure history, we developed a novel multiplex sero-assay enabling simultaneous measurement of antibodies to a broad variety of common infections and applied it to several unique clinical cohorts to interrogate the infectious hypothesis of AD. Methods Using nearly 6,000 samples from three studies (TUDA, TIMC-BRAiN, NILVAD), plasma IgG to 50 pathogens was measured via a multiplex bead-based assay. Associations were examined in the community-based TUDA cohort and further explored in clinical cohorts (TIMC-BRAiN, NILVAD) using paired plasma/cerebrospinal fluid (CSF) samples and high-sensitivity biomarkers of inflammation and neurodegeneration. Linear regression results are presented as Beta Coefficients (B), 95% Confidence Intervals, and p-values with adjustment for important clinical covariates. Results In TUDA (n=4,796, age: 73.7±8.17 years, 67.2% female), Herpes Simplex Virus 1 (HSV1) seropositivity was significantly associated with poorer total RBANS scores (B: -3.78, 95%CI: -5.50 to -2.07, p<0.001) and poorer performance on all RBANS domains. Cytomegalovirus (CMV) seropositivity was significantly associated with poorer total RBANS performance (B: -1.38, 95%CI: -2.23 to -0.52, p=0.002). In NILVAD, CMV seropositivity was associated with greater baseline dementia severity (B: 1.47, 95%CI: 0.58 to 2.36, p=0.001 on CDR-Sb). In clinical cohorts (TIMC-BRAiN, NILVAD), pathogen seropositivity was not associated with AD biomarkers or AD clinical progression over 18-months. Across all three cohorts, herpesvirus seropositivity was consistently associated with elevated systemic inflammatory markers (IL-6, TNF-α). Conclusion Herpesvirus exposure (HSV1, CMV) was robustly associated with poorer cognitive performance, potentially mediated by non-specific systemic inflammatory effects. However, direct involvement of HSV1 or CMV in AD pathogenesis or progression was not supported by the current analysis.