Herpesvirus Exposure, Cognitive Decline and Alzheimer Disease in Older Adults: Insights from a Multi-Cohort Study Using a Novel Multiplex Sero-assay
Bibliographic record
Abstract
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.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.003 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".