Adult Vaccination History and Plasma Biomarker Signatures in the Asymptomatic PREVENT-AD Cohort

Background: Epidemiological studies increasingly associate several adult vaccinations with lower risk of Alzheimer disease (AD) and dementia, but the biological mechanisms underlying these observations remain unclear. We investigated whether adult vaccination history is associated with AD-related and immune-related biomarker profiles in cognitively unimpaired individuals at increased familial risk for AD. Methods: This exploratory study included 192 participants from the PREVENT-AD cohort. Adult vaccination and infection histories were collected using a structured questionnaire and examined in relation to plasma and cerebrospinal fluid (CSF) biomarkers. Adjusted regression models evaluated individual vaccine exposures, vaccination-profile breadth, broader proteomic signatures, CSF biomarkers, viral-history interactions, and psychological symptoms, with false-discovery-rate (FDR) correction applied for multiple testing. Results: Influenza, herpes zoster, pneumococcal, and Td/Tdap vaccination were not associated with FDR-significant differences in the principal plasma amyloid and tau biomarker panel. Hepatitis B vaccination was associated with lower plasma total tau/MAPT, p-tau181, and p-tau231 after correction within the AD biomarker panel, although these findings may reflect residual behavioral or healthcare-related confounding. Greater vaccination-profile breadth was associated with higher plasma NPTX1 (beta = 0.261, p = 0.007, q = 0.049), whereas its nominal association with a lower Amyloid Beta 42/40 ratio did not survive FDR correction. Nominal herpes zoster associations with lower CSF Amyloid Beta 42 and pTau were similarly attenuated after correction. No robust FDR-significant associations emerged from viral-history interaction or psychological symptom analyses. Conclusions: Adult vaccination history was not associated with a broad plasma amyloid or tau signature in this asymptomatic, familial-risk cohort. However, the association between broader vaccination exposure and higher NPTX1 suggests a potentially distinct synaptic-related signal, while the hepatitis B findings identify additional hypothesis-generating tau-related associations. Longitudinal studies incorporating vaccine timing, infection burden, and repeated biomarker measurements are needed to determine whether vaccination influences biological pathways relevant to AD resilience.