Zoster Vaccination and Dementia: Interpreting the Signal and Testing the Mechanisms.

Several observational studies and recent natural experiments suggest that herpes zoster vaccination is associated with fewer subsequent dementia diagnoses. Quasi-experimental analyses that exploit date-of-birth eligibility thresholds, largely involving the live attenuated zoster vaccine, strengthen causal inference by reducing confounding from preventive-care behaviors and healthcare utilization; however, they do not establish mechanism or distinguish disease prevention from delayed diagnosis. Three non-mutually exclusive pathways merit direct evaluation: reduced cumulative varicella-zoster virus reactivation burden, including recurrent and possibly unrecognized events; vaccine-induced immune modulation that alters immune aging and inflammatory responses; and neurovascular and neuroinflammatory injury as intermediate pathways linking zoster to later cognitive decline. Priority should now shift to stronger causal designs, pathway-focused analyses of reactivation and vascular intermediates, and prospective studies incorporating longitudinal immune phenotyping and blood-based biomarkers.