Atovaquone/proguanil use and zoster vaccination are associated with reduced Alzheimer’s disease risk in two cohorts: implications for a latent Toxoplasma gondii mechanism

• Systematic screening identifies atovaquone-proguanil and VZV vaccination as associated with lower dementia risk over 10 years. • National cohort findings are independently replicated in TriNetX (>120 million individuals) • Atovaquone-proguanil shows a stronger association with reduced Alzheimer’s disease risk among VZV-unvaccinated individuals. • Toxoplasma gondii seropositivity is associated with increased dementia risk. • Findings support a testable neuroimmune hypothesis involving VZV reactivation of latent protozoal infection in Alzheimer’s disease. Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with a multifactorial and incompletely understood etiology. Identifying exposures associated with reduced AD risk may help generate mechanistic hypotheses and inform future prevention strategies. To investigate such associations, we analyzed electronic health records from a national Israeli health provider, retrospectively comparing 9,124 individuals with AD to 18,248 matched controls. We systematically screened prior medication purchases recorded up to 10 years before diagnosis. Significant associations, adjusted for residual confounding, were further evaluated in the TriNetX network, where large propensity score-matched cohorts were compared for incident dementia following medication exposure or vaccination. Among all exposures assessed, strong protective associations were observed for atovaquone-proguanil, an antiprotozoal agent with established activity against Toxoplasma gondii , and for two different varicella-zoster virus (VZV) vaccines. These associations persisted after adjustment for demographic factors, comorbidities, and baseline healthcare utilization, and were independently reproduced in TriNetX across three strata of exposure age (50–59, 60–69, 70–79 years). In addition, T. gondii seropositivity was associated with increased dementia risk among individuals tested. In exploratory analyses, the magnitude of the association between atovaquone-proguanil and subsequent dementia appeared to differ according to prior VZV vaccination status, suggesting a possible interaction between protozoal suppression and antiviral immunity. Together, these findings provide population-level evidence consistent with a latent T. gondii -related mechanism in AD pathogenesis, and highlight testable targets for future mechanistic and interventional research.