Atovaquone/Proguanil Use and Zoster Vaccination Are Associated with Reduced Alzheimer's Disease Risk in Two Cohorts: Implications for a Latent Toxoplasma gondii Mechanism

INTRODUCTION: Identifying modifiable risk factors for Alzheimer's disease (AD) may shed light on novel mechanisms and inform prevention strategies. Increasing evidence suggests that latent pathogens may contribute to AD pathogenesis via chronic neuroinflammation. METHODS: We conducted a large-scale, dual-cohort study to identify exposures associated with reduced Alzheimer's disease (AD) risk. In a national Israeli cohort (Leumit Health Services; 2004-2024), we analyzed 9,124 AD patients and 18,248 matched controls. We systematically screened medication exposures in the matched cohort for associations with significantly reduced AD risk (OR < 0.5, FDR < 0.05). To account for potential residual confounding, we applied conditional logistic regression models adjusted for age, sex, socioeconomic status, and relevant comorbidities. Findings were independently validated in the U.S.-based TriNetX network, which includes electronic health records from over 120 million patients across 69 healthcare organizations. Propensity score-matched Cox proportional hazards models were used to estimate hazard ratios (HRs) for dementia incidence across stratified age groups. RESULTS: Atovaquone/proguanil (Ato/Pro), an antiprotozoal agent active against Toxoplasma gondii, was strongly associated with reduced AD risk in both cohorts (LHS: OR 0.36 [95% CI, 0.20-0.61]; TriNetX: HRs 0.34-0.51, p = 10-17 to 10-40 across age groups 50-59, 60-69, and 70-79). Both recombinant and live attenuated varicella-zoster virus (VZV) vaccines were also significantly protective (ORs 0.16-0.37), and T. gondii seropositivity was associated with a 2.43-fold increased risk of dementia (p = 0.0013). Notably, Ato/Pro's protective effect was more pronounced in individuals without prior VZV vaccination (HR 0.51 [0.43-0.59]) compared to vaccinated individuals (HR 0.71 [0.59-0.85]). DISCUSSION: This dual-cohort study - spanning over 120 million patients across two nations - demonstrates strong and reproducible associations linking Ato/Pro use and VZV vaccination to reduced AD risk. The findings support a mechanistic model in which latent T. gondii infection, potentially reactivated by herpesvirus co-infection may contribute to AD pathogenesis. Ato/Pro may protect by eliminating or suppressing T. gondii, while VZV vaccination may reduce viral triggers of parasite reactivation. These results point to novel preventive strategies and reinforce the infectious hypothesis of Alzheimer's disease.