Atovaquone/Proguanil and Zoster Vaccines Reduce Alzheimer’s Risk: A Role for Toxoplasma gondii?

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Abstract

INTRODUCTION

Identifying modifiable risk factors for Alzheimer’s disease (AD) may provide insights into its etiology and inform prevention strategies.

METHODS

We analyzed 9,124 AD patients and 18,248 matched controls from a national cohort (2004– 2024). Logistic regression, adjusted for age, gender, socioeconomic status, and comorbidities, identified medications tied to significant AD risk reduction (OR<0.5, FDR<0.05) for the decade following their uptake. Findings were validated in TriNetX (120M U.S. patients) using propensity score-matched Cox models for dementia hazard ratios (HR).

RESULTS

Atovaquone/proguanil (Ato/Pro) use was associated with lower AD risk (OR 0.36 [95% CI, 0.20– 0.61]; HR 0.43 [95% CI, 0.35–0.53]), as were both varicella-zoster virus (VZV) vaccines (OR 0.16–0.37). Toxoplasma gondii seropositivity increased AD risk (HR 2.43, p=0.001).

DISCUSSION

Ato/Pro and VZV vaccines were AD-protective, with Ato/Pro’s effect strongest in VZV-unvaccinated patients, supporting a hypothesis that latent T. gondii infection, reactivated by herpesvirus superinfection, may drive AD pathogenesis.

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