Beyond association: A quantitative analysis of the infectious burden in Alzheimer's disease

The etiology of Alzheimer's disease (AD) remains a subject of intense investigation. While the 2024 Lancet Commission report attributes approximately 45% of global dementia cases to 14 modifiable risk factors, it notably excludes infectious agents due to debated causality. This exclusion contrasts with growing evidence that pathogens, specifically Herpes Simplex Virus Type 1 (HSV-1), Porphyromonas gingivalis, and Chlamydia pneumoniae, may contribute to neuroinflammation, tau pathology and amyloidogenesis. This paper evaluates the Pathogen Hypothesis of AD through a quantitative framework. Synthesizing data from nationwide cohort studies, we apply a Population Attributable Fraction (PAF) model to estimate the potential disease burden associated with infectious agents. Our sensitivity analyses, utilizing E-values to quantify robustness against unmeasured confounding, suggest that, under the assumption of causality, infectious agents yield illustrative PAF scenarios ranging from 19% to 31% from single-pathogen models, which expands to 31% to 52% in joint models of sporadic AD cases. We explicitly model the heterogeneity between cohorts and the synergistic interaction with the APOE ε4 allele. Furthermore, we address recent failures in antimicrobial clinical trials (VALAD, GAIN), arguing that these outcomes reflect a need for precision biomarker stratification rather than a refutation of the hypothesis. These findings argue for the integration of precision pathogen suppression into dementia prevention protocols.