Beyond Association: A Quantitative Analysis of the Infectious Burden in Alzheimer's Disease

The etiology of Alzheimers 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 drive 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 disease burden driven by infectious agents. Our sensitivity analyses, utilizing E-values to quantify robustness against unmeasured confounding, suggest that infectious burden infectious burden may account for a plausibility range of 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 {varepsilon}4 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.