Repeated clinical trial failures in Alzheimer's disease: The pitfalls of pursuing epidemiological associations.

Interventions for Alzheimer's disease (AD) have repeatedly been advanced from epidemiological associations, biological hypotheses and preclinical findings, yet many have failed in randomized trials and some have produced signals of clinical worsening. We examine illustrative successful and unsuccessful programs across infectious, inflammatory, metabolic, lipid, iron, dietary, hormonal and amyloid domains to determine what they reveal about causality and therapeutic translation. Negative results may indicate a non-causal or poorly specified target, but may also reflect inadequate central nervous system exposure, target engagement, disease-stage alignment, biomarker selection, population representativeness, statistical power, outcome selection or trial design. More informative programs distinguish prevention from symptomatic treatment, confirm AD pathology, establish central exposure and interpret target engagement together with clinical and functional outcomes rather than treating biomarker movement as a surrogate for benefit. We propose a causal-validation framework integrating convergent human evidence, mechanistic direction, central target engagement, supportive downstream biology, stage-appropriate and inclusively validated populations, and adequate design and power. Applying this framework before phase 3 testing should improve target selection, sharpen interpretation of negative trials and reduce costly late-stage failure.