Proton pump inhibitors (PPIs) are among the most widely prescribed drugs worldwide, and their relationship with Alzheimer's disease (AD) remains clinically uncertain because epidemiological and mechanistic evidence conflict. This evidence-weighted mechanistic review critically synthesizes PPI immunopharmacology in AD and grades the strength of mechanistic and human evidence while explicitly considering bias and confounding. Mechanistic evidence indicates context-dependent dual actions. Putative neuroprotective pathways include suppression of microglial/astrocytic inflammation via STAT3 inhibition, liver X receptor-mediated Aβ clearance, antioxidant effects, cholinesterase inhibition, and possible autophagy induction. Conversely, harmful pathways include inverse γ-secretase modulation increasing Aβ1-42, V-ATPase inhibition impairing microglial lysosomal Aβ degradation, choline acetyltransferase inhibition, vitamin B12 deficiency with hyperhomocysteinemia, and indirect gut dysbiosis/endothelial dysfunction. Epidemiological findings are inconsistent and limited by protopathic bias, residual confounding, exposure and outcome misclassification, inadequate APOE ε4/CYP2C19 stratification, and heterogeneity in PPI agent, dose, and duration. Experimental evidence suggests that some PPIs can modulate AD-relevant pathways in opposing directions, but the human relevance, direction of the net effect, and any causal role in AD remain unestablished. Putative modifiers such as PPI type, dose, duration, and genetic susceptibility are hypothesized rather than demonstrated. Rigorous prospective, agent-specific studies incorporating pharmacokinetic and, where feasible, genetic stratification are needed. Clinically, general medication-safety measures, judicious prescribing, periodic review/deprescribing where appropriate, and nutritional monitoring in at-risk long-term users are reasonable independent of any assumed AD effect; current evidence does not support PPI changes specifically to modify dementia risk.
