Gingipains as macromolecular mediators at the periodontal-brain interface: Mechanistic, diagnostic, and therapeutic evidence in Alzheimer's and Parkinson's diseases.
Level 5 - mechanism / opinion, no new human data
Narrative review synthesizing mechanistic, preclinical, postmortem, and clinical trial literature.
PubMed 42392383 · doi:10.1016/j.ijbiomac.2026.153320
What was done
Narrative review synthesizing epidemiological meta-analyses, postmortem brain tissue analyses, in vitro/in vivo mechanistic models, and clinical trial results investigating the role of Porphyromonas gingivalis cysteine proteases (gingipains RgpA, RgpB, and Kgp) in Alzheimer's disease (AD) and Parkinson's disease (PD).
What was found
The review reports meta-analytic associations between periodontitis and elevated risk of AD/PD (odds ratios/hazard ratios ranging from 1.2 to 3.5). Gingipains have been detected in over 85% to 90% of postmortem AD and PD brains, correlating with tau/α-synuclein pathology and neuroinflammation. Preclinical models show gingipains disrupt the blood-brain barrier, activate NF-κB/NLRP3 signaling, and seed protein aggregation. In therapeutic trials, the small-molecule gingipain inhibitor atuzaginstat (COR388) failed primary clinical endpoints in the Phase 2/3 GAIN trial, though post-hoc subgroup benefits were noted in P. gingivalis-positive participants.
Why it matters
It consolidates evidence on the periodontal-brain axis and highlights both the translational potential and substantial clinical development hurdles of targeting oral pathogens for neurodegenerative diseases.
Limits
As a narrative review, it reports no new empirical data and lacks a systematic search methodology. Direct human causation remains unproven, and targeted therapeutics have so far failed to achieve primary endpoints in phase 2/3 human clinical trials.
Cited by
- supports Porphyromonas gingivalis excretes a substance called gingipain, which can travel to the brain.