Identification of Chlamydia pneumoniae and NLRP3 inflammasome activation in Alzheimer’s disease retina

Abstract Chlamydia pneumoniae is an intracellular bacterium implicated in Alzheimer’s disease (AD), but its role in retinal pathology and disease progression is unclear. Here we identify Chlamydia pneumoniae inclusions in the retina, showing higher burden in AD retina and brain, increasing with APOEε4, disease stage, and cognitive deficit. Retinal and cortical proteomics reveal bacterial-infection and related NLRP3-inflammasome pathways. Retinal NLRP3 is elevated in mild cognitive impairment and activated in AD dementia, evidenced by increased caspase-1, cleaved interleukin-1β, and cleaved N-terminal gasdermin-D. Chlamydia pneumoniae associates with amyloid-β 42 , inflammation, apoptosis, pyroptosis, and AD status. In neuronal cultures and APP SWE /PS1 ΔE9 model mice, infection induces amyloid-β, inflammasome activation, neuroinflammation, and neurotoxicity, and chronic infection worsens cognition. Fewer pathogen-colocalized microglia are found in AD retinas, implying impaired clearance. Machine learning detects retinal Chlamydia pneumoniae or NLRP3, combined with amyloid-β 42 , as predictors of AD diagnosis and stage. These findings support a disease-amplifying role for Chlamydia pneumoniae and propose NLRP3-attenuation or antibiotic-based early interventions.