The Ocular Microbiome and Alzheimer’s Disease: Emerging Insights

Abstract

Highlights This review highlights the growing potential of microbiome research to broaden understanding of Alzheimer’s disease. While the gut and oral microbiomes currently provide the strongest evidence, the ocular microbiome represents an exciting emerging area, supported by the close biological relationship between the eye and brain and offering potential opportunities for novel biomarkers and targeted therapeutic strategies. What are the main findings? The gut and oral microbiomes currently provide the strongest evidence linking microbial dysbiosis to Alzheimer’s disease, while the ocular microbiome has emerged as a biologically plausible but largely unexplored component of the eye–brain connection. The ocular surface shares anatomical and functional connections with the central nervous system, and overlaps between ocular microbial taxa and those reported in some Alzheimer’s disease brain studies provide a rationale for investigating a potential ocular-brain microbial interface. What are the implications of the main findings? The ocular microbiome represents a novel frontier in Alzheimer’s disease research that may provide unique insights into neuroinflammation, retinal neurodegeneration, and brain health through a readily accessible tissue interface. Integrating ocular microbiome profiling with retinal imaging, tear biomarkers, and spatial biology approaches could enable the discovery of new biomarkers and therapeutic targets for Alzheimer’s disease, provided that future studies establish causal mechanisms and address methodological challenges in low-biomass microbiome research. Abstract Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β plaques, neurofibrillary tau tangles, neuroinflammation, and progressive cognitive decline. Beyond these classical pathological features, emerging evidence implicates microbial dysbiosis as a contributing factor, with the gut and oral microbiomes currently providing the strongest evidence for microbiome AD associations. In contrast, the ocular microbiome represents a biologically plausible but largely unexplored candidate whose potential contribution to AD pathogenesis remains hypothetical and requires rigorous investigation. The ocular surface shares embryological, anatomical, and functional connections with the central nervous system, and the retina has emerged as a non-invasive window into neurodegenerative brain changes. Bacterial taxa detected in ocular specimens, including Cutibacterium acnes and Acinetobacter johnsonii, overlap with those reported in some studies of AD brain tissue, prompting speculation about an ocular–brain microbial interface. However, this overlap does not establish microbial trafficking, and no direct evidence currently supports the proposition that ocular microorganisms translocate to, colonize, or contribute causally to AD brain pathology. This review critically appraises the existing evidence, graded by methodological rigor and evidence strength, across gut, oral, nasal, ear, and ocular microbiome compartments. We address the substantial methodological challenges inherent in low-biomass microbiome research, emphasize the importance of distinguishing contamination artifacts from biological signals, and delineate the evidence gaps that separate association from causation. We conclude by proposing a research framework that places the ocular microbiome as an emerging hypothesis warranting experimental validation, rather than an established contributor to AD.