Could the eye offer a window into early-stage neurodegenerative disease? In a retrospective study presented at the annual meeting of the Association for Research in Vision and Ophthalmology (ARVO) 2025, we investigated the relationship between mitochondrial disorders—particularly those with ocular involvement—and the prevalence, incidence and risk of dementia.
Key Findings
Prevalence
Dementia prevalence was significantly higher in all mitochondrial subgroups than in controls: 18.7% (ocular), 15.0% (systemic) and 17.4% (combined) vs. 2.7% in controls.
Risk elevation
Adjusted ORs were notably elevated: 5.39 for ocular, 2.88 for systemic and 6.84 for the combined group. Notably, the ocular group showed a sharper increase in dementia risk despite not having systemic involvement.
Incidence rates
The age-adjusted incidence of all-cause dementia per 1,000 person-years was 22.3 in the ocular group, 17.1 in the systemic group and 26.8 in the combined group, compared with just 3.4 in the control population.
Survival outcomes
Cox regression revealed that the ocular group had a 3.86-fold increased HR for developing dementia, even after adjusting for key covariates such as hypertension, diabetes and smoking history.
These consistent trends across prevalence, incidence, odds and time-to-event models suggest that ocular mitochondrial disease is not just an isolated ophthalmic concern but may serve as an early systemic indicator of neurodegenerative risk.
Using the UK Biobank, one of the largest population-based datasets globally, our findings suggest that patients with ocular mitochondrial disease have significantly increased odds of developing dementia, possibly surpassing systemic mitochondrial subgroups.
Background
Mitochondrial dysfunction has long been implicated in neurodegeneration, with Alzheimer and Parkinson disease both showing evidence of impaired bioenergetics and oxidative stress. The retina, being highly metabolically active and embryologically linked to the brain, offers a unique opportunity for early disease detection.
While prior studies have explored mitochondrial dysfunction in neurodegenerative risk in animal models, the impact of isolated ocular and systemic mitochondrial diseases has remained underexplored in humans.
Methods summary
Using International Classification of Diseases, Tenth Revision codes, we identified individuals within the UK Biobank diagnosed with ocular or systemic mitochondrial disease. These participants were compared with age-, sex-, and socioeconomic status–matched controls at a 1:3 ratio. Outcomes included all-cause dementia, Alzheimer disease and vascular dementia.
We calculated adjusted ORs and incidence rates per 1,000 person-years, and performed Cox proportional hazards modelling to examine time-to-dementia outcomes (Figure 1). Kaplan-Meier survival analyses further delineated subgroup differences (Figure 2).
Implications for ophthalmology practice
This study underscores the potential for ophthalmologists to play a frontline role in dementia risk stratification. Given the retina’s accessibility and shared pathophysiology with the brain, integrating cognitive screening or neurologic referral pathways into ophthalmic practice may be warranted for patients with mitochondrial eye disorders.
As advanced imaging modalities such as optical coherence tomography and electroretinography evolve, the next frontier in research may be directly quantifying mitochondrial dysfunction in the retina and correlating that with neuropathology. Techniques such as fluorescence lifetime imaging ophthalmoscopy or fluorescence lifetime imaging microscopy hold promise as non-invasive tools to detect retinal bioenergetic deficits that could predict dementia risk over time.
Conclusion
While this is not a causative study, our findings reinforce mitochondrial dysfunction as a central part of dementia pathophysiology. Previous studies suggest that mitochondrial dysfunction may be prodromal, occurring well before the onset of clinical dementia symptoms. We propose that mitochondrial dysfunction represents a potential biomarker and a therapeutic target in neurodegenerative disease.
Ocular mitochondrial disease may offer a clinically meaningful early signal of dementia risk.Ophthalmology may be pivotal in neurodegenerative disease prevention. Bridging disciplines—literally and metaphorically—could unlock new frontiers in early diagnosis and integrated care.
Acknowledgments
This research was conducted under the mentorship of Dr Manju Subramanian (Boston Medical Center and Boston University Aram V. Chobanian & Edward Avedisian School of Medicine). I am grateful to the Faculty of Medical and Health Sciences at the University of Auckland for supporting my participation at the ARVO 2025 Annual Meeting.
Viha Vig | E: vigviha@gmail.com
Viha Vig is a final-year medical student at the University of Auckland, New Zealand. Her research interests include neuro-ophthalmology, oculomics, understanding brain health through the eye and health equity. She presented this study at the ARVO 2025 Annual Meeting and aspires to bridge translational research with clinical impact.
