# Disease Mechanisms at the Intersection of Glaucoma and Alzheimer's Disease

> **NIH NIH R21** · UNIVERSITY OF WISCONSIN-MADISON · 2021 · $414,306

## Abstract

Project Summary / Abstract:
Alzheimer’s disease (AD) and glaucoma are two of the most prevalent age-related neurodegenerative disorders
recognized worldwide. Globally, AD is the most widespread cause of dementia and a substantial cause of death,
while glaucoma is the leading cause of irreversible blindness. In glaucoma, a characteristic optic neuropathy is
associated with progressive visual field defects. There is currently no cure for either disease, although treatments
that lower intraocular pressure can slow progression of vision loss glaucoma. In AD patients, characteristic
neuropathologic changes in the brain include amyloid beta (Aβ) plaques and neurofibrillary tangles composed
of hyperphosphorylated tau. Aβ and tau have also been observed within the optic nerve (ON) and retina of both
AD patients and glaucoma patients. Other shared disease features include microglial activation and progressive
neurodegeneration, which in glaucoma primarily affects RGCs and their axons in the ON. AD patients are 2-3
times more likely to develop glaucoma than those without AD. Epidemiologic studies have also examined the
risk for glaucoma patients to develop AD and have identified associations that are not attributable to age alone,
or to medications. Together, these findings indicate the potential for shared or synergistic mechanisms
responsible for, or contributing to, both diseases. Potential mechanisms include, but are not limited to, microglial
activation, protein aggregation and mislocalization, and impaired dendritic and synaptic inputs. We hypothesize
that glaucoma and AD act synergistically to intensify neuroinflammation, AD- like pathology, and
neurodegeneration, accelerating progression and functional decline in both diseases. However, it is
challenging to elucidate mechanisms for this observed shared risk for glaucoma and AD in older human
populations with other age-associated co-morbidities. Given the profound cumulative negative impact of both
diseases on the health of the aging population, and lack of effective therapies, there is an urgent need for
improved understanding of the interaction of glaucoma and AD. To address our central hypothesis, the proposed
studies will interrogate the histologic, transcriptomic and protein expression changes in specific eye and brain
regions over the course of disease progression in two complementary models of glaucoma (optic nerve crush
and ocular hypertension induced by intraocular microbead injection) in mice with normal and AD transgenic
backgrounds, relating these neuropathologic changes to rate of functional decline in memory, cognition and
vision. Success in these studies will provide mechanistic insight into the interaction between AD and glaucoma,
illuminating and prioritizing shared and novel targets to inform the development of new therapeutic strategies to
slow disease progression and enhance quality of life in AD and glaucoma patients.

## Key facts

- **NIH application ID:** 10306895
- **Project number:** 1R21AG074395-01
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Gillian Jane McLellan
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $414,306
- **Award type:** 1
- **Project period:** 2021-09-30 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10306895

## Citation

> US National Institutes of Health, RePORTER application 10306895, Disease Mechanisms at the Intersection of Glaucoma and Alzheimer's Disease (1R21AG074395-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10306895. Licensed CC0.

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