Is there a link between glaucoma and dementia?

By Liz Meszaros

For many years, researchers have suspected and tried to prove the presence of a link between glaucoma and dementia, said Yvonne Ou, MD. Definitive answers, however, have been hard to come by.

“Glaucoma is a neurodegenerative disorder involving the optic nerve, and shares some traits with other neurodegenerative disorders, such as Alzheimer’s disease (AD). These diseases affect older populations and involve selective loss of certain types of neurons,” said Dr. Ou, of the Glaucoma Service, and assistant professor of ophthalmology, University of California, San Francisco.

Glaucoma and dementia have several factors in common. They are both neurodegenerative, chronic, and progressive diseases that are age-related and cause irreversible neuronal cell loss. They are both also a major public health concern as the population of the United States ages.

“Do we really have enough evidence to say that glaucoma is ocular AD? Or that AD could be considered cerebral glaucoma?” Dr. Ou said. “I’m not going to be able to answer those questions fully, and I don’t even think, as a field, we necessarily have answers to those questions fully.”

Connecting the data

Dr. Ou reviewed some of the laboratory and epidemiologic-based data.

Early epidemiologic data suggested a link between these two diseases. In 1978, Chandra, et al., noted a higher frequency of glaucoma in AD patients using death certificate records.¹ In 2002, institutionalized patients in Germany had an increased prevalence of glaucoma in AD (24.5%) versus control patients (6.5%).²  In 2006, Japanese patients were shown to have an increased prevalence of glaucoma in AD (23.8%) versus control patients (9.9%).³

“But what if the question is flipped around: Do patients with glaucoma have an increased risk of AD or other dementias?” she queried.

In 2007, longitudinal hospital admissions data from Denmark showed no increased risk of AD in glaucoma patients;⁴ and in 2011, 69 normal-tension glaucoma patients who were followed for 13 years showed no increased risk of AD.⁵

Dr. Ou and colleagues also conducted a longitudinal analysis of 63,235 open-angle glaucoma (OAG) patients identified through an administrative claims database that showed no increased risk of AD or other dementia over 14 years.⁶

“Indeed, there was a suggestion that there might be a decreased rate of AD diagnosis in glaucoma patients aged 68 and older compared to control patients without open-angle glaucoma,” she said.

More recently, however, researchers conducted a prospective study, called the “Three-City-Alienor Cohort,” which included 812 patients aged ≥72 years.⁷

“After adjusting for age, gender, education, family history of glaucoma, vascular comorbidities, and APOE4 (Apolipoprotein E-e4), they found that OAG patients were four times more likely to develop dementia, which is quite striking,” said Dr. Ou. “They showed that this was associated with vertical cup:disc ratio and rim:disc ratio, but interestingly, no associations with high intraocular pressures (IOPs) and IOP-lowering medications.”

This raises the intriguing possibility that perhaps our patients whom we label ‘normal-tension glaucoma’ are perhaps the patients who have an increased risk of dementia diagnosis,” Dr. Ou noted.

She explained that currently, she and her colleagues are looking at this question from a slightly different perspective in a study centered on mild cognitive function in glaucoma patients compared with control patients.

“We are trying to tease out whether these mild cognitive changes might be predictive of later onset dementia in glaucoma patients,” she said. (See graph for common neurodegenerative changes.)

 “Alzheimer’s patients may have RNFL thinning and optic nerve changes that can be used as early biomarkers of disease.” Dr. Ou pointed out. “There’s a lot of discussion about early biomarkers in all diseases, including glaucoma. Certainly, there’s a lot of excitement about whether retinal changes, lens changes can be predictive of AD or early biomarkers of the disease. As ophthalmologists, we may be playing a role in those diagnoses in the future.”

Dr. Ou added that glaucoma patients might have an increased risk of developing dementia. There is still work ongoing in this area. She concluded that there might be shared underlying pathologic mechanisms connecting the two diseases. This is a real area of interest because we can potentially identify novel targets or learn from both fields to try to better treat our patients.

References

1. Chandra V, Bharucha NE, Schoenberg BS. Conditions associated with Alzheimer's disease at death: case-control study. Neurology. Feb 1986;36(2):209-211.

2. Bayer AU, Ferrari F, Erb C. High occurrence rate of glaucoma among patients with Alzheimer's disease. Eur Neurol. 2002;47(3):165-168.

3. Tamura H, Kawakami H, Kanamoto T, et al. High frequency of open-angle glaucoma in Japanese patients with Alzheimer's disease. J Neurol Sci. Jul 15 2006;246(1-2):79-83.

4. Kessing LV, Lopez AG, Andersen PK, Kessing SV. No increased risk of developing Alzheimer disease in patients with glaucoma. J Glaucoma. Jan 2007;16(1):47-51.

5. Bach-Holm D, Kessing SV, Mogensen U, Forman JL, Andersen PK, Kessing LV. Normal tension glaucoma and Alzheimer disease: comorbidity? Acta Ophthalmol. DOI: 10.1111/j.1755-3768.2011.02125.x (2011) (Epub ahead of print).

6. Ou Y, Grossman DS, Lee PP, Sloan FA. Glaucoma, Alzheimer’s disease and other dementia: A longitudinal analysis. Ophthalmic Epidemiol. 2012 Oct;19(5):285-92.

7. Helmer C, Malet F, Rougier M-B, et al. Is there a link between open-angle glaucoma and dementia?: The Three-City-Alienor Cohort. Ann Neurol. 2013;74:171-179.

Graph

Common neurodegenerative changes that glaucoma and AD share

Decreased RGC numbers and RNFL thinning

Optic nerve fiber loss

Retinal amyloid-β and phosphorylated tau

Caspase activation and APP cleavage

Amyloid-β-induced RGC apoptosis

Increased tau in vitreous (glaucoma) and CSF (AD)