People with a normal-tension glaucoma are at high risk for developing Alzheimer’s disease


A large, nationwide study from Taiwan shows that people with a specific type of glaucoma, called normal-tension glaucoma, are at high risk for developing Alzheimer’s disease. The researchers say people with this type of glaucoma should be screened for Alzheimer’s disease.

The study will be presented at AAO 2022, the 126th annual meeting of the American Academy of Ophthalmology.

Glaucoma is a group of eye diseases that damage the optic nerve, the tissue that connects the eye to the brain. The most common types of glaucoma involve abnormally high pressure inside the eye. But normal-tension glaucoma, also known as low-tension glaucoma, is a form of glaucoma in which damage occurs to the optic nerve even though eye pressure is within the normal range.

Previous studies evaluating the link between glaucoma and Alzheimer’s disease offer mixed results, but few studies focused only on normal-tension glaucoma.

To learn more, researchers analyzed data from the Taiwan National Health Insurance Research Database collected over a 12-year period. They compared the incidence of Alzheimer’s in 15,317 people with normal-tension glaucoma and 61,268 age- and gender-matched people without glaucoma.

After adjusting for diabetes, hypertension, hyperlipidemia, coronary artery disease and stroke, they found that people with normal-tension glaucoma were 52 percent more likely to develop Alzheimer’s compared with those without glaucoma.

Those who were older, female or had a history of stroke had the highest incidence. Additionally, they found that use of glaucoma eye drops did not protect against Alzheimer’s disease or increase the incidence.

“From a public health perspective, policy makers are encouraged to enforce Alzheimer’s screening for at-risk patients with normal-tension glaucoma and to provide more substantial and integrated care,” said lead researcher Yu-Yen Chen, MD, Ph.D. from the Taichung Veterans General Hospital in Taiwan.

While not everyone with glaucoma will develop Alzheimer’s disease, this study underscores how they are related. They both occur when nerve cells deteriorate and die, a process called neurodegeneration. In glaucoma, neurodegeneration affects the retinal ganglion cells in the optic nerve, causing blindness over time. In Alzheimer’s, it affects nerve cells in the brain responsible for memory and cognition.

It is hoped that further investigation into the similarities and differences between these illnesses will reveal new treatments for both conditions.

With an increasingly aging population, neurodegenerative diseases have inevitably brought great challenges to society and people on a global level. This demographic shift and the development of neurodegenerative diseases are not only followed by a deterioration of cognitive function and the impediment of independence for individuals but also by an overall exacerbation of the health burden on the society (Mancino et al., 2018; Gupta et al., 2021; Nicholas et al., 2021).

As the typical representatives of neurodegenerative diseases, Alzheimer’s disease (AD) is considered the most frequent type, accounting for 60–70% of dementia cases (Hansson, 2021), while glaucoma is the most common cause of irreversible blindness and the most common type of optic neuropathy (Quigley and Broman, 2006; Chang and Goldberg, 2012).

Because of the severity and universality of these diseases, both serve as critical points for further study in other neurodegenerative diseases.

Recent studies have highlighted that there are connections between AD and glaucoma, suggesting that AD and glaucoma could be considered the age-related neurodegenerative diseases that may coexist in the aging population (Mirzaei et al., 2017; Giorgio et al., 2018; Mancino et al., 2018).

This phenomenon could be deduced because these two neurodegenerative diseases do share some similarities at both epidemiologic and pathophysiologic levels, with potential inter-organ crosstalk between brain and eye. From an epidemiologic perspective, there is evidence that AD patients would have a significantly higher rate of glaucoma occurrence (Chandra et al., 1986; Helmer et al., 2013; Mancino et al., 2018).

Chandra et al. first reported an increased prevalence of glaucoma among senile and pre-senile dementia patients (Chandra et al., 1986). This was supported by other studies, which found a nearly sixfold higher prevalence of glaucoma in AD patients than in the control group (Bayer et al., 2002a,b).

Similarly, a higher frequency of glaucoma has been reported in dementia patients in other studies. Tamura et al. (2006) found that Japanese patients with AD had a higher prevalence of open- angle glaucoma (Elyashiv et al., 2014). Furthermore, a large epidemiological study performed in the European population also found indications of a positive clinical correlation between the two diseases (Jefferis et al., 2013).

While investigating the relationship between these two diseases from a pathophysiological perspective, scientists found that AD and glaucoma both affect the elderly, causing chronic and progressive irreversible cell death, wherein the process of neurodegeneration and aging is accompanied by metabolic dysfunction.

Common features, such as amyloid-β (Aβ) protein accumulation or aggregation, tau protein aggregation, and hyperphosphorylation, are now known to be shared between AD and glaucoma (Criscuolo et al., 2017). As a classic mechanism of AD development, the aggregation and accumulation of Aβ and tau proteins is then followed by a series of metabolic dysfunction processes (Origlia et al., 2010).

Coincidentally, in glaucoma, the synaptic circuitry and retrograde trafficking of neurotrophic factors are also impaired by increased retinal levels of soluble Aβ protein (Poon et al., 2011; Della Santina et al., 2013; Gupta et al., 2014). Meanwhile, one of the known causes of glaucoma, namely high intraocular pressure, is also thought to induce Aβ protein expression, leading to an early reversible phase of retinal degeneration (McKinnon et al., 2002; Guo et al., 2007).

Tau protein is also a neuronal toxicant that aggregates to result in AD (Engelborghs et al., 2008; Sahara et al., 2008; Fá et al., 2016). Similarly, phosphorylated tau protein was also found in aged retina and glaucoma (Lieven et al., 2007; Gasparini et al., 2011; Bull et al., 2012). In addition to these AD-like pathological changes in glaucoma, there are some glaucoma-like pathological changes in AD. As an optic neuropathy, glaucoma is characterized by retinal ganglion cell death and a thinning of the nerve fiber layer (Mancino et al., 2018).

Interestingly, these changes have also been observed in AD patients. In addition to the affected neurons in the brain, widespread axonal degeneration has been observed in the optic nerves, as well as loss of retinal cells, especially ganglion cells in AD patients (Hinton et al., 1986; Quigley et al., 1989; Sadun and Bassi, 1990; Weinreb and Khaw, 2004). These findings illustrate the shared mechanisms between AD and glaucoma on pathophysiologic levels and serve as the basis for clinical therapies.

Nevertheless, similarities in epidemiology and pathophysiology remain unexplored in terms of their explanations and applications. Our primary challenge in dealing with these two representative neurodegenerative diseases is a scarce understanding of AD and glaucoma.

Cumulative evidence indicates that the neuropathological process of AD and glaucoma is initiated several years before any clinical manifestations or diagnosis in patients (Ntsapi et al., 2018; Hansson, 2021). However, therapies are more likely to be effective at early pre-symptomatic or prodromal stages than when clinical manifestation and irreversible neurodegeneration occur (Hansson, 2021).

Thus, determining the neurodegenerative mechanisms of AD and glaucoma is crucial for the exploration and development of new therapeutics.
With the growing knowledge of AD and glaucoma, there are increasing genome-wide association studies (GWASs) and related studies that have revealed several genetic variants affecting the two diseases (Tanzi and Bertram, 2001; Miller et al., 2004; Fan and Wiggs, 2010; Fingert, 2011; Bettens et al., 2013; Gharahkhani et al., 2021). More than 20 AD risk genes have been identified; however, the complete mechanisms through which these genes modulate disease remain unclear (Tanzi, 2012; Iadecola, 2013; Pruzin et al., 2017; Rojas-Gutierrez et al., 2017; Apostolova et al., 2018), with a similar condition was also being observed in glaucoma research (Janssen et al., 2013; Wiggs and Pasquale, 2017).

A recent review mentioned that a large number of genes, such as CAV1, CDKN2B, and GAS7, were found to be involved in the development of glaucoma in recent GWASs (Janssen et al., 2013). ANGPT1 and SVEP1 et al., 2021). GLIS1 was shown to be associated with glaucoma by regulating and maintaining trabecular meshwork function (Nair et al., 2021). Although there is an overlap in the epidemiology and pathophysiology between AD and glaucoma, whether the shared features of the two diseases could be explained genetically, that is, whether they are genetically related, remains unknown.

At present, the potential shared genetic architecture between AD and glaucoma remains inconclusive, and further investigation is warranted.
This study aimed to elucidate the shared genetic architecture and the underlying molecular mechanisms of AD and glaucoma. By investigating the overlapping genetic loci and candidate genes, we aimed to identify the biological relationship between AD and glaucoma, and finally provide an explanation for the shared epidemiologic and pathophysiologic features of these two representative neurodegenerative diseases.


In conclusion, we found encouraging evidence that AD and glaucoma share a genetic architecture that modulates their development and causes shared features in epidemiology and pathophysiology. Although these shared genes have not yet been well studied at the moment, they inspire us that there may be new mechanisms that have yet to be discovered, and that these genes themselves may play a significant role in the disease process individually. With a deeper cognition of the two diseases at the genetic and cellular levels, their shared genetic architecture is likely to become a popular area for research focused on developing novel and effective therapies for AD, glaucoma, and other neurodegenerative diseases.

reference link :

Zheng C, Liu S, Zhang X, Hu Y,Shang X, Zhu Z, Huang Y, Wu G, Xiao Y, Du Z, Liang Y, Chen D, Zang S, Hu Y, He M, Zhang X and Yu H (2022) Shared genetic architecture between the two neurodegenerative diseases: Alzheimer’s disease and glaucoma.

Front. Aging Neurosci. 14:880576. doi: 10.3389/fnagi.2022.880576

Source: AAO


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