A national study in Taiwan also revealed that POAG, NTG and PACG were each associated with an increased risk of developing AD.  Photo: Andrew Rixon, OD. Click image to enlarge.

There is a pertinent need to better understand the relationship between glaucoma and Alzheimer’s disease (AD). Recently, researchers in Taiwan designed a nationwide large study to investigate the association between AD and different classes of topical glaucoma medications using a national health insurance research database. They determined that using topical alpha-2 adrenergic agonists should be undertaken judiciously, especially in middle-aged and older populations. Their findings also indicated glaucoma may increase the risk of AD regardless of glaucoma subtype.

Using insurance claims data from an 11-year period, a total of 202,000 participants were included in the study, which was published in Eye, with 101,000 in each group (glaucoma patients and controls). Those with glaucoma must have received a monotherapy regimen (alpha-2 adrenergic agonists, cholinergic agonists, beta-blockers, prostaglandin analogs or pilocarpine) for over 90 days. Glaucoma was further categorized into primary open-angle glaucoma (POAG), normal-tension glaucoma (NTG), primary angle-closure glaucoma (PACG) and unspecified glaucoma.

Glaucoma patients on topical alpha-2 adrenergic agonist monotherapy exhibited a significantly higher AD risk (adjusted hazard ratio; aHR: 1.15), the study found, compared to those on beta-blockers.

“Our observations indicating that alpha-2 adrenergic agonists potentially confer an increased risk of developing AD when compared to beta-blockers may be explained by the glycogen synthase kinase 3 beta (GSK3β) signal pathway,” the researchers explained in their paper. “An increased amount of Aβ, a protein that accumulates with age even in healthy older adults, activates the GSK3β signal pathway, leading to tau hyperphosphorylation and subsequent neurodegeneration.” They go on to explain that in the presence of α2 adrenergic agonists, “Aβ oligomers can function as an allosteric ligand”—a binding agent of sorts—"for the α2A adrenergic receptor. This interaction leads to the activation of the pathogenic GSK3β/tau cascade.”

Irrespective of the type of glaucoma, individuals with glaucoma had a significantly higher risk of AD compared with those without glaucoma (POAG aHR: 1.23; NTG aHR: 1.49; PACG aHR: 1.35; unspecified glaucoma: aHR: 1.36).

The researchers believe their findings may help inform better tailoring of long-term treatment regimens for glaucoma.

“Eyecare practitioners and neurologists need to be aware of the potentially higher risk of AD development associated with alpha-2 adrenergic agonists compared with beta-blockers among glaucoma patients,” they concluded in their paper for the journal.