Dementia Drugs Seen Lowering Risk for Macular Degeneration

Use of acetylcholinesterase inhibitors (AChEIs) for dementia, such as donepezil (Aricept), may reduce the risk that patients will develop age-related macular degeneration (AMD), researchers said.

Each year of AChEI treatment was linked with a 6% lower hazard of AMD (HR 0.94, 95% CI 0.89-0.99, P<0.001), according to propensity-matched analysis of 9,642 patients ages 55-80 who received medical services in the U.S. Veterans Affairs health system from 2000-2023. The study, led by Joseph Magagnoli, MS, of the University of South Carolina in Columbia, appeared in JAMA Ophthalmology.

“Randomized clinical trials would be needed to determine if there is a cause-and-effect relationship, and further research is required to validate these findings across diverse populations,” the researchers wrote.

An estimated 18.3 million Americans age 40 and older have early-stage AMD and another 1.49 million have the late-stage form that seriously impairs vision, a 2022 study reported.

Magagnoli and colleagues noted conflicting research into whether Alzheimer’s disease and AMD are connected, but they also observed that the two diseases may have similar causes related to buildup of beta-amyloid proteins.

In light of the possible link, the researchers launched their analysis into the role of AChEIs.

These drugs are used to slow cognitive loss, although there’s long been controversy about their clinical worth in light of their “modest” effectiveness. In 2012, a commentary rapped the FDA’s approval of a higher-level dose of Aricept as “perplexing” and “depressing” due to the extra risk of gastric problems.

For the new study, researchers tracked 12,487 VA patients with Alzheimer’s diagnoses who were given AChEIs — donepezil, rivastigmine (Exelon), and galantamine (Razadyne) — and 4,898 receiving a different type of dementia drug, the N-methyl-D-aspartate antagonist memantine (Namenda), either concurrently or separately. These patients were compared with a control group of 8,486 patients who took neither drug but were otherwise similar.

As is typical in VA studies, nearly all patients were men. About 70% were classified as white and some 15% as Black. Comorbidities were more common among controls than in those using either memantine or AChEIs, with mean Charlson scores of 2.16 versus 1.55. More than 85% of patients were 65 or older; the overall mean age was 72.

Raw data indicated that AMD rates were 4% lower in the AChEI group (HR 0.96; 95% CI 0.93-0.99) per year of exposure versus controls. The difference expanded slightly to 6% per year when 4,821 patients on AChEIs were matched with controls not using dementia drugs according to AMD propensity scores. Overall, with up to 25 years of follow-up, 299 patients in the AChEI group developed AMD versus 373 among controls. The difference became most apparent after about 17 years of AChEI use, although at that point only a tiny fraction of the original cohorts were still being followed.

What might be going on? “A growing body of work suggests that AChEIs have mechanisms of action beyond their cholinesterase inhibition, possibly limiting inflammation, an important target for AMD,” Magagnoli and colleagues wrote. These drugs “have been shown to promote vasoprotection, maintaining the integrity of the microvasculature of the eye, and possibly hemodynamic dysfunction that results in AMD.”

The authors also pointed out that AChEIs “have been associated with several non-AD benefits, including reduced mortality, myocardial infarction, and stroke risk, as well as slower progression of CKD [chronic kidney disease].”

Study limitations included its retrospective nature, the possibility of unmeasured confounders, and its focus on the VA population, which is not representative of the general older public. The study also didn’t account for genetic risk factors, the researchers noted.

And it didn’t take into account the side effects of AChEIs or their cost. While the drugs were considered to be “fairly well-tolerated” in a 2010 review, a more recent meta-analysis linked the medications to higher risks of several psychiatric adverse effects including anorexia, agitation, insomnia, and depression.

In regard to cost, a 2022 analysis determined that AChEIs as a whole are cost-effective for improving dementia symptoms. Whether they would be so for AMD risk reduction is another matter.

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