Acetylcholinesterase Inhibitors for Alzheimer Disease May Reduce AMD Risk

Joseph Magagnoli, MS

Credit: University of South Carolina

A recent cohort study evaluated the association of acetylcholinesterase inhibitors (AChEIs), a common pharmacological treatment for Alzheimer disease, with the incidence of age-related macular degeneration (AMD) among patients with the brain disorder.¹

The retrospective analysis of nearly 22,000 patients diagnosed with Alzheimer disease in the US Department of Veterans Affairs (VA) healthcare system revealed those treated with AChEIs exhibited a slightly lower risk of AMD development, compared with untreated patients.

“The findings suggest that AChEIs may have a slightly beneficial association with a reduced risk of AMD. Randomized clinical trials would be needed to determine if there is a cause-and-effect relationship,” wrote the investigative team, led by Joseph Magagnoli, MS, of clinical pharmacy and outcomes sciences at the University of South Carolina College of Pharmacy.

With a lack of curative therapies for Alzheimer disease, AChEIs have been used to increase the quality of life for patients with the disease.² A chronic and progressive retinal disease, AMD is a leading cause of blindness and is hypothesized to result from inflammatory activity in the macula. Magagnoli and colleagues hypothesized that AChEIs used for Alzheimer disease treatment may mitigate inflammatory processes linked to AMD pathogenesis and reduce the risk of incident AMD.¹

For this analysis, the investigative team assessed the correlation between treatment with AChEIs and the incidence of AMD among a nationwide sample of veterans diagnosed with Alzheimer Disease eligible for VA care before 2020. The study time frame encompassed January 2000 to September 2023. Patients were required to be between 55 and 80 years old at the index date, have no preexisting AMD diagnosis, and undergo an eye examination within the study follow-up.

The primary study outcome was the diagnosis of incident AMD extracted from inpatient and outpatient diagnosis data. Cohorts were divided into mutually exclusive treatment groups, consisting of those exposed to Alzheimer disease pharmacologic treatment and those unexposed to treatment. Pharmacologic treatments included the AChEIs (donepezil, rivastigmine, and galantamine) and N-methyl-D-aspartate (antagonist, memantine).

Overall, a total of 21,823 patients with Alzheimer disease were included in the analysis. Most patients were treated with an AChEI (n = 12847) or memantine (n = 4898). The average age of the study population was 72.3 years, and most individuals were male (n = 21,313; 97.7%) and White.

Upon analysis, Cox models with time-dependent AChEI exposure showed each additional year of AChEI treatment was associated with a 4% lower risk of AMD (hazard ratio [HR], 0.96; 95% CI, 0.93 - 0.99). After propensity score matching, a total of 4821 patients were left in each cohort group. Analyses showed those treated with AChEI had consistently lower cumulative AMD incidence over the study follow-up period (log-rank P value <.001).

Further propensity score–matched Cox models revealed every additional year of AChEI treatment was associated with a 6% lower risk of AMD (HR, 0.94; 95% CI, 0.89 - 0.99). Other variables associated with a greater hazard of AMD included age (HR, 1.08; 95% CI, 1.06 - 1.09), White race (HR, 2.96; 95% CI, 2.13 - 4.10), and other/unknown race (HR, 2.84; 95% CI, 1.94 - 4.16).

In the study conclusion, Magagnoli and colleagues indicated the need for randomized clinical trials to determine the correlation between AChEIs and AMD development, particularly to validate if AChEIs have clinically meaningful secondary benefits among patients with Alzheimer disease.

“While improving cognitive outcomes is the primary goal of therapy with AChEIs, these secondary benefits can play a significant role in the decision to treat or continue treatment,” investigators wrote. “The reported associations are important because they potentially suggest broad therapeutic potential that should be evaluated with further randomized clinical trials to confirm the findings.”

References

1. _{Sutton SS, Magagnoli J, Cummings TH, Hardin JW, Ambati J. Alzheimer Disease Treatment With Acetylcholinesterase Inhibitors and Incident Age-Related Macular Degeneration. JAMA Ophthalmol. Published online January 04, 2024. doi:10.1001/jamaophthalmol.2023.6014}
2. _{Tahami Monfared AA, Byrnes MJ, White LA, Zhang Q. Alzheimer’s disease: epidemiology and clinical progression. Neurol Ther. 2022;11(2):553-569. doi:10.1007/s40120-022-00338-8}