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Original Investigation
January 4, 2024

Alzheimer Disease Treatment With Acetylcholinesterase Inhibitors and Incident Age-Related Macular Degeneration

Author Affiliations
  • 1Dorn Research Institute, Columbia VA Health Care System, Columbia, South Carolina
  • 2Department of Clinical Pharmacy and Outcomes Sciences, College of Pharmacy, University of South Carolina, Columbia
  • 3Department of Epidemiology & Biostatistics, University of South Carolina, Columbia
  • 4Center for Advanced Vision Science, University of Virginia School of Medicine, Charlottesville
  • 5Department of Ophthalmology, University of Virginia School of Medicine, Charlottesville
  • 6Department of Pathology, University of Virginia School of Medicine, Charlottesville
  • 7Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville
JAMA Ophthalmol. 2024;142(2):108-114. doi:10.1001/jamaophthalmol.2023.6014
Key Points

Question  Does the use of acetylcholinesterase inhibitors (AChEIs), commonly prescribed for Alzheimer disease (AD), influence the incidence of age-related macular degeneration (AMD)?

Findings  This cohort study discovered that patients with AD treated with AChEIs had a slightly lower hazard of developing AMD compared with untreated patients. AChEI treatment showed a reduction in AMD risk, while memantine treatment exhibited no association with AMD incidence.

Meaning  These results suggest potential benefits of AChEIs in reducing the risk of AMD, if confirmed in randomized clinical trials; further research is required to validate these findings across diverse populations.

Abstract

Importance  Age-related macular degeneration (AMD) is a serious and common ophthalmologic disorder that is hypothesized to result, in part, from inflammatory reactions in the macula. Alzheimer disease (AD) treatment, acetylcholinesterase inhibitors (AChEIs), have anti-inflammatory effects and it remains unclear if they modify the risk of AMD.

Objective  To investigate the association between AChEI medications and the incidence of AMD.

Design, Setting, and Participants  This propensity score–matched retrospective cohort study took place at health care facilities within the US Department of Veterans Affairs (VA) health care system from January 2000 through September 2023. Participants included patients diagnosed with AD between ages 55 and 80 years with no preexisting diagnosis of AMD in the VA database.

Exposure  AChEIs prescription dispensed as pharmacologic treatments for AD.

Main Outcomes and Measure  The first diagnosis of AMD.

Results  A total of 21 823 veterans with AD (mean [SD] age, 72.3 [6.1] years; 21 313 male participants [97.7%] and 510 female participants [2.3%]) were included. Propensity score–matched Cox model reveals each additional year of AChEI treatment was associated with a 6% lower hazard of AMD (hazard ratio, 0.94; 95% CI, (0.89-0.99).

Conclusions and Relevance  This observational study reports a small reduction in the risk of AMD among veterans with AD receiving AChEIs. 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.

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1 Comment for this article
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RE: Alzheimer Disease Treatment With Acetylcholinesterase Inhibitors and Incident Age-Related Macular Degeneration
Tomoyuki Kawada, MD | Nippon Medical School
Sutton et al. conducted a propensity score-matched retrospective cohort study to investigate the association between acetylcholinesterase inhibitors (AChEI) medications and the incidence of age-related macular degeneration (AMD) in patients, aged from 55 to 80 years (1). The hazard ratio (95% confidence interval) of each additional year of AChEI treatment for AMD was 0.94 (0.89-0.99). I have comments about the study.

Regarding tissue zinc concentration, Ahn et al. reported that extracellular zinc promoted extracellular beta-amyloid aggregation, and depletion of intracellular zinc induced protein synthesis-dependent neuronal apoptosis (2). They speculated that redistribution of zinc from intracellular to extracellular space would contribute
to neuronal apoptosis in Alzheimer's disease (AD). Decreases in tissue zinc may be associated with the risk of AD and AMD, which could be explained by common neurodegeneration.

Jabbehdari et al. reviewed common pathways in their pathogenesis of AMD and neurodegenerative disorders, including inflammation, oxidative stress, and impaired autophagy (3). They made an emphasis on their shared mechanisms and potential therapeutic targets. Namely, not only the risk reduction of incident AMD, but also suppression of disease progression in AMD may be speculated by modulating the immune response, reducing oxidative stress, enhancing autophagy, and reducing specific protein aggregation. I understand that AChEI has a possibility to become one of the effective medications for AMD, which should be explored by further studies.

References
1. Sutton SS, Magagnoli J, Cummings TH, et al. Alzheimer Disease Treatment With Acetylcholinesterase Inhibitors and Incident Age-Related Macular Degeneration. JAMA Ophthalmol. 2024 Jan 4. doi: 10.1001/jamaophthalmol.2023.6014
2. Ahn YH, Kim YH, Hong SH, et al. Depletion of intracellular zinc induces protein synthesis-dependent neuronal apoptosis in mouse cortical culture. Exp Neurol 1998;154(1):47-56.
3. Jabbehdari S, Oganov AC, Rezagholi F, et al. Age-related macular degeneration and neurodegenerative disorders: Shared pathways in complex interactions. Surv Ophthalmol 2023 Nov 23. doi: 10.1016/j.survophthal.2023.11.003
CONFLICT OF INTEREST: None Reported
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