AChEIs for Alzheimer Disease Treatment And the Risk of Incident Age-Related Macular Degeneration
Acetylcholinesterase inhibitors (AChEIs), a class of medications frequently used in Alzheimer disease (AD) treatment due to its anti-inflammatory properties, may also reduce the risk of incident age-related macular degeneration (AMD) among patients with AD, according to the results of a recent observational study.
Previous literature utilizing AChEIs for the treatment of other conditions have shown positive associations for the medication class beyond AD treatment. Enter Joseph Magagnoli, MS, and colleagues, who sought to explore if these associations could be further applied to the risk of AMD, as AMD has been hypothesized to partly result from inflammatory processes within the eye.
Joseph Magagnoli further discusses the results of their study, as well as the relationship between AD and AMD and remaining gaps in the literature.
Consultant360: To begin, what prompted this study?
Joseph Magagnoli, MS: Our research team has a dedicated focus on AMD, with Dr Ambati leading efforts to unravel the molecular basis of macular degeneration. Comprising interdisciplinary experts including a physician, pharmacist, and data scientists, our team employs preclinical investigations and biology experiments complemented by real-world medical databases to identify potential applications for established drugs (drug repurposing). In the case of this manuscript, our exploration of inflammation, coupled with the potential of AChEIs to impact inflammation, guided our hypothesis.
C360: What is currently known on the association between AD and AMD?
Joseph Magagnoli: The existing research on the relationship between AMD and AD is mixed. Some studies show a positive association between AMD and AD, while others show no association.
The two conditions are similar in that both are age-related and characterized by drusen in AMD and plaques in AD. Importantly, neuroinflammation is thought to play a significant role in both disease states, and it is currently unknown how the treatment of one disease impacts the subsequent incidence of the other.
C360: Your study found that participants with AD treated with AChEIs had a lower cumulative incidence of AMD than the untreated group. Were there any patient-specific factors, such as age or AD severity, that may have had a role in these results?
Joseph Magagnoli: We accounted for many patient-specific factors and balanced the treated and untreated groups over these factors. The idea was to generate two cohorts of patients that, on average, have the same characteristics only differing by AChEI use.
There are some patient level factors that we could not account for, including AD severity which would be difficult to assess in most databases. Another possible patient level factor that we could not account for is genetic susceptibility to AMD. These would need to be addressed in subsequent research or clinical trials.
C360: Are there any other medications currently used to treat AD that have similar anti-inflammatory effects and may be a potential therapeutic for managing AMD or other eye disorders in these patients?
Joseph Magagnoli: Memantine, another drug used in AD, was included in the study. Some preclinical research suggests that memantine may have anti-inflammatory effects. However, we did not observe any association between memantine use and AMD in our study. The recently approved monoclonal antibody drugs for AD were not considered in this study.
C360: Your study notes that these results add to the growing literature on the use of AChEIs for non-AD related outcomes. What are the next steps for future research in this area?
Joseph Magagnoli: Several questions persist. Although our study examined class-wide associations of AChEI use, future investigations could explore the effects of individual drugs within this class. Understanding how these medications may prevent AMD through mechanisms such as inflammation modulation requires further exploration. A randomized control trial would be needed to evaluate the clinical relevance of this pathway for AMD. There is an ongoing clinical trial of an inflammasome inhibitor in geographic atrophy (NCT06164587).
Reference:
Sutton SS, Magagnoli J, Cummings TH, Hardin JW, Ambati J. Alzheimer disease treatment with acetylcholinesterase inhibitors and incident age-related macular degeneration. JAMA Ophthalmol. 2024;142(2):108-114. doi:10.1001/jamaophthalmol.2023.6014