In November 2022, van Dyck et al (2022) reported the results of an 18-month, double-blind, phase 3 trial of 1795 participants with early Alzheimer’s disease and evidence of amyloid. Half received lecanemab, a monoclonal antibody that binds to soluble amyloid-beta (Aβ) protofibrils. Lecanemab reduced amyloid markers, giving ‘moderately less decline on measures of cognition and function than placebo at 18 months but was associated with Alzheimer’s disease adverse events’ (van Dyck et al, 2022).
Although media outlets hailed the results as ‘historic… lecanemab made a tiny difference to cognitive deterioration on cognitionto cognitive deterioration on cognition scales over 18 months, which although statistically significant may not be clinically significant’ (Kmietowicz, 2022). Perhaps tempering media-fuelled expectations, Adhikari et al (2022) considered amyloid-related imaging abnormalities (ARIA) among some Alzheimer’s disease participants who received therapeutic anti-Aβ antibodies. The authors noted that the molecular mechanisms behind ARIA remain undefined; and identified ‘many allergy-related proteins involved in pro-inflammatory responses and endothelial dysfunction …’
In relation to amyloid-lowering therapies in Alzheimer’s disease, there is a seldom-explored ethical dimension to medical research worth considering. Daly et al (2022) remind us that in research ethics, patients should only be enrolled onto clinical randomised controlled trials (RCTs) if there is uncertainty over the outcome of treatment with an intervention or placebo and assert that ‘if repeated RCTs show that a treatment is inefficacious or unsafe, we are ethically bound to withhold it’ (Daly et al, 2022). The importance of that last statement is apparent in the context of their observations that ‘to date, 40 Phase II/III RCTs of amyloid-lowering therapies in Alzheimer’s disease have failed to improve, and often worsen, cognition. It is objectively unlikely that the 41st trial will be successful’ (Daly et al, 2022).
Given the present bleak therapeutic landscape for Alzheimer’s disease patients and their families, Daly et al (2022) contemplate the extent to which hope could be heightened unreasonably at the expense of hype generated by amyloid-lowering therapy whose strategies should be exposed to rigorous scrutiny, notwithstanding their occupation of ‘a central place in the drug development pipeline as of 2022’ (Daly et al, 2022). The discussion of these and other related questions should not be limited to medical scientists but extended to wider. Its members are entitled to consider ethical concerns about profits from drug development versus the wellbeing of Alzheimer’s disease patients and their families.
Mintzer (2018) took another angle when addressing amyloid-lowering therapeutic strategies by suggesting that even if they should be found to be effective, safe and approved for use, their efficacy will be demonstrated at a population level rather than an individual one. Mintzer (2018) considers the possibility of being able to identify individuals who are cognitively normal but with detectable amyloid in their brain and who could be inferred to have asymptomatic Alzheimer’s disease. For example, among 50 000 people who present with amyloid in their brain, although more participants receiving treatment will remain asymptomatic after a given time than those receiving placebo, not all participants receiving treatment will be symptom-free, and not all participants receiving placebo will develop Alzheimer’s disease: ‘In other words, we will be able to predict efficacy in a population sample but not in an individual. This creates a major problem, both from the individual point of view as well as from an economic community standpoint’ (Mintzer, 2018). Mintzer (2018) proposes that it is more ethically acceptable to find a means of identifying those participants who are likely to benefit from amyloid-lowering treatment with the minimum potential for adverse events. But that would require both ensuring the safety and efficacy of the medication and developing specific biomarkers that would provide a greater chance a greater chance of experiencing the benefits of the treatment with minimal safety concerns. Mintzer (2018) acknowledges that such an approach might slow the development of new therapies while awaiting the identification of specific biomarkers, but argues that ‘unless these biomarkers are identified, society will not be able to afford to provide those treatments. Specifically, we propose moving from a model that focuses on the benefits to a group to a model that focuses on the benefits to the individual’.
Medical science must not only refine the developments of Alzheimer’s disease therapeutics in the light of emerging evidence, but it is also essential to devise an appropriate ethical framework in which such developments can occur.
Alzheimer’s Disease hikari UK, Khan R, Mikhael M, et al. Therapeutic anti-amyloid β antibodies cause neuronal disturbances. Alzheimer’s dement. 2022;1–18. https://doi.org/10.1002/alz.12833
Daly T, Herrup K, Espay A. An ethical argument for ending human trials of amyloid-lowering therapies in Alzheimer’s Disease. AJOB Neurosci. 2022. https://doi.org/10.1080/21507740.2022.2129858
Kmietowicz Z. Why press releases don’t tell the whole story. Br Med J. 2022; 379: o2938. https://doi.org/10.1136/bmj.o2938
Mintzer J. Perspective from clinical research: Ethical issues in Alzheimer’s disease research. J Law Med Ethics. 2018; 46: 699–703. https://doi.org/10.1177/1073110518804231
van Dyck CH, Swanson CJ, Aisen P et al. Lecanemab in early Alzheimer’s disease. N Eng J Med. 2022. https://doi.org/10.1056/NEJMoa2212948