Researchers from Cambridge have raised concerns about the efficacy of new amyloid immunotherapy drugs in significantly reducing the impact of Alzheimer’s disease. Published in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, the team from Cambridge Public Health highlights several significant hurdles that could curtail the benefits of these treatments. These include a questionable risk-benefit ratio, limited patient eligibility, and the substantial costs of widespread implementation. Alzheimer’s disease accounts for approximately 70% of the 55 million dementia cases globally, though its precise definition remains contentious. A hallmark of the disease is the accumulation of amyloid proteins, which form plaques in the brain. According to the cascade hypothesis, which is a leading theory, this accumulation triggers a series of events that culminate in dementia symptoms.
The development of treatments aimed at reducing these symptoms and slowing the disease’s progression has been sluggish. However, recent breakthroughs in amyloid immunotherapy involving using the immune system to clear amyloid plaques have generated significant interest. Results from two completed phase III randomised controlled trials showed that these drugs could reduce the rate of cognitive and functional decline. However, the reductions were statistically significant but clinically minimal. Despite these findings, the Cambridge researchers point out that the differences in decline between patients on the drug and those on placebo were minimal, making it difficult for physicians to discern any real advantage after 18 months. Moreover, the trials revealed severe side effects such as brain swelling and bleeding. In one study of the drug donanemab, three deaths were attributed to the treatment.
The long-term impacts of these drugs, beyond the duration of the trials, remain largely unknown. Long-term placebo-controlled trials would be challenging, particularly as some drugs have already been approved. The US Food and Drug Administration has approved two such drugs. At the same time, the European Medicines Agency has recommended against approving one (lecanemab) due to the marginal benefits not outweighing the risks. The UK’s Medicines and Healthcare Products Regulatory Agency is poised to decide on these drugs.
Edo Richard, a professor of neurology at Radboud University Medical Centre in the Netherlands and co-author of the study, expressed concern about the enthusiasm surrounding these drugs. He stressed the importance of providing balanced information to help patients make informed decisions, especially given the desperation many feel when facing early-stage Alzheimer’s. Media reports suggest these drugs are suitable for all Alzheimer’s patients; however, the trials only included participants with early symptomatic Alzheimer’s and excluded those with other contributing conditions. These trial participants represent a tiny fraction—less than 8%—of the early Alzheimer’s population typically seen in health services, who are usually a decade or more older.
Dr Sebastian Walsh, NIHR Doctoral Fellow in Public Health Medicine at Cambridge Public Health and lead author, noted that even if approved, the drugs would only be suitable for a small subset of Alzheimer’s patients. Potential users would need extensive assessments before gaining access, and the benefits observed in trials were minimal. Effective administration would require identifying and treating patients at the earliest stages of the disease when symptoms are mild, a process that can be difficult.
The logistical and resource challenges of deploying such treatments are formidable. Even if the drugs are approved for a limited number of patients, many more would need assessments to determine their eligibility. This requirement would place additional strain on already stretched health services. Professor Carol Brayne, Co-director of Cambridge Public Health, highlighted the difficulty of rolling out these treatments on a large scale, even in high-income countries, and pointed out that most dementia occurs in low- and middle-income countries, where resources are even scarcer.
She also mentioned the potential for a more significant impact from addressing inequalities and health experiences throughout life, noting that the complexity of dementia often extends beyond a single protein issue. The team concludes that the current evidence does not support the use of amyloid immunotherapy in significantly reducing the suffering caused by dementia at a community level. As such, ongoing research into alternative approaches remains critical. With the global population ageing, finding effective support mechanisms for those living with dementia is more urgent than ever. Still, the promise shown by amyloid immunotherapies for select groups is insufficient to tackle the broader risk of dementia.
More information: Sebastian Walsh et al, Considering challenges for the new Alzheimer’s drugs: Clinical, population, and health system perspectives, Alzheimer s & Dementia. DOI: 10.1002/alz.14108
Journal information: Alzheimer’s & Dementia Provided by University of Cambridge
