Amyloid immunotherapy for early Alzheimer's: Promising but fraught with challenges

By Dr. Chinta SidharthanReviewed by Susha Cheriyedath, M.Sc.Aug 7 2024

In a recent perspective piece published in the Alzheimer's Association's journal Alzheimer's & Dementia, researchers from the United Kingdom and the Netherlands examined the pros, cons, and challenges associated with the use of amyloid immunotherapy drugs for treating early Alzheimer's disease from the clinical lens and the perspectives of health systems and population health.

Perspective: Considering challenges for the new Alzheimer's drugs: Clinical, population, and health system perspectives. Image Credit: Juan Gaertner / Shutterstock

Clinical perspective of amyloid immunotherapy

Amyloid immunotherapy involves using antibodies that target the amyloid β protein to prevent its accumulation and the formation of amyloid plaques, one of the major hallmarks of Alzheimer's disease. The recent approval of amyloid therapy by the United States (U.S.) Food and Drug Administration (FDA) has been contentious due to reports of adverse effects and the lack of clarity about the long-term impacts of this treatment method.

The two phase III trials for the amyloid immunotherapy drugs donanemab and lecanemab have reported that compared to the placebo, the drugs have been successful in lowering the rate of functional and cognitive decline. However, the observed effect sizes are well below the minimum threshold for clinical importance.

The researchers also observed that only 80% of the participants completed the clinical trials, and the dropout rates were higher in the intervention groups than in the placebo groups, which could have potentially biased the results in favor of amyloid immunotherapy.

Furthermore, adverse events such as amyloid-related imaging abnormalities or ARIA, including hemorrhage and brain edema, have been reported in close to 30% of the participants. The trials for donanemab reported three deaths due to ARIA, while the open-label trial extension for lecanemab had two deaths due to hemorrhages and amyloid-linked inflammation.

Individuals carrying the apolipoprotein E4 (APOE4) allele who were at higher risk of Alzheimer's disease also showed greater rates of adverse reactions and lower treatment response rates, indicating that genetic testing is necessary before amyloid immunotherapy is recommended as a treatment option.

Furthermore, amyloid immunotherapy is based on the amyloid cascade hypothesis, which implicates amyloid accumulation in the brain as a cause of dementia. While this treatment is founded on the hypothesis that clearance of amyloid accumulation over time will slow the progression of the disease, the long-term effects of this treatment remain unknown.

Implications for population health

Participants were recruited for the phase III trials for the amyloid immunotherapy drugs based on the diagnoses of mild dementia or mild cognitive impairments and elevated amyloid levels characteristic of early Alzheimer's disease. The trials for donanemab also recruited participants based on elevated levels of tau protein.

The exclusion of Alzheimer's disease patients with comorbidities and co-neuropathies meant that to maximize efficacy, these phase III trials focused on a highly homogeneous group, making the findings difficult to generalize to the broader population of Alzheimer's disease patients. The exclusion of patients with mixed dementia pathologies also impacted the applicability of the findings to the general patient population.

The data from these clinical trials were in contrast with the press coverage for these drugs, which claimed that these amyloid immunotherapy drugs had broad applicability. However, the trial data indicated that a very small percentage of Alzheimer's disease patients met the eligibility criteria for the trials.

The average age of the trial population was also younger than the average age of the global Alzheimer's patient population, further reducing the generalizability of the results. The researchers believe that the exclusivity of the clinical trial study population, combined with the small effect sizes reported by the trials, poses specific challenges to translating the efficacy into benefits for the broader population scale.

Perspectives from healthcare

The researchers discussed the amyloid immunotherapy drugs that have currently been approved for clinical use and the reception of these drugs among the Alzheimer's disease patient population. The current FDA-approved drugs include aducanumab, lecanemab, and donanemab.

While aducanumab was approved based on successful amyloid clearance as an endpoint, the low uptake of the drug resulted in the discontinuation of phase IV trials and termination of aducanumab marketing by Biogen in the U.S. Both lecanemab and donanemab have been approved with no labeled contraindications for patients with comorbidities or co-neuropathologies. However, the recommendations include caution while prescribing these drugs to individuals at high risk of hemorrhage or those carrying the APOE4 high-risk allele.

The health system perspective of amyloid immunotherapy also examined the financial and resource requirements for the treatment method. These included positron emission tomography (PET) scans, lumbar punctures for amyloid marker assessments, various clinical evaluations, magnetic resonance imaging scans for detecting amyloid accumulation, and genetic testing for the high-risk APOE4 allele to determine eligibility for the therapy.

The substantial financial and resource burden of the diagnostic process to determine eligibility for amyloid immunotherapy and the subsequent requirements for administering therapy, including specialized centers to carry out infusions, also add to the challenges in making the method viable in middle to low-income countries.

Conclusions

Overall, through this perspective piece, the researchers presented a concise view of the current challenges in making amyloid immunotherapy a broadly applicable and affordable treatment option for early-stage Alzheimer's disease.

While the research for developing more effective treatment options for Alzheimer's disease continues, the current opinion about amyloid immunotherapy is that several clinical, population-scale, and healthcare-associated concerns and challenges need to be addressed to make it a favorable therapeutic option.