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

In a recent perspective piece published in the Journal of the Alzheimer’s Association Alzheimer’s and dementiaresearchers from the United Kingdom and the Netherlands examined the benefits, harms, and challenges associated with using amyloid immunotherapy drugs for the treatment of early Alzheimer’s disease from the clinical lens and from healthcare systems and public health perspectives.

Perspective: Considering challenges for the new Alzheimer’s drugs: clinical, population, and health care perspectives. Image credits: Juan Gaertner / Shutterstock

Clinical perspective of amyloid immunotherapy

Amyloid immunotherapy involves the use of antibodies that target the amyloid β protein to prevent its accumulation and the formation of amyloid plaques, one of the key hallmarks of Alzheimer’s disease. The recent approval of amyloid therapy by the US Food and Drug Administration (FDA) has been controversial due to reports of side effects and the lack of clarity about the long-term effects of this treatment method.

The two Phase III trials for the amyloid immunotherapy drugs donanemab and lecanemab reported that the drugs, compared to placebo, were 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 noted that only 80% of participants completed the clinical trials, and dropout rates were higher in the intervention groups than in the placebo groups, which could have potentially skewed the results in favor of amyloid immunotherapy.

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

Individuals carrying the apolipoprotein E4 (APOE4) allele and at higher risk for Alzheimer’s disease also showed a greater number of side effects and a lower response to treatment, indicating that genetic testing is necessary before recommending amyloid immunotherapy 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. Although this treatment is based on the hypothesis that the accumulation of amyloid over time will slow the progression of the disease, the long-term effects of this treatment remain unknown.

Public health implications

Participants were recruited for the phase III trials of the amyloid immunotherapy drugs based on a diagnosis of mild dementia or mild cognitive impairment and elevated amyloid levels characteristic of early Alzheimer’s disease. The donanemab studies 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 very homogeneous group, making the findings difficult to generalize to the broader population of patients with Alzheimer’s disease. The exclusion of patients with mixed dementia pathologies also affected the applicability of the findings to the general patient population.

The data from these clinical trials contrasted with press coverage of these drugs, which claimed that these amyloid immunotherapy drugs had broad applicability. However, the study data showed that a very small percentage of patients with Alzheimer’s disease met the eligibility criteria for the studies.

The mean age of the study population was also younger than the mean age of the global population of Alzheimer’s patients, further reducing the generalizability of the results. The researchers believe that the exclusivity of the clinical trial population, combined with the small effect sizes reported by the studies, poses specific challenges in translating efficacy into benefits on the broader population scale.

Perspectives from healthcare

The researchers discussed the amyloid immunotherapy drugs currently approved for clinical use and the reception of these drugs among the Alzheimer’s disease patient population. Current FDA-approved medications include aducanumab, lecanemab, and donanemab.

Although aducanumab was approved based on successful amyloid clearance as an endpoint, the drug’s low uptake resulted in the discontinuation of phase IV trials and the termination of marketing of aducanumab by Biogen in the US. Both lecanemab and donanemab are approved with no labeled contraindications for patients. with comorbidities or co-neuropathies. However, the recommendations include caution in prescribing these medications to individuals at high risk for bleeding or to individuals carrying the high-risk allele APOE4.

From the healthcare system perspective of amyloid immunotherapy, the financial and resource requirements for the treatment method were also examined. These include positron emission tomography (PET) scans, lumbar punctures for assessing amyloid markers, various clinical evaluations, magnetic resonance imaging scans for detecting amyloid accumulation, and genetic testing for the high-risk APOE4 allele to determine if you qualify comes for 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 for performing infusions, also contribute to the challenges in making viable of the method 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 research into developing more effective treatment options for Alzheimer’s disease continues, the current view on amyloid immunotherapy is that several clinical, population, and healthcare-related issues and challenges must be addressed to make it a beneficial therapeutic option.