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News on antibody therapies in Alzheimer's disease: Is lecanemab the breakthrough ?


As stated in my book on neurodegeneration in chapter 3.2.4, the so-called Aβ-clearing, i.e. the clearing of amyloid deposits via the vascular and CSF system or also by means of infused amyloid antibodies, is of particular importance in the search for effective Alzheimer therapies. Some of these approaches showed very good efficacy in initial trials, i.e., they led to the reduction of Aβ-oligomers and the resolution of amyloid plaques. Although in terms of functional improvements, clinical trials have so far been unsuccessful, meta-analyses of several antibody studies have demonstrated an association between reduction of Aβ-plaques and slower progression of the disease.


In particular, improvements in memory function occurred at higher doses of antibodies specifically targeting Aβ-oligomers and smaller protein aggregates, e.g., aducanumab (Aduhelm). In a recent article published in the New England Journal of Medicine, van Dyck and colleagues now provide compelling evidence that treatment with the new antibody lecanemab can significantly reduce the number of amyloid plaques and markedly improve clinical symptoms compared with placebo-treated controls. Although lecanemab did not completely halt memory loss, the results of the 18-month study of about 1800 patients were very promising.


The approval of Aβ-reducing antibodies for cognitive deficits occurring in the early stages of Alzheimer's disease is highly controversial among experts, not only because of the high costs, but especially because of the sometimes considerable side effects. Localized brain swelling and hemorrhages occur in some of the patients treated. They are more common in people who are carriers of the APOE4 gene (a variant that carries a high risk of developing Alzheimer's disease) and necessitate magnetic resonance imaging (MRI) to detect and treat these sequelae. Of the lecanemab-treated participants, 13% showed such side effects, although only 3% had associated symptoms (such as headache) and these were mostly reversible. One person treated with lecanemab died of a brain hemorrhage during the study and three others after it ended, as did one person who received the placebo.


Strikingly, lecanemab significantly reduced the amount of Aβ-plaques as well as CSF- and blood-based biomarkers of Aβ-plaques and tau phosphorylation. The treatment slowed the accumulation of tau fibrils (tangles) in the brain, altered several neuroinflammatory and neurodegenerative biomarkers, and reduced clinical parameters of cognitive decline by approximately 30%. The differences between the treatment group and patients receiving the placebo were highly significant and increased over time.


The study thus confirms the hypothesis that Aβ-aggregates are involved in the development of Alzheimer's disease and provides a basis for the development of combination therapies that simultaneously target Aβ-peptides and tau fibrils. Furthermore, it will facilitate researchers and clinicians to identify Aβ, tau, and other biomarkers that can be associated with clinical benefit of treatment.


References:


van Dyck CH, Swanson CJ, Aisen P, ..., Kramer LD, Iwatsubo T (2022) Lecanemab in early Alzheimer's disease. New England Journal of Medicine 388:9


Reiman EM (2023) Drug trial for Alzheimer's disease is a game changer. Nature 615:42


Image credit: iStock/Love Employee

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