Hugh Kim & Dongjoon Im
We’ve explored the connection between various diseases and specific proteins, such as Creutzfeldt-Jakob Disease (CJD) and variant Creutzfeldt-Jakob Disease (vCJD) caused by prion proteins, Alzheimer’s Disease (AD) linked to amyloid-β and tau proteins, and Parkinson’s Disease (PD) associated with α-synuclein.
If you’ve reviewed the material, you might have noticed that most neurodegenerative diseases exist at the intersection of well-established facts and areas still shrouded in mystery. This lack of comprehensive understanding complicates treatment, leaving symptomatic therapy as the primary strategy for managing these conditions.
Decades of research in clinical medicine, physiology, and biochemistry have contributed to a significant accumulation of knowledge. Based on these findings, numerous hypotheses have been proposed, leading to the development of various therapeutic candidates, many of which are undergoing clinical trials. One notable advancement is the development of antibody therapeutics for Alzheimer’s Disease (e.g., aducanumab, lecanemab, and donanemab), which target amyloid-beta plaques to slow disease progression.
Amyloid Hypothesis and Its Evolution
The Amyloid Cascade Hypothesis, which emphasizes the causal relationship between amyloid-β peptides and Alzheimer’s Disease, remains one of the most enduring and compelling theories. Efforts to treat Alzheimer’s by targeting and removing amyloid-β peptides have yielded mixed results, leading to skepticism about the hypothesis in the scientific community.
During the mid-2010s, as failures continued to mount, alternative or complementary hypotheses emerged. Amid this shift, aducanumab—a monoclonal antibody targeting amyloid-β aggregates—was introduced. The researchers behind aducanumab attributed prior failures to issues with earlier antibodies, not the hypothesis itself, asserting that amyloid-β remains a valid target.
Aducanumab was discovered in individuals resistant to Alzheimer’s Disease and specifically targets the aggregated forms of amyloid-β, such as soluble oligomers and insoluble fibrils, while sparing monomeric amyloid-β. This selectivity is crucial, as the antibody binds to structural motifs unique to pathogenic aggregates, disrupting their formation.
Following aducanumab’s FDA approval under the Accelerated Approval pathway, other antibodies targeting pathogenic protein aggregates, such as Biogen and Eisai’s lecanemab and Eli Lilly’s donanemab, have also received FDA approval as treatments for early Alzheimer’s disease, with evidence supporting their ability to reduce amyloid plaques and slow cognitive decline.
Challenges and Limitations
Despite the introduction of therapies targeting amyloid-β, significant limitations persist. Aducanumab, for instance, faced challenges in demonstrating sufficient efficacy, nearly halting clinical development before higher-dose studies led to its approval. Even so, its effectiveness remains limited to patients with early mild cognitive impairment.
The difficulty lies in precisely targeting amyloid-β, a disordered protein that exists in various states before and after forming aggregates. This variability complicates the development of therapies that can effectively neutralize pathogenic forms.
Alternative Approaches
As antibody therapies continue to face challenges, disease-modifying therapies (DMTs) focusing on early intervention have gained attention. These treatments aim to slow disease progression and delay symptom onset.
From the perspective of the Amyloid Hypothesis, DMTs involve strategies to inhibit the formation of amyloid-β aggregates. Approaches include preventing amyloid-β generation by modulating enzymes or reducing aggregation nucleation and elongation processes.
References
- Hardy, J. A. and Higgins, G. A. Science 1992, 256(5054), 184-185
- Cummings, J. L., et al. Alzheimers Res Ther 2014, 6(4), 1-7
- Sevigny, J., et al. Nature 2016, 537(7618), 50-56
- Logovinsky, V., et al. Alzheimers Res Ther 2016, 8(1), 1-10; Irizarry, M. C., et al. Alzheimers Dement 2016, 12, P352-P353
- Golde, T. E. J Neurochem 2006, 99(3), 689-707
- Lee, H. H., et al. Angew Chem Int Ed 2014, 126(29), 7591-7595
- Choi, T. S., et al. J Am Chem Soc 2017, 139(43), 15437-15445
- Im, D., et al. J Am Chem Soc 2022, 144(4), 1603-1611
Leo & Leah 
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