(318a) Anti-Amyloid Failures Increase As Aducanumab for Alzheimer’s Disease Flops: A Chemical Engineer’s Perspective

Although the amyloid (abeta peptide, Aβ) hypothesis is 25 years old, is the dominant model of Alzheimer’s Disease (AD) pathogenesis, and currently guides the development of potential treatments, it is still controversial. One possible reason is a lack of a clear mechanistic path from the cleavage products of the amyloid precursor protein (APP) such as soluble Aβ monomer and a series of recently discovered soluble molecular fragmentsto the deleterious effects on synaptic form and function^{1, 2}. Another reason is the successive failure of antibodies against Aβ and secretase inhibitors, highlighted by the recent decision by Biogen and Eisai to terminate two phase III trials of their anti-Aβ antibody, aducanumab³. Both biophysical properties of these molecular entities and the balance between production and clearance are considered critical for AD pathogenesis. From a review of the recent literature including aggregation kinetics⁴ and structural morphology⁴, Aβ clearance⁴, molecular simulations⁵, long term potentiation measurements with inhibition binding, and the binding of a commercial monoclonal antibody, aducanumab, we hypothesize that the N-terminal domains of neurotoxic Aβ oligomers are implicated in causing the disease. We call this the “N-Terminal Hypothesis for AD”⁶. Recently reported experimental structures also show a flexible/exposed N-terminal region (Aβ_1-14) in the disease relevant Aβ_1-42 fibril⁷. Additionally, since monomers are not neurotoxic while dimers, trimers etc. are, this suggests that at least two N-termini are necessary for LTP deficit induction. It then follows that the mechanism of toxicity could be due to multivalent interactions between the N-termini (≥2) of Aβ oligomers with glutamate N-methyl D-aspartate receptors. MD simulations demonstrate increased flexibility of the protective versus the causative variants for N-termini in dimers⁸. Taken together, these collective findings strongly suggest that the N-terminus of Aβ oligomers could be causative for AD. Many of the failed antibodies bind to the N-terminus but may not bind multivalently. Since about one in a 1000 antibody molecules pass the blood brain barrier is it possible that too few pass through to exert a long-term affect. Finally, it maybe that AD, which is thought to take ~20 years to mature, is being treated too late and has progressed to far to be reversed. This suggests that early detection is critical⁹.

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