Chapter 103
Neurodegeneration — 9
So far, we see two monoclonal antibodies directed to β-amyloid clearing plaque (up to 80 percent with donanemab), a delay of a few months in cognitive decline, but with significant risks, accelerated brain shrinkage, and high cost. The dissociation between the marked reduction of brain amyloid but only modest clinical improvement matters. Moreover, the treatment strategy is highly complex, even with use of a blood biomarker such as p-tau217. The potential qualifying patient must undergo PET and MRI imaging; come to a specialized clinic for the antibody infusion every two or four weeks; have frequent MRIs before fifth, seventh, and fourteenth infusion (the FDA recommendation for lecanemab); and undergo follow-up PET imaging.
The participants in these trials were about 90 percent white, so we have insufficient evidence for other races and ethnicities. The evidence for the two monoclonal antibodies that were deemed positive is flanked by an extraordinary series of failures of other β-amyloid antibodies, such as crenezumab, bapineuzumab, gantenerumab, solanezumab, and others. It was particularly disconcerting to see the lack of benefit in people who were asymptomatic but carried a gene mutation for Alzheimer’s.
Speculation abounds as to why two of so many different antibodies seemed to achieve a small clinical benefit. Each of these binds to different parts (epitopes) of the Aβ-42 protein. Their binding strength to β-amyloid varies, with donanemab being the strongest. In any case, the anti-amyloid approach is on fallow ground, despite the past FDA support.
The field has moved to testing the antibodies in people who are asymptomatic but with biomarker-based risk (such as p-tau217) in multiple clinical trials. The idea is that the risk will be decreased and the benefit augmented before there has been accumulation of Tau and more advanced pathological changes in the brain. Another direction is to test multiprong therapies, such as targeting β-amyloid, Tau, and the gliosis-linked brain inflammation. Tau-directed monoclonal antibodies, antisense oligonucleotides, and vaccines are being pursued in clinical trials.