The amyloid cascade hypothesis of Alzheimer's disease suggests that aggregation of misfolded amyloid-β sets the stage for a feedback loop between chronic inflammation of brain tissue and tau aggregation. It is that second step that causes severe pathology and death, and once it is underway in earnest a patient's amyloid-β burden is of little relevance. This the explanation given for the lack of patient benefits resulting from the successful clearance of amyloid-β using forms of immunotherapy. The industry has now shifted to testing these treatments in patients at an earlier stage of Alzheimer's disease, and there are preliminary signs that this might be producing results. Even so, it may still be the case that amyloid-β is only a sidebar to other, more important disease mechanisms. Some researchers argue for chronic inflammation, driven by factors such as persistent viral infection, to be the true cause, for example.
Some researchers have long argued for starting amyloid immunotherapy early, before neurofibrillary tangles spread and neurons die all over the brain. They have recently added flesh to the bone of this idea. Despite coming from different anti-amyloid antibody therapies - donanemab, lecanemab, gantenerumab - the findings paint a convergent picture. In short, participants at the earliest stages of the respective cohorts enrolled in each trial gained the most cognitively from treatment. The findings are preliminary, often involving post hoc analyses of small numbers of participants remaining from large trials.
In one striking tease, about two-thirds of participants with very early Alzheimer's disease who took lecanemab actually improved on the Clinical Dementia Rating Scale Sum of Boxes Scores (CDR-SB) over 18 months, compared with about one-third of a matched placebo group. Other findings offered the first concrete indication that amyloid immunotherapy may be able to prevent Alzheimer's disease. In the Dominantly Inherited Alzheimer Network secondary prevention trial, presymptomatic mutation carriers taking gantenerumab for eight years had half the odds of developing symptoms as did those on placebo.