Finding the Limits of Amyloid Clearance as a Treatment for Alzheimer's Disease

Alzheimer's disease is associated with a slow buildup of amyloid-β aggregates in the brain over the years of later life. The amyloid cascade hypothesis puts this process as the first step in the development of Alzheimer's disease, setting the stage for later neuroinflammation, tau aggregation, and cell death in the brain. This view of the condition has yet to lead to meaningful therapies, however. Several immunotherapy approaches have succeeded in clearing a meaningful degree of amyloid-β in human trials. Clinical improvement in those patients was very limited at best, even given a generous interpretation of the data.

Now a more recent anti-amyloid immunotherapy trial has resulted in a clear slowing of the progression of Alzheimer's disease following complete or near-complete clearance of amyloid-β aggregates. While the modest slowing of progression was not the result hoped for, in the sense that it is still too little benefit for the costs involved, it is nonetheless a much less ambiguous set of data than was the case for past trial outcomes in this class of therapy.

The data might be taken as a reinforcement of the view that amyloid-β is an important part of the early pre-clinical stages of Alzheimer's disease, but becomes increasingly irrelevant as the condition proceeds. Based on the research of recent years, the later stages of Alzheimer's are coming to look like a self-sustaining feedback loop between chronic inflammation, cellular senescence, immune dysfunction, and tau aggregation, culminating in widespread cell death in the brain.

The foundation of that later stage is perhaps created by amyloid-β aggregation, but it could in principle also arise from persistent infection. This data suggests that amyloid-β does indeed play a role, and that the genesis of later stages of Alzheimer's disease is not all a matter of other mechanisms. Yet the modest size of the outcome following complete amyloid-β aggregate clearance also suggests that amyloid-β simply isn't a viable target for patients exhibiting clinical symptoms.

Donanemab Confirms: Clearing Plaques Slows Decline-By a Bit

It has been clear for a while that anti-amyloid antibodies can sweep plaque from the brain, but until now the question of whether this slows cognitive decline has remained hotly contended. Despite some positive signals from four such antibodies, the data have been messy and hard to interpret. At the a recent conference, researchers presented the cleanest data yet on this question. In a Phase 2 trial, the company's anti-amyloid antibody donanemab met its primary endpoint. Participants did not get better. Even so, donanemab slowed their decline by an average of 32 percent on a combined cognitive and functional measure.

Donanemab banished plaque from the brain in a majority of participants, while nudging down the rate of neurofibrillary tangle accumulation in the frontal cortex and other regions. The trial included several innovative elements, such as screening participants by tangle burden, using tau PET as a secondary outcome measure, and stopping dosing once amyloid was gone. Most Alzheimer's researchers welcomed the findings. At the same time, researchers emphasized that, as with other anti-amyloid immunotherapies, the cognitive benefit was small. "The donanemab story is the most encouraging news on the amyloid front, ever, but whether the effect size is clinically meaningful is questionable."

Donanemab is unique among Alzheimer's disease (AD) immunotherapies in that it targets a modified version of amyloid-β (Aβ) that has a pyroglutamate attached to the N terminus. This pathological form of Aβ is highly prone to aggregate, depositing in the core of all amyloid plaques, but is found nowhere else in the brain. In Phase 1 trials, donanemab busted up plaques fast, in many cases clearing all deposits within six months. However, even dramatic amyloid clearance has not translated into a clear cognitive benefit in past Phase 2 and 3 immunotherapy trials.

Given that donanemab completely cleared plaque, the researchers acknowledged that a 32 percent slowing may represent the most it can achieve in people at this stage of AD. "This is probably the ceiling for an amyloid-lowering drug." To do more for patients, researchers likely will have to treat earlier in a prevention paradigm, or combine anti-amyloid treatment with an anti-tau drug, he suggested.

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