Doubling Down on the Failure of Amyloid-β Clearance

After decades of work, researchers have finally achieved therapies that can effectively clear amyloid-β aggregates from the brains of patients with Alzheimer's disease. Unfortunately clinical trials have shown no robust benefit to patients as a result. As illustrated by today's open access paper, a sizable contingent in the research community feel that the evidence for amyloid-β aggregation to be the root of the condition remains convincing. Failure means, in their eyes, that the challenge is more difficult than hoped, and the answer should be an increased effort to run longer clinical trials, find more and better anti-amyloid therapies, and in general an increased investment in and focus on clearance of amyloid-β.

Meanwhile, many other groups have their own viewpoints, some of which are gathering a sizable body of evidence in support of different interpretations of the core amyloid cascade hypothesis of Alzheimer's disease. No-one disputes that amyoid-β aggregation is associated with the condition and harmful in animal models, but why it is there, which form of amyloid-β or which of the surrounding biochemistry should be the target, or whether amyloid-β is irrelevant to later stages of the condition, and whether amyloid-β is a side-effect of other, more important pathological mechanisms, such as sustained inflammation of brain tissue or persistent viral infection - these are all ongoing debates that have given rise to significant research programs, clinical trials, and potential therapeutics. Many of these hypotheses and the approaches that arise from them will turn out to be wrong. That list may well include the currently dominant approach to amyloid-β clearance.

If amyloid drives Alzheimer disease, why have anti-amyloid therapies not yet slowed cognitive decline?

Alzheimer's disease (AD) is a major threat to our aging society and will be even more so in the future as life expectancy rises. Scientists from many different disciplines have worked intensively over four decades to try to identify the triggers of the disease and, based on these findings, to develop therapeutic strategies. However, although many clinical trials using approaches based on seemingly well-identified targets have been conducted, none of them seems to have reached its final goal: to substantially slow cognitive decline. This dispiriting news has led some to conclude that decades of intense research have failed because scientists wasted their time focusing on the wrong mechanism. But is this really true? Do we indeed have no idea what triggers AD? Were all clinical trials a failure? In other words, did we simply lose valuable time by working on the wrong targets, and are there mysterious "alternative pathways" that scientists have entirely missed so far?

For decades, scientists have focused their research on a presumably stereotyped neuropathology, namely amyloid plaques and neurofibrillary tangles, both of which are found in all patients with AD. Amyloid plaques are composed of abnormal aggregated forms of the amyloid β-proteins (Aβ) that are generated normally by enzymatic cleavage from the amyloid precursor protein (APP). Amyloid plaques are extracellular, whereas neurofibrillary tangles, composed of aggregated tau proteins, occur within neurons. How are these defining lesions connected, and what triggers the pathology initially? Based on overwhelming genetic evidence, Aβ accumulation and its aggregation into amyloid plaques is capable of initiating the disease and is therefore often placed at the top of a theoretical cascade of events which, via multiple steps, leads to widespread neuronal dysfunction and death. This rather linear view of molecular events has been challenged by the proposed "cellular phase" of AD which, instead of the long-pursued neurocentric view, brings the virtually simultaneous interplay of different types of brain cells, and not just neurons, into focus. As a consequence, alternative pathways, some of which may be independent of Aβ accrual, might also trigger the disease. In this sense, AD may be thought of as a syndrome that has many different causes. But did we really miss the main pathogenic triggers and need to completely reorient AD research?

dyshomeostasis is an early, invariant, and necessary feature of AD pathogenesis. Then why has only one anti-amyloid agent achieved regulatory approval, and even then, under highly controversial circumstances? The most plausible explanation that emerges from available knowledge is that translating the robust preclinical and biomarker science of Aβ pathobiology into clear-cut clinical benefit has been logistically difficult and fraught with missteps. In our view, anti-amyloid trials have often included inadequate compounds, less than ideal patient selection, initiation of treatment too late in the biological process, and faulty trial execution, including premature trial termination and the expectation that slowing this chronic disease can be accomplished in just 12 to 18 months. The seemingly improved execution of the current Phase III antibody clinical trials (lecanemab, donanemab, and gantenerumab) suggests that we may soon obtain more convincing evidence that sustained amyloid lowering leads to decreased pathological tau, less neurodegeneration, and the blunting of cognitive and functional decline. It would therefore be highly unwise to slow or abandon our efforts to confirm anti-Aβ therapeutic candidates, particularly since alternative, albeit highly attractive, targets (such as tau, ApoE4, and microglial modulation) are well behind Aβ lowering in the quest to lessen the disease course for patients.

If genetic, biochemical, animal modeling, fluid biomarker, and imaging studies all support Aβ as a rational target, and anti-Aβ immunotherapy reduces markers of neurodegeneration and provides some cognitive benefit, what can bring us to full success? It will be quantitative preclinical confirmation that certain antibodies (and other types of therapeutic agents) efficiently lower and neutralize Aβ oligomers as well as amyloid seeds in vivo, followed by the rigorous design and meticulous execution of clinical trials in humans confirmed to have AD pathobiology and treated for at least 18 to 24 months, with validated markers of AD pathology and multiple cognitive and functional end points that confirm each other. Of special importance would be the development of fluid and imaging markers of synaptic dysfunction, since the latter is a particularly important correlate of AD pathobiology.