Optimism for the Future of Amyloid-β Clearance

In today's popular science article, the SENS Research Foundation offers a more rosy picture of the near future of amyloid-β clearance than is the usual fare these days. Amyloids are misfolded or otherwise altered proteins that can aggregate to form solid deposits that disrupt cellular biochemistry. In principle they should all be removed. Their existence is a form of harmful change that takes place with age, and the connections to cell dysfunction are quite clear. The failure of amyloid-β clearance to produce meaningful benefits in Alzheimer's patients has led to some disillusionment, however.

Alzheimer's may be a condition in which amyloid-β aggregation is not the major pathological mechanism. I still agree with much of what is said here, that amyloids should be cleared regardless of whether Alzheimer's transitions to a later stage in which amyloid-β is irrelevant to pathology, regardless of whether amyloid-β is the primary agent in the onset stage of Alzheimer's. There is enough evidence for harms to result from amyloid-β that it should be removed. My primary concern regarding that point is that the present technologies capable of effective amyloid-β clearance in the brain, forms of immunotherapy, are just not safe enough to be deployed across the entire population, even setting aside the question of whether costs could be sufficiently reduced at that scale. Better approaches are needed.

From Parachutes to Jetpacks: Clearing Brain Beta-Amyloid with Donanemab or Lecanemab Works, Though More Must be Done

In its Phase III clinical trial, lecanemab became the first therapy to unambiguously put the brakes on the trainwreck of neurodegenerative aging. The monoclonal antibody cleared beta-amyloid protofibrils from patients' brains and slowed the downward plunge of Alzheimer's disease by some 27%, leading to FDA approval. And now comes donanemab, a monoclonal antibody that for the first time specifically targets beta-amyloid that has been cut down to and modified into pyroglutamate at position 3 (pE3-Abeta). While we are still awaiting publication in a peer-reviewed journal, the press release from Eli Lilly tells us that over the course of a relatively short trial, donanemab passed the goalpost of slowing the progression of Alzheimer's-type neurodegenerative aging (AD).

The people expressing disappointment with the donanemab trial results are absolutely right to insist that the ultimate goal should be to prevent AD from emerging - and to reverse it in its early stages if it does. As we've been highlighting for years, achieving this triumph will require the application of one of two "damage-repair" strategies. One approach is to begin removing beta-amyloid as soon as it starts to accumulate in the brain - meaning, in a person's forties or fifties. This would prevent beta-amyloid from driving tau aggregates widely across the brain, and thus prevent the destruction of neurons downstream. It would also likely prevent some of the excess senescent cell burden in the AD brain and better-preserve brain mitochondrial function.

Of course, that is not how these medicines are being used today. But while the clinical trials for these amyloid-clearing therapies didn't start that early in the disease process, part of the reason they succeeded was exactly that they began treating patients earlier in the disease process than had been done in previous trials. Starting to clear the brain of beta-amyloid alone in people experiencing "mild" cognitive impairment or early-stage AD was still not an early enough start to head off the cascade of horrors in the AD brain entirely - but it was early enough that doing so could still have a substantial effect.

To realize the full potential of removing beta-amyloid alone, you would want to begin treatment before the cascading destruction downstream of beta-amyloid had set in earnest - before people even began questioning whether they might be starting to slip. Happily, after the success of lecanemab in Phase III, the National Institutes of Health joined forces with Esai and decided to take this next logical step. Together, they have launched the AHEAD Study. This clinical trial will test lecanemab in volunteers with no evidence of cognitive impairment, but who have either intermediate (in one trial) or higher (in another) levels of beta-amyloid in their brains. The goal will be to see if starting at this early stage can keep people free from ever developing MCI and dementia in the first place.

Beta-amyloid clearance can potentially be made safer and more effective by replacing the current generation of binding antibodies with catabodies. Catabodies are catalytic antibodies that cleave their targets directly where they encounter them instead of having to bind to them and drag them to the circulation for eventual disposal via the liver or passive degradation. Catabodies offer the potential of greater safety since they break up their target on site, instead of having to drag it out through the brain's vasculature, where it may cause damage and inflammation. Indeed, the damage inflicted by wrenching beta-amyloid out of the brain is the most worrisome risk associated with the current beta-amyloid targeting antibodies, taking the form of vascular swelling and microbleeds.