Fight Aging!

There are now several immunotherapies capable of clearing amyloid-β aggregates from the aging brain, and a sizable amount of clinical trial data to look through. Sadly, this approach doesn't much help patients in the later stages of Alzheimer's disease, but the evidence to date suggests that it may be useful in prevention if the clearance is conducted early enough. Amyloid-β aggregation causes mild cognitive impairment in and of itself, but really just sets the stage for a set of different processes, inflammation and tau aggregation, that drive the late stage of Alzheimer's disease. At that point, clearing amyloid-β makes little difference to the outcome. It is worth noting that these immunotherapies bear a meaningful risk of serious side-effects. That side-effect profile will have to improve if anti-amyloid-β therapies are to become widely used as a preventative treatment in patients prior to evident cognitive impairment.

Clinical trials have proven that the anti-amyloid therapies donanemab and lecanemab slow the terrible fall into neurodegenerative aging of the Alzheimer's type (AD). As we noted, one key reason these trials succeeded where many promising antibodies had failed is that they started giving people these treatments earlier in the course of the disease. The reason why early treatment is critical is not primarily because there's less beta-amyloid in the brain earlier on in the course of AD. Instead, the benefit of acting early comes from the greater opportunity for beta-amyloid clearance to hold off other kinds of aging damage that occur downstream of it in the brain.

In the original Phase III trial for donanemab, the researchers didn't just compare all the subjects who received the antibody to those who received the placebo, but also compared people who received the treatment and who had "moderate" levels of tau aggregates in their brains to all the treated subjects combined (that is, those with moderate levels plus those with high levels together). Donanemab slowed the downward drag of the disease in all groups, but it was more effective in people who were less burdened by brain tau aggregates. When scientists used the integrated Alzheimer Disease Rating Scale (iADRS) to test donanemab's effectiveness in preserving the ability of people in the trial to carry on the day-to-day business of life and social interaction, they found that it slowed the fall by 35% in people with a medium tau burden, but by only 22% in the combined population. And on top of all that, early donanemab treatment yielded a significantly greater reduction in the number of cells called astrocytes in the brain that had abandoned their normal housekeeping activities and become "reactive."

These trials provide robust evidence supporting the classical "Amyloid Cascade" - the idea that neurodegenerative aging of the Alzheimer's type is a domino-tumble of destruction that starts as beta-amyloid drives tau aggregates to invade additional regions of the brain, leading to neurons first failing to interact with each other and eventually dying, all culminating in dementia. Following this logic, it seems increasingly likely that clearing out beta-amyloid early enough might forestall AD for decades - intervene in outwardly healthy middle-aged people with seemingly intact brains, and keep treating them indefinitely to save their minds.

Link: https://www.sens.org/amylosens-alzheimers-marathon-decathlon/