Continued Discussion of the Ability of Immunotherapies to Remove Amyloid-β from the Brain

Is amyloid-β aggregation an important cause of Alzheimer's disease, or is it a side-effect of other, more important mechanisms? Near all age-related conditions are complex, with multiple interacting mechanisms involved. Absent a way to remove just one of those mechanisms, it is quite hard to say which are more or less important. In Alzheimer's disease this is made worse by the fact that the animal models are very artificial: few shorter lived mammals naturally develop anything even remotely resembling the biochemistry of Alzheimer's disease. Thus whether or not a treatment produces benefits in animal models is a poor indicator of whether or not it will produce benefits in humans. The quality of the model rests on unproven assumptions about the relevance of specific mechanisms to the condition.

There are now several approaches shown to be capable of removing a large fraction of amyloid-β from the brains of human patients, after many years of slow and painful development. The evidence from human trials shows that benefits to cognitive function and disease progression are muted at best, and more likely absent. This is unfortunate, but we can't expect every choice of target to be a success.

The poor outcomes of trials of anti-amyloid immunotherapies strongly suggest that amyloid-β is not an important mechanism in Alzheimer's disease, or at least if it is, then this is the case only during the early, slow development of the condition, setting the stage for immune dysfunction, neuroinflammation, and tau pathology. Because the onset of amyloid-β aggregation is so slow, it might be years yet before further trials of amyloid-β clearance reveal whether or not it produces benefits to patients in terms of postponing or preventing mild cognitive impairment and Alzheimer's disease. Nonetheless, this is how work on aging and age-related conditions must progress: the most optimal way forward is to find a plausible mechanism, address it, and see what happens. Then move on to the next.

On Donanemab, Plaques Plummet. Off Donanemab, They Stay Away

The FDA's controversial approval of aducanumab hinged on the premise that clearance of amyloid would be "reasonably likely" to bestow a cognitive benefit. Data presented at the Alzheimer's Association International Conference (AAIC) support the idea that two other antibodies could clear that low bar, as well. Researchers reported that the plaque-dissolving strength of donanemab, an antibody trained against forms of amyloid-β (Aβ) detectable only in plaques, tracked closely with plummeting plasma p-tau217. Weaving their data into a disease-progression model that had been generated from past trial data, they claimed that the amyloid- and tau-lowering effects of the drug correlated with a slowing of cognitive decline. Separately, data from lecanemab's Phase 2 trial and open-label extension studies provided yet more support for that antibody's disease-modifying effect, despite the travails that have beset its path through clinical development.

Both donanemab and lecanemab have received breakthrough therapy status from the FDA. Similarly to aducanumab, this means that their sponsors could apply for accelerated approval based primarily on changes in surrogate biomarkers that demonstrate amyloid reduction.

The donanemab trial enrolled 257 participants who had early symptomatic AD, amyloid in their brains, and - notably - an intermediate level of neurofibrillary tangles based on PET scan. After an initial period, when 131 volunteers randomized to the treatment group gradually received higher and higher doses of donanemab, the trial settled in on monthly infusions of 1,400 mg donanemab. This was given until a person's amyloid burden dropped below 25 centiloids - the level in healthy young controls - at which point the dose was lowered to 700 mg. If amyloid fell below 11 centiloids, or below 25 for two consecutive scans, the person was switched to placebo.

The 76-week trial met its primary cognitive endpoint, showing a 32 percent slowing of decline on the Integrated Alzheimer's Disease Rating Scale (iADRS). By 24 weeks, donanemab had completely cleared plaques in 40 percent of participants in the treatment group; by the trial's end, 68 percent had reached normal levels. Once a person's amyloid complete cleared, their levels stayed down for the remainder of the trial. Among the participants with "deep amyloid clearance," i.e., amyloid levels below 11 centiloids, and who were switched to placebo by 24 weeks, amyloid burden crept up only slowly by 76 weeks, barely cresting 11 centiloids, on average. At this rate, it would take 14 years for amyloid to accumulate back to baseline level for this group, or about 90 centiloids.


I guess what we see published now is the result of work done for the last several years. If the researchers are invested in such studies they will want to push it to publication. And hope that something better comes out.

I would say a lower hanging fruit would be to do studies on clearing atherosclerosis plaques. Easy to measure, it has known clinical significance and if can be done for the whole body, might even help with AD, or at least good old -age dementia.

Posted by: Cuberat at August 16th, 2021 2:50 PM

So... if amyloid buildup is NOT the cause of Alzheimer's, what do you think is?

Chronic inflammation caused by the immune system attacking (senescent cells, or something else?)

Posted by: GREGORY S SCHULTE at August 16th, 2021 4:54 PM

We don't know but we know that the last couple of years have shown that removing amyloid-β doesn't reverse nor slow-down AD, it might play a role in the beginning but it might be a side-effect of chronic inflammation, for example

Posted by: Cuberat at August 16th, 2021 5:55 PM

Amyloid build-up may be a side effect of production of an unusable form of Amyloid and Alzheimer's is caused by the LACK of useful amyloid.

Posted by: Robert Read at August 17th, 2021 9:10 AM

Key mechanisms behind synapse degeneration in Alzheimer's brain discovered
Targeting newly identified signaling pathway holds promise for treatments of neurodegenerative disorders
Date: August 18, 2021
Source: University of California - San Diego
Summary: Neurobiologists have uncovered the long-sought-after mechanisms behind the maintenance and decline of key synapses implicated in brain disorders such as Alzheimer's disease. The researchers identified the main components driving amyloid beta-associated synapse degeneration, which is found in the brains of people with Alzheimer's. The findings suggest an alternative approach to addressing neurodegenerative disorders: protect synapses by directly blocking the toxic actions of amyloid beta.

Posted by: Jones at August 19th, 2021 1:25 AM

Does Alzheimer's disease start inside nerve cells?
Date: August 18, 2021
Source: Lund University
Summary: An experimental study has revealed that the Alzheimer's protein amyloid-beta accumulates inside nerve cells, and that the misfolded protein may then spread from cell to cell via nerve fibers. This happens at an earlier stage than the formation of amyloid-beta plaques in the brain, something that is associated with the progression of Alzheimer's disease.

Posted by: Jones at August 19th, 2021 1:28 AM

The best part of treatment is amyloid plaques required for neuropathology confirmed diagnosis of AD.
Therefore when die from AD- like dementia; if no amyloid plaques; you did not die from AD.

Still demented; still dead; but less amyloid.

Posted by: Alan Green at August 22nd, 2021 1:32 PM
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