The amyloid hypothesis is not dead - just like the tau hypothesis is not dead. The $1m question is what role do the proteins play and at what stage and to what degree
There are so many plausible Alzheimer’s theories that it makes me wonder: are multiple of them right? Is Alzheimer’s really many different diseases that present the same way?
Quite possibly - however we haven't developed enough discerning power to differentiate between what may be a potential 'Alzheimer's Cluster' and say Fronto-temporal, Lewy Body, Vascular, etc etc.
I assume "the amyloid hypothesis" is the hypothesis that plaques cause Alzheimer's. That hypothesis is indeed dead. There are plenty of successful plaque treatments. Basically none of them are effective.
> Alzheimer's disease is believed to occur when abnormal amounts of amyloid beta, accumulating extracellularly as amyloid plaques, and tau proteins, accumulating intracellularly as neurofibrillary tangles, form in the brain affecting neuronal functioning and connectivity, resulting in a progressive loss of brain function.
Wikipedia is correct to say it's widely believed that plaques cause Alzheimer's, because the new evidence is still encountering resistance. The hallmark of science is falsification. We now have many drugs that remove amyloid plaques with few side effects. Removing plaques does not improve symptoms or halt progression [1, 2].
Furthermore, 60% people over 80 have these plaques but only 10% develop dementia [3].
Ergo, the hypothesis that plaques cause of Alzheimer's is pretty much falsified. More than likely they may be a biomarker of some kind that may be associated with cognitive decline of some sort.
I can't get the whole paper, but your first link seems to be saying that we've put all our eggs into one basket and we are ignoring too many other theories. It doesn't go so far as to say the amyloid angle is bunk, does it?
Your second link says this:
> researchers have said experimental treatments targeting the beta amyloid protein might not have worked in the past because the doses were too low or the patient populations used for the trials should have been younger
Again, that doesn't seem to be concluding the amyloid & tau street is a dead end.
The Alzheimer's Association site (alz.org) agrees:
> Alzheimer's has no cure, but one treatment — aducanumab (Aduhelm™) — is the first therapy to demonstrate that removing amyloid, one of the hallmarks of Alzheimer’s disease, from the brain is reasonably likely to reduce cognitive and functional decline in people living with early Alzheimer’s.
> I can't get the whole paper, but your first link seems to be saying that we've put all our eggs into one basket and we are ignoring too many other theories. It doesn't go so far as to say the amyloid angle is bunk, does it?
> Furthermore, the blind adherence to the “Amyloid code” [297] has resulted in the overwhelming rationalization of clinical trial failures - the lack of validation of the amyloid hypothesis – as being due to recurring issues in their planning and execution, not that the hypothesis has failed in its validation. This viewpoint, described as “sheer obstinacy in the face of compelling proof ..[of being]… on the wrong track” [285] has also compromised the translational approach to AD therapeutics making the criteria for compound advancement from preclinical research to the clinic exclusively based on either a blind faith in a hypothesis or animal models that have proven irrelevant.
This addresses the special pleading you quoted from people who continue trying to explain away the failures of the amyloid model.
The writing is on the wall, but as they say, "science advances one funeral at a time".
which does nothing to explain why people with APP mutations such as found in fAd develop early onset Alzheimers. So the mystery of Amyloid and its role in dementias persists
The simplest explanation is that APP mutations cause some other dysfunctions which then causes Alzheimer's. It's these other dysfunctions we should be looking for.
We still haven’t proven that amyloid plaques don’t have at least some level of responsibility. Just because we now have the ability to clear plaques, and it hasn’t lead to improvement, doesn’t prove that amyloid plaques aren’t involved in disease progression.
Now let me be clear, I’m not a cheerleader for any of them. I have read every original paper on the pathophysiology of AD from the 60s through to 2014 and I saw in detail the debate bounce back and forth from Amyloid to Tau with sprinkles of ‘Type 3 diabetes’ and inflammation and back again like a game of tennis. The science will come out the way it will come out.
But there is nothing about our ability to remove plaques with no change in the disease that says that amyloid plaques don’t have a role in disease pathogenesis. Could be the damage is done and clearing them is irrelevant. We just don’t know enough
