A narrative of this-one-theory-being-kept-down-by-the-man is attractive, but a bit thin in practice. The amount we do not know about anything in biology (especially the brain) is staggering. Few researchers are willing to make definitive statements owing to our ignorance in the space. Biological research is the closest one can come to direct manifestation of Murphy's Law.
Many are invested in the amyloid hypothesis, but only because it is the most compelling target to date. Everyone knows the emperor has no clothes. If/when better evidence comes to light, the field would move accordingly. Until that time, pharma companies will keep throwing billions of dollars at abeta hoping that their compound will have an effect where others have failed.
Edit: corrected typo pointed out from below
When speaking of biology, assume we know less than we think.
I think should have been "we do not know"
However a series of high profile articles and editorials have said that we have. For the latest example, read https://www.scientificamerican.com/article/alzheimers-inc-wh....
Given that, I will continue to believe that this area of science absolutely have acted in a non-scientific way.
This is a bit of an idealistic view.
It's entirely possible for large players within a given system to pick and choose winners, specifically in where they direct funding. This isn't the same thing as actively platforming against a particular path, just funding the one that they see as most promising.
I think the argument here revolves not around the "gerontologists hate this one trick that big pharma doesn't want you to know" but rather than there's some small number of people making decisions based on their own biases with regard to research directions and there's a dissenting group that would like to see broader research done before committing the finite available resources to just that one path.
In short, there are good reasons at this point to believe that amyloid-β's primary function is as antimicrobial peptide, and thus various infections may cause the seeding of amyloid-β deposits. These deposits may then persist for years beyond any useful benefit, especially if the brain's clearance mechanisms are impaired.
Note that, per [2]:
Importantly, in the antimicrobial protection model, neurodegeneration is not mediated by pathogen activities that directly kill neurons. Rather, Aβ innate immune pathways targeting pathogens mediate the AD [Alzheimer's Disease] neuropathogenesis that leads to widespread neurodegeneration. Thus, our model is consistent with the amyloid cascade hypothesis and overwhelming data showing the primacy of Aβ in AD pathology.
[1]. Dominy et al (2019). Porphyromonas gingivalis in Alzheimer’s disease brains: Evidence for disease causation and treatment with small-molecule inhibitors. https://doi.org/10.1126/sciadv.aau3333
[2]. Eimer et al (2018). Alzheimer’s Disease-Associated β-Amyloid Is Rapidly Seeded by Herpesviridae to Protect against Brain Infection. https://doi.org/10.1016/j.neuron.2018.06.030
While it may be considered andectoal, this fits with what i've seen in my family. In my mind and from what i've read it seems to be more of a combination of factors - diabetes, an APOE gene, toss in a little depression/loss of purpose/retirement/isolation, etc
I find the studies with gamma interesting: https://www.alzheimers.gov/clinical-trials/gamma-induction-a...
I think it would be good to bring more attention to noticing when things start to slip, because as things progress there can be less openess to trying new things/focus on maintaining state.
To me that indicates that this isn't a controversy between scientists, but an example of corruption / regulatory capture. Biogen spent a bunch of money researching a drug based on an unproven theory. When their results were very poor, the FDA allowed them to switch to accelerated approval, then ignored their unanimous panel of experts to grant that approval. This allows Biogen to sell an extremely expensive drug and recoup some of their loses before the ongoing studies required under accelerated approval further undermine the drug's claims of effectiveness.
For what it is worth, there seems to be a lot of internal debate around the causes, symptoms, and treatments of CTE. In fact, there are debates as to whether CTE is a distinct tauopathy or even exists at all (at least in the form the public understands it).
"As NPR's Jon Hamilton has reported:
"This drug has generated all kinds of excitement because it is the first approved drug that does more than just relieve the symptoms of Alzheimer's. This drug actually affects an underlying disease process by reducing the amount of sticky amyloid plaque that builds up in the brain. The catch is that removing this plaque may not actually help patients avoid memory loss and thinking problems. One big study showed that it did. Another showed that it didn't.""
In other words, the drug works against what may be a symptom of the disease, but hasn't reliably been shown to do anything for the actual problem.
Science is hard.
Oh, and by the way,
"The drug will be administered through infusions every four weeks, resulting in a yearly cost of about $56,000, the companies said. That's the list price, which doesn't necessarily reflect the out-of-pocket costs for someone who has insurance and/or Medicare. Preliminary estimates suggest patients' copayments for the drug could cost around $11,500 annually."
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It is natural to ask: "sure, we see amyloid-β plaques with Alzheimer's Disease, but could there be a confounder, rather than amyloid-β being the cause?" However, we have strong evidence that it's the cause.
In fact, in a subset of cases, we have smoking gun evidence that amyloid is the cause: certain mutations or duplications of the APP (amyloid precursor protein), PS1 & PS2 (presenilin 1 & presenilin 2, parts of the enzyme γ-secretase involved in cleaving APP to make amyloid-β) genes guarantee that one gets Alzheimer's, and typically quite early (between the age of 30 and 60 for the onset of clinical symptoms). We have mapped out the structure and function of the corresponding proteins extremely well, and we know how, functionally, those specific mutations affect the behavior of those proteins: either to increase total amyloid-β production, or to increase production of the specific peptide (amyloid-β 42) implicated in Alzheimer's Disease. [1] I am not aware of another plausible effect of those mutations besides this one, and the mutations guarantee you get Alzheimer's Disease.
Now, this represents approximately 1% of Alzheimer's cases, the so-called autosomal dominant variety, so it's a priori conceivable that the other cases have a different cause. In the remaining cases, we have evidence consistent with an impairment of amyloid clearance mechanisms, however that evidence is more circumstantial and in some cases compatible with other hypotheses. But the disease looks like exactly the same disease as the 1% of cases in which we have smoking gun evidence of amyloid being the cause: we still see the same progression of amyloid-β, followed by a progression of hyperphosphorylated tau, followed by neurodegeneration and cognitive decline, and with the same sequence of brain regions and cognitive symptoms.
Suppose there are two bank robberies. In the first, we have smoking gun evidence of the culprit: a video camera showing a guy getting out of his car, with a clear image of his face and the license plate, and then of him walking into the bank, pointing a gun at the teller, the teller handing over a bag of cash, and him walking out with that bag of cash. In the second: we also have footage of the same guy and the same license plate at the scene of the crime, but an occlusion prevents clear footage of the exact moment of the robbery. However, the robbery occurred in the same town and on the same day, and eyewitness reports are that the robbery was conducted in basically the same manner. In that case, is there much question as to the identity of the robber?
**
As for the track record of amyloid-targeting therapy for Alzheimer's, I think it's fair to say that it's been less successful than hoped for but that also:
1) There has been a mixture of benefit and no effect; rather than the mixture of benefit, no effect, and harm which you'd expect to see if the drugs really were useless. For example:
A) The recent phase 2 trial of the similar drug donanemab showed success in its primary endpoint of reducing cognitive decline, by 32% (p = 0.04). [2]
B) The recent phase 2b trial of another similar drug lecanemab had promising results, although it didn't pass its primary endpoint, arguably due to a needlessly convoluted Bayesian statistical analysis. It showed reductions in cognitive decline of 26%, 30%, or 47% (p = 0.125, 0,034, or 0.017), depending on endpoint. [3]
C) With respect to aducanumab [4], the first phase 3 trial, EMERGE, passed its primary endpoint and all pre-designated secondary cognitive endpoints, with p-values for the high dose arm between 0.0006 and 0.0493 (0.0120 on the primary endpoint), and effect sizes ranging from an 18% slowdown to a 40% slowdown in cognitive decline (22% on the primary endpoint).
The second phase 3 trial, ENGAGE, did not show statistically significant benefits on any pre-designated endpoints, but the effect sizes still ranged from -3% to 18% (-2% on the primary endpoint). So given only pre-designated endpoints, we have two trials, one of which showed a clear benefit, and the other of which showed no effect, or very slight benefit if we give some weight to pre-designated secondary endpoints. From a Bayesian perspective, this has to be seen as weak evidence of benefit.
Lastly, both trials showed a substantial and significant (p < 0.001 in EMERGE, p < 0.01 in ENGAGE) reduction in phosphorylated tau, a neuropathology both regionally and chronologically highly correlated with volume loss and cognitive decline in Alzheimer's Disease.
2) The amyloid cascade hypothesis offers explanations for past failures of amyloid-targeting therapy, for example poor target specificity (some therapies such as semagacestat were not proven to engage amyloid in the first place, and were also known to produce other toxic effects unrelated to reduction in amyloid), deficient screening of participants (in some cases, patients were selected only for cognitive symptoms and not for the presence of amyloid, thereby reducing statistical power), and not intervening early enough (no one believes amyloid is the main proximate cause of neurodegeneration, so if you intervene late, it might be too late to prevent the cascade of problems it's believed to cause).
By contrast, I'm not aware of alternative hypotheses which even offer a story which can account for the known facts, such as the aforementioned evidence in the APP and PS1/PS2 genes.
**
For those interested in learning more, a good starting point for the current state of the science is [5]. A more up-to-date and comprehensive review paper is [6].
[1] Haass et al (2012). Trafficking and proteolytic processing of APP. https://doi.org/10.1101/cshperspect.a006270
[2] Mintun et al (2021). Donanemab in Early Alzheimer’s Disease. https://doi.org/10.1056/nejmoa2100708
[3] Swanson et al (2021). A randomized, double-blind, phase 2b proof-of-concept clinical trial in early Alzheimer's disease with lecanemab, an anti-Aβ protofibril antibody. https://doi.org/10.1186/s13195-021-00813-8
[4] Petersen et al (2019). EMERGE and ENGAGE Topline Results: Two Phase 3 Studies to Evaluate Aducanumab in Patients With Early Alzheimer’s Disease. https://investors.biogen.com/static-files/ddd45672-9c7e-4c99...
[5] Selkoe and Hardy (2016) The amyloid hypothesis of Alzheimer's disease at 25 years. https://doi.org/10.15252/emmm.201606210
[6] Long and Holtzman (2019) Alzheimer Disease: An Update on Pathobiology and Treatment Strategies. https://doi.org/10.1016/j.cell.2019.09.001
If amyloid plaques are just a symptom, then it's much less obvious that treating them will have positive effects on the symptoms you actually care about.
I could see this treatment being something like exercise and diet for type-2 diabetes. Exercise and diet may help prevent diabetes, but neither will "cure" the condition once the point-of-no-return has been crossed. In other words, you can turn a cucumber into a pickle, but you can't turn a pickle back into a cucumber.
As I recall, the claim (by the dissenters) in the article was that big names in research had staked their reputation on the plaque theory. Those big names were claimed to use their weight to suppress any research into alternative theories. The article then stated that the little bit of research into alternative explanation seemed promising, and that there were trials on removing plaque that did not seem to cure Alzheimer.
This news about a controversion FDA approval feels like it is related to this controversy. And to my mind, it strengths the case for 'plaque does not cause Alzheimer'.