AD researcher here (late to the thread). As much as I loath the 'cabal' mentality, I personally think amyloid-beta is the cause of AD. Just because a few treatments focused on Abeta haven't cured AD isn't convincing in the slightest that Abeta accumulation is not a causative mechanism. (1) AD is a disease of the elderly - a group not particularly receptive to treatment, (2) AD pathology is likely due to a sequelae that took decades to manifest into symptoms; undoing tens of years of buildup is not going to be easy, (3) even if the treatment could clean up a large portion of Abeta accumulation (and that's a big IF) it wont restore lost memories.
With regard to evidence, the article mentions APP gene variant causes early onset AD; but there is another variant in the APOE gene that is the strongest genetic risk factor in late-onset AD. This gene too is in the Abeta buildup pathway.
With that said, I think that NIH study sections allocating AD research funding should not give preference to a particular molecule or theory. If the Abeta hypothesis is indeed the most compelling, grants focused on Abeta topics should naturally be stronger. They shouldn't need any additional bias to stand out.
There is plenty of evidence against amyloid-beta hypothesis.
(1) Pathological levels of amyloid-beta and tau are present in cognitively normal individuals.
(2) Some individuals clinically diagnosed with AD do not have amyloid-beta pathology
(3) spatial appearance, progression and absolute amount of amyloid plaques does not correlate with declining cognition more conclusively than other pathologies.
(4) It's not even clear that that amyloid-beta pathology is the first AD biomarker. Not even among those with APP, PSEN1 and PSEN2 biomarkers.
(5) it looks like autosomal dominant AD may be a different disease than sporadic AD and results there don't apply.
(1) We know that "pathological levels" does not always result in symptoms across many diseases. E.g. Plenty of people walking around with pathological levels of coronavirus are asymptomatic.
(2) Amyloid plaques are not the only thing that causes dementia. However genuine AD diagnoses are confirmed post mortem via autopsy and are typically assigned a BRAAK score (most large scale studies require plaque confirmation for cohort inclusion; i.e. AD definitionally requires amyloid presence).
(3) From the large datasets I've worked with, BRAAK score and AD age of onset are HIGHLY correlated. I'm genuinely curious to hear what biomarkers are more correlated.
(4) What is clear-er?
(5) Agree LOAD and EOAD are not identical diseases.
>However genuine AD diagnoses are confirmed post mortem... inclusion; i.e. AD definitionally requires amyloid presence).
Guidelines and diagnostic criteria based on amyloid-hypthotiesis is not good reference point if we question amyloid-hypthotiesis.
>I'm genuinely curious to hear what biomarkers are more correlated.
>original neuropathological guidelines for AD were built on the correlation of amyloid plaques and NFT counts to cognition, much research since has established amyloid plaques are less well correlated to the clinical and anatomical progression of AD than other pathologies, including synapse loss [266] and NFTs [184, 197]. ... evidence since has indicated neuritic plaques correlate to declining cognition better than do diffuse plaques [188], indicating that even if NFTs correlate better, plaques counts are still useful determinants of dementia severity. https://link.springer.com/article/10.1007/s00401-018-1918-8
>(4) What is clear-er?
There is evidence that appearance of NFTs, clusterin (protein) or vascular dysregulation. The problem is that procedures and hypotheses for disease progression are based on amyloid-hypthotiesis, so there is not enough work made to find earlier biomarkers.
NFT and Abeta are part of the traditional AD diagnosis. NFT studies have seen no lack of funding. But for the record, I do think tau plays a role. I'm not sold either way on ABeta or Tau (maybe both).
"synapse loss" is a better correlate for dementia because, obviously. But synapse loss is the outcome of the disease, not the cause of the disease.
The point is that evidence for amyloid-hypothesis is near non-existent unless you take it as a starting point and do circular reasoning.
In clinical trials patients who show the biggest decrease in brain amyloid or tau are not correlated at all with any particular clinical improvement (small as they are).
In mice you can prevent amyloids but don't prevent the disease.
And your big brain idea is that it's all about the tangles not the plaques (but not NF tangles from tau mechanisms; it's actually hard to tell because the alt hypothesis you cited above basically say that it's not diffuse Abeta and NTF, instead it's ABeta and NFT inside neurons.
I don't think mixed results from one or two clinical trials warrants a total pivot (see my first post). But, again, I'm not opposed to exploring novel avenues. Anyone who lives long enough will get dementia, so both broad and deep insights are certainly welcome.
Ok, there's more than I knew about. "We found 12 eligible studies in 443 identified records, involving 6736 patients, mean age 71.4 ± 2. We found a small benefit in cognitive outcomes in patients treated with Aβ-mAbs."
So there's a small benefit to using antibody treatment. To me suggests that Abeta is a good target, but antibodies are not a sufficient Rx.
I think it would be more accurate to state that interactions between APP and presenilin are very likely causative in late onset AD. Currently the known consequence of that interaction is production of Abeta, ergo the amyloid hypothesis.
However, if another outcome of that interaction were found, then the "amyloid cascade hypothesis" would be easier to reject.
Recent work by several independent groups has focused on disruptions to the endolysosomal system as an alternative causative mechanism, e.g. Lee et al, 2022, discussed in the link below. One should note that despite the claim in the title, the authors may actually finger APP-C99 as causative in the original paper, which I have read very carefully (or rather fail to distinguish between Abeta and APP-C99).
ApoE is not necessarily in the a-beta buildup pathway. One idea that was tossed around was that increased cholesterol yielded alkylation factors (like 9Hydroxy nonenal or oxidized cholesterol metabolites) that then modify a-beta but there's not really any strong evidence that that happens in vivo.
Iirc there's something about lipid raft homeostasis being out of whack leading to increased likelihood of amyloid nucleation, but our ability to measure lipid rafts in vivo is even weaker.
With regard to evidence, the article mentions APP gene variant causes early onset AD; but there is another variant in the APOE gene that is the strongest genetic risk factor in late-onset AD. This gene too is in the Abeta buildup pathway.
With that said, I think that NIH study sections allocating AD research funding should not give preference to a particular molecule or theory. If the Abeta hypothesis is indeed the most compelling, grants focused on Abeta topics should naturally be stronger. They shouldn't need any additional bias to stand out.