In Medical News Today: What causes Alzheimer's? Not toxic amyloid, new study suggests

[Jmac]

Many researchers have argued that the accumulation of toxic beta-amyloid in the brain causes Alzheimer's. However, a new study offers some evidence contradicting this sequence.

https://www.medicalnewstoday.com/articles/327412.php#4

[J11]

Jmac, the figure below is from the January 10th, 2020 post on alzforum.
This is another study that shows the impressive power of tau (over amyloid) to predict brain atrophy.
It would seem that the implications of such research are profound.

If current inclusions for Alzheimer's trials simply look at amyloid, then only a vague idea could be derived about the nature of the neurodegeneration that would likely occur. Thus you wind up with variation in patient cognitive status in treatment and control that are all over the map. With the methylene blue studies and other AD studies, the within individual variation on ADAS-COG at 52 weeks was ~10 (i.e., the individual standard deviation). This despite the fact that the patients a year earlier were specifically chosen to have very very similar cognitive status.

{ I reworked the numbers on the methylene blue Comparison A from the second phase 3 AD trial
using SD(per) =1. This time instead of a factor of ~1 from the bottom, there is a factor of ~8. A significant result could be obtained with an 8 fold lower treatment effect? I am not sure whether SD(per) =1 is feasible with tau biomarker imaging, though as a rough guide this calculation illustrates the power such biomarkers might offer.}

What this suggests to me is that current AD trials are trying to find a signal with a great deal of noise present. Roughly, as seen in the figure, reporting that a patient has amyloid in a particular brain region or has x amount of amyloid does not appear all that useful; while tau aligns almost 100% with later brain atrophy. (Yet, I am not entirely clear whether my interpretation is correct as perhaps the areas shown with heavy amyloid buildup only occur in patients who also typically have tau present. This does not seem overly likely to me.) Having a much better predictive biomarker could greatly change the AD clinical trial landscape. This would be a very big win for the AD community.

For as seen below the tau scan almost precisely predicted the brain atrophy. This might be translated into shorter trials with less patients (implying less cost) allowing for more innovative treatments to enter the clinical trial process ultimately leading to more rapid progress in finding an effective treatment for AD.

tauatrophy.jpg

https://www.alzforum.org/news/research- ... ill-shrink

[rws]

It's all known for years, and was discussed here. Amyloid is an antimicrobial and part of the innate immune system. Researchers did not exclude this function so far from the pathologic process, but still only a few want to think further and test the brain infection hypothesis. It is a global self-scare lock because scientists still can damage their reputation with such work.

[dfmcapecod]

If one were looking at the research field as a whole today, globally, which biomarker is the predominate leader in practice for AD related trials? A beta-amyloid tracer or tau tracer? I'm looking for a back of the napkin type answer here, 60/40, or 80/20 with some % using both.

If money were no object, which tracer would be used in baselining and all subsequent followups? Would the clinical best answer be BOTH? or would it be something else.

Personally I think a vast majority of people with AD and their caregivers are still unaware of the power of the tracers, and I believe the medical community is still uneducated and somewhat quiet about this. For reasons I'm not entirely sure. Is it cost, is it FDA approval. Just trying to understand this another layer deeper.

[NF52]

If one were looking at the research field as a whole today, globally, which biomarker is the predominate leader in practice for AD related trials? A beta-amyloid tracer or tau tracer? I'm looking for a back of the napkin type answer here, 60/40, or 80/20 with some % using both. ...

Can "it depends" be an answer?
Tau (both normal and toxic) has not been able to be studied in living brains until recently, when PET tracers were developed. Here's a detailed listing by category of clinical trials in Alzhiemer's and related dementias funded by the NIA in 2019. NIA-Funded Active Alzheimer’s and Related Dementias Clinical Trials and Studies None of the categories lists tauopathies, or tau-immunotherapy.
Here's a 2019 deep dive into tau-related research by a European group, indicating the complexity of tau forms, and a brief excerpt on current trials: A walk through tau therapeutic strategies

Recently, the development of positron emission tomography (PET) radioligands presumably binding to tau has enabled the in vivo mapping and quantification of tau pathology... Despite the field being aware that tau pathology correlates well with the onset and progression of AD for almost 40 years, it is only now that tau targetted therapy has become attractive for clinical trials. A multitude of tau antibodies and vaccines have been tested in preclinical studies in the last two decades. Currently, eight humanised tau antibodies and two tau vaccines have entered clinical trials either for AD or frontotemporal dementia (FTD).

And here's a chart, updated yearly, of the status of drug development trials, with tau and amyloid indicated. All tau trials are in Phase 1 or 2 (outer circles) indicating safety, dosing and efficacy are the targets before large scale trials.Alzheimer's disease drug development pipeline: 2019