Researchers Reverse Alzheimer's in Mouse Models

[aequalsz]

Not sure if this has already been posted. But for possible future reference...

https://www.usnews.com/news/national-ne ... use-models


a=z
4/4 70.5 yo male

[Harrison]

Unfortunately this is an example where something promising in mouse models does not pan out. Today Merck announced they are stopping work on their BACE inhibitor, which is the approach mentioned in the news story above. Here are the details:
https://www.alzforum.org/news/research- ... itor-trial

[NF52]

Hi aequalsz,
Harrison's helpful post has a kernel of good news. Merck itself is continuing a trial with asymptomatic individuals. BACE-1 inhibitors work on the theory that inhibiting the Amyloid Precursor Protein from "cleaving" at the wrong spot and causing fragments which are more easily changed into beta amyloid will prevent amyloid plaques from messing up our brains. (At least that's the layperson's explanation I'm going with today!)
So the question of whether they will "cure" AD is answered (they won't) the question of whether they will delay or prevent AD is to-be-answered, hopefully with trials targeted at people at higher risk than the general population: people ages 60-75 with APOE 3/4 or 4/4. If you're interested, check out Clinical Trials.gov, or the article for more info.

(And both "a=z" and "70.5" sounds like someone who enjoyed teaching math and/or science. I had a grandmother who did the first and a grandfather who did the second. Great preparation for a long and happy life!)
NF52 (65 and counting)

[NotSure]

Hi NF52

Really tired of the a=z moniker (from when I worked at NASA 18 years ago - something to do with SVD analysis IIRC. ) Teaching math and science? Well at least both offspring were NMS finalists. So am now moving on to...

NotSure

[NF52]

Hi NotSure,
Another moniker that makes a great conversation starter. Thanks for all that work at NASA--I'm of the generation that viewed space exploration with wonder--even if I never wanted to go on anything more challenging than a ferris wheel. You could probably blow the roof off the cognitive tests given for studies. Let's hope some of those post-docs working on the mice studies are as smart as a literal "rocket scientist".

NF52

[Karengo]

Hello NotSure, Welcome to the community! Thanks for joining in the conversation here. In case you've not found it yet, I want to invite you to read our Primer written by our physician member, Stavia. You can find it under the Welcome tab as well. If you're looking for more information on a particular topic, you may find it in our Wiki Also if you click on the three vertical dots in the upper right, you will find our search function to look for posts and members. Feel free to write more in OurStories if you would like to share something about yourself

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~Karengo

[Tiramisu1984]

NF52, lovely explanation and you highlighted one of the most important nuances; prevention. I was reading this while putting on sunscreen before a walk. Sunscreen doesn't cure skin cancer; it's a preventive measure against skin cancer.

I just wish these trials included people in their early fifties (like me).

[rrao2015]

Flies, worms, rodents do not develop AD. We force it upon them by over expressing the human genes several fold. Later we try to reverse any symptoms by using drugs. No wonder, these drugs finally fail in the clinical trials.

The entire AD community was keenly following the first BSM (beta secretase modulator)- verubecestat that failed miserably in the first round. It was tested in patients with late AD. In the second round, Merck decided to test their compound in early AD. Just three days ago, Merck announced that it is stopping its Phase 3 clinical study in patients with early stage disease after early data showed virtually no chance that it would work.

This is a testimony to an incorrect hypothesis and rationale.

I am an optimistic scientist, but in the case of AD, I wonder what will it take for AD scientists to realize that there is more to AD than just Abeta or Tau. I still strongly believe that if the patients metabolic and biochemical parameters get normalized first, these failed drugs will do wonders.

[Epsilon?]

The interesting thing to me is the reversal of plaques. This could be measurable on PET scan in humans. Of course the animal model is highly artificial and we would need a drug for humans that was both highly active and safe. from the paper:



If you could prescreen with PET, treat and repeat the PET you could establish an effect without enrolling thousands of subjects. If candidate drugs did not show an effect you could avoid long term large group testing. It is unclear if any of this will pan out.

[NF52]

The interesting thing to me is the reversal of plaques. This could be measurable on PET scan in humans....we would need a drug for humans that was both highly active and safe... If you could prescreen with PET, treat and repeat the PET you could establish an effect without enrolling thousands of subjects. If candidate drugs did not show an effect you could avoid long term large group testing. It is unclear if any of this will pan out.

Hi again, Epsilon?,
An effect of reversal of beta amyloid on PET scans or CSF in humans has already been established, at least on a short-term basis in several BACE-1 inhibitors. Here's a brief summary of the early results of two drugs which showed reductions in beta amyloid of from 63%-90%: JNJ 54861911 (Janssen division of Johnson& Johnson) and CNP520 (Novartis & others in partnership) http://www.alzheimersanddementia.com/ar ... 0653-7/pdf

Unfortunately, showing that these drugs dramatically reduce amyloid in the brain is only the "proof of concept" phase. Now they have to show that the drugs also affect one or more of several events or biomarker outcomes approved by the FDA recently as markers for a successful Alzheimer's drug. And they have to show evidence that these drugs would be safe at doses that would be effective if taken for possibly decades prior to the risk of onset of mild cognitive impairment.
https://www.fda.gov/downloads/Drugs/Gui ... 596728.pdf

Phase 2/3 Trials for both safety and efficacy are now underway and enrolling people (with slightly different risk parameters) in the Generations 1 and 2 studies and the EARLY study. Both are being done in both the U.S. and other countries.
Here's a link to the EARLY study with study locations noted: https://globaltrialfinder.janssen.com/t ... 911ALZ2003
Here's a link to the Generations Study with locations noted: https://www.generationprogram.com/#Main

In spite of Merck's drug trial being ended, it appears that there is still considerable interest in the BACE-1 hypothesis.