
A prospective Alzheimer’s trial reports - hprotagonist
https://blogs.sciencemag.org/pipeline/archives/2020/02/10/a-prospective-alzheimers-trial-reports
======
ISL
As I tell my students all the time -- properly-executed, an experiment that
doesn't work is not a failure. If you don't internalize this idea, you will
find experimental physics to be psychologically untenable.

If you build an experiment (at any scale) to test out an idea that you think
is going to work, and it doesn't work, _you made progress_. Now you know
something really essential -- that thing that seemed like a well-motivated
idea has some kind of unknown flaw. With that in hand, you can proceed to try
something better, whether it is a refined approach or something entirely new.

Without doing the experiment, that well-motivated idea would still look like
something worth trying.

If a large team of people were willing to spend years and lots of resources on
an Alzheimer's clinical trial, it was likely to be because they thought it had
a real chance of working. If it didn't work, we all benefit from their effort.

~~~
bigfudge
Out of interest, roughly what proportion of experiments in physics "don't
work"? Does data that fails to support the experimental hypothesis get
published prominently in physics journals?

~~~
knzhou
99% of experiments in fundamental physics "don't work" in this sense. _All_ of
them get published. If you got funded to build an apparatus, people are going
to want to know what you saw.

You can check for yourself, by looking at the experimental papers on the arXiv
[0]. Every paper here that mentions data, but doesn't have the word
"discovery" in the title, is a negative result. There are thousands of such
papers.

0: [https://arxiv.org/list/hep-ex/current](https://arxiv.org/list/hep-
ex/current)

~~~
mortenjorck
I suppose you could think of it as an unexplored continent that has very
specific requirements to survey each region. You mount an expedition, and you
probably just find more trees and brush. The important thing, though, is that
now that area is on a map, and the map keeps getting bigger.

------
streptomycin
_As that last-linked blog post makes clear, I don’t find that evidence
compelling, and most certainly not compelling enough to approve the drug as it
stands. But with the way the FDA is behaving these days, God only knows what’s
going to happen. People are investing on just that basis, although rarely
stated in quite those words. But if you can look at the ruins of all the
attempts to show efficacy with anti-amyloid antibody therapies and decide that
the Biogen /Eisai data represent a real ray of hope, you have a sunnier
disposition than I do._

I share the cynicism! Early drugs targeted amyloid plaques because it seemed
like a good idea. But after so many failures, I can't think of any reason so
much time and money is spent on a failed hypothesis other than hoping for a
false positive. Because a false positive, even with very modest results, would
result in a ridiculously profitable drug given the complete lack of
Alzheimer's treatments we currently have.

~~~
melling
Because there’s very little money is invested in Alzheimer’s research. People
were very conservative in their choices.

We were spending a lot more on AIDS research 20 years ago than on Alzheimer’s
today:

[https://www.ncbi.nlm.nih.gov/books/NBK222902/](https://www.ncbi.nlm.nih.gov/books/NBK222902/)

This produced great results for AIDS, which many people thought would never be
treatable.

Anyway, medical research is expensive. Considering the number of people who
will get Alzheimer’s and the cost to deal with the disease, you would have
thought we’d have been spending more on research for the past several decades.

Maybe soon we will all agree that it’s probably worth investing more on
research?

~~~
olliej
A huge amount is invested in Alzheimer’s, but comparing to aids and hiv isn’t
a reasonable thing to do:

HIV and AIDS kill people, and they do so quickly.

There’s also a foothold on how to treat it - whereas for Alzheimer’s we don’t
even have an understanding of what actually causes it. Once we know the actual
cause I suspect we’ll see research funds skyrocket.

~~~
jgust
> Once we know the actual cause I suspect we’ll see research funds skyrocket

I agree with your hypothesis, but saying it out loud seems backwards. In an
ideal world, wouldn't we see research funds rise now in order to discover the
cause (the hard part) rather than for the treatment (the less hard part).

~~~
olliej
no - there's a huge amount of research already happening, but the biggest cost
in drug development occurs after you have a target. The reason funding
_appears_ low, is because the expensive parts of drug discovery are late in
the process - things like the large scale trials, etc. I would not be
surprised if (I have not looked it up) a significant contributor to the amount
spent on research in HIV is on late stage trials, because realistically at
this point the majority of new HIV drugs should actually work, and you need
the large scale tests to see if the drugs work _better_.

~~~
chupa-chups
I'd like to see sources please, since I don't believe that claim. The years
and years of research of many teams all over the world should exceed the
amount of money required for large-scale trials by orders of magnitude.

Please note that I don't speak of an individual research team but of all teams
globally combined working on that goal.

~~~
vikramkr
I'm sure that for any given drug you'll see a pattern of later research
costing more, but as a field, unless we happen to get lucky early on with
figuring out the basic science (which we clearly didn't with
neurodegeneration), we'll need years (or decades to centuries - emperor of all
maladies is an excellent read into the amount of work and time it took to
understand cancer to the level we do now) to understand what to spend money on
drugs on, and we'll have to pay for all the dead ends there too.

------
derefr
Something interesting I stumbled upon recently:
[https://en.wikipedia.org/wiki/Aldehyde_dehydrogenase#Patholo...](https://en.wikipedia.org/wiki/Aldehyde_dehydrogenase#Pathology_\(aldehyde_dehydrogenase_deficiency\))

Specifically these quotes:

> Some case-control studies claimed that carriage of ALDH2x2 allele was a risk
> of late-onset Alzheimer's disease independent of the apolipoprotein E gene
> (the odds for LOAD in carriers of ALDH2x2 allele almost twice that of non-
> carriers). Moreover, ALDH gene, protein expression and activity are
> substantially decreased in the substantia nigra of Parkinson's disease
> patients. These reports are in line with findings implementing toxic lipid
> oxidation-derived aldehydes in these diseases and in neurodegeneration in
> general.

> The ALDH2-/\- mice display age-related memory deficits in various tasks, as
> well as endothelial dysfunction, brain atrophy, and other Alzheimer's
> disease-associated pathologies, including marked increases in lipid
> peroxidation products, amyloid-beta, p-tau and activated caspases. These
> behavioral and biochemical Alzheimer's disease-like deficits were
> efficiently ameliorated when the ALDH2-/\- mice were treated with isotope-
> reinforced, deuterated polyunsaturated fatty acids (D-PUFA).

D-PUFA is interesting (and being investigated for use in other diseases, e.g.
Huntington's) but it's just addressing the proximal cause of the
neurodegeneration (= the build-up of peroxidation products in the brain)
rather than the mechanism by which those products are produced.

I'm much more curious to know whether introduction of exogenous ALDH2 into the
body (perhaps above wild-type expressed levels of ALDH2) might be
neuroprotective/prophylactic against neurodegenerative disease. As far as I
can search, though, nobody's ever even extracted+purified an ALDH2 enzymatic
solution, let alone tested it for such effects.

------
wiremine
Anyone have any breakdown of what this means for the laymen out here on HN? I
get the gist this was a major (but not unpredicted) failure, but am I reading
it wrong? Was this for one category of drugs, or a hypothesis about the cause
of Alzheimer's in general, or both?

~~~
exhilaration
There was a good HN discussion a few weeks back about this:
[https://news.ycombinator.com/item?id=21911225](https://news.ycombinator.com/item?id=21911225)
It's becoming increasingly clear that the entire Amyloid-beta plaque
hypothesis has been wrong and last 20+ years of Alzheimer's research and drug
development has been wasted.

~~~
nextos
Yes. My comment triggered most of that discussion.

I have really good solid evidence for another common disease being caused by
infection or microbiome dysbiosis. But I am encountering a lot of resistance
in the field despite my theory, models and data being much more solid than the
status quo to explain said disease and my research coming from a famous lab.

I guess it's really hard for lots of people to accept most of their careers
were spent chasing the wrong hypothesis.

I've reached a tipping point where I think I can only push it further and
develop a drug in a startup. Alzheimer's and Parkinson's are also something I
want to tackle because the mechanism is analogous. If someone wants to help or
some VC is interested, just let me know. Contact email is in my profile. These
diseases have a big CS / information theory component.

~~~
Vomzor
What’s the disease?

My personal experience and the research I’ve read makes me believe you are
absolutely right.

~~~
esdott
Probably something like MS or another auto-immune disorder that could be
microbiome and/or dopamine related. Could also be type 1 diabetes, RA,
Crohn's, etc. Those would be my guess.

------
aazaa
> I really don’t know what else to say at this point. I’ve been writing this
> blog since 2002, several years after my own experiences with Alzheimer’s
> drug discovery, and ever since then I have chronicled the failure of drug
> after drug aimed at the amyloid hypothesis. Different mechanisms, different
> dosing, different patient populations, different trial designs: none of it
> has worked. Not once. I myself include the most recent Biogen/Eisai antibody
> efforts in that list – yes, the one that they’ve submitted to the FDA and
> are trying to get approved, a decision about which I have made my position
> abundantly clear.

What's remarkable isn't the failure of this trial, but the complete lack of
efficacy for any drug working through the "amyloid hypothesis."

[https://en.wikipedia.org/wiki/Biochemistry_of_Alzheimer%27s_...](https://en.wikipedia.org/wiki/Biochemistry_of_Alzheimer%27s_disease#Amyloid_hypothesis)

Either this hypothesis is completely wrong, or all of the drugs in all of
these trials aren't able to address the amyloid.

Given the weight of evidence, it seems like there's not much left of the
amyloid hypothesis to even poke a hole through.

------
eternalny1
Amyloid plaques are clearly not the problem, but I thought we already knew
that? When did these experiments get launched?

There are people who appear to be genetically immune to Alzheimer's yet build
up massive amyloid plaques. They do not show any symptoms of the disease, so
shouldn't this have been ruled out by now?

~~~
jcranmer
Looking back through Derek Lowe's posts, I don't think he considered the
amyloid hypothesis dead until around 2016 or so.

The study was started in December 2012, according the clinicaltrials.gov
posting. At that time, you had the first round of amyloid blockers that didn't
work, but you were in the midst of the hail-mary round of "maybe it works if
you catch it early/in this group of people/etc." tests. Indeed, this is one of
those studies.

------
alfon
I found this old presentation making a set of hypothesis regarding Alz
etiology, possible mechanisms and possible treatments somewhat interesting:
[https://www.youtube.com/watch?v=j1FmK4582mA](https://www.youtube.com/watch?v=j1FmK4582mA).

I am obviously biased towards this concept, as I have personally seen my mom
slow reverse her early dementia with the help of an experimental Mercury
removing drug, but since Alzheimer is really only confirmed by Autopsy, and we
happen to live close by a Chlor Alkali plant that has been dumping Hg to the
environment for decades, we would never know if she would have eventually died
/ get diagnosed of Alz.

~~~
eyegor
Mercury poisoning can also cause things like memory loss and neuropathy. It
seems like a reasonable explanation given your anecdata.

[https://en.wikipedia.org/wiki/Mercury_poisoning](https://en.wikipedia.org/wiki/Mercury_poisoning)

~~~
alfon
Right, although apparently it can as well, at a very low levels cause the same
degeneration to neurons as seen in Alzheimer disease, unlike any other heavy
metal tested as far as I know. I found this video pretty interesting:
[https://www.youtube.com/watch?v=XU8nSn5Ezd8](https://www.youtube.com/watch?v=XU8nSn5Ezd8)

~~~
vikramkr
yeah, mercury is dangerous with how toxic it can be at low levels in an
organic form. If you have a case for mercury poisoning, is it possible to sue
the company responsible via class action lawsuit or the like? Sorry to hear
about what you're going through, I hope the drug works and wish you all the
best.

------
lvs
If I reduce your load of gunshot wounds near zero but to a nonzero value, the
pathogenesis of your disease will still worsen. This blogger will then claim
that the gunshot wound hypothesis is flawed!

The data shows that reducing amyloid-beta load is not sufficient to confer a
clinical benefit. That's all the data shows. The failure of these drugs does
not preclude the role of amyloid formation in the diseases.

In particular, there is no known dose-response relationship for amyloid-beta
or other pathogenically-implicated amyloid proteins.

The conclusion is similar: these drugs aiming to reduce amyloid load are
illogical. But the subsequent claim that the amyloid hypothesis is wrong does
not follow.

~~~
nate_meurer
> _The data shows that reducing amyloid-beta load is not sufficient to confer
> a clinical benefit._

No, this trial was designed to test whether _preventing_ amyloid plaque
formation can prevent Alzheimer's. To the extent that it does not (which
appears to be the conclusion), then it's safe to say that amyloid hypothesis
is wrong.

In other words, if these patients do not acquire amyloid plaque, but still
acquire Alzheimer's at the same rate and severity, then amyloid plaques
logically cannot be the cause of Alzheimer's.

This should no longer surprise anyone. These studies, coupled with the
existence of people who have been found to be loaded with amyloid plaque and
yet do NOT get Alzheimers [1], should be plenty to change the direction of
research.

1 - [https://www.sciencemag.org/news/2019/11/colombian-woman-s-
ge...](https://www.sciencemag.org/news/2019/11/colombian-woman-s-genes-offer-
new-clues-staving-alzheimer-s)

------
it
This seems quite consistent with the idea that microtubules are the locus of
the real action of consciousness and memory. The amyloid theory would then be
confusing cause and effect. If that's so, plaques don't cause Alzheimers; they
are the side-effect of a process that causes Alzheimers: disintegration of
microtubules.

------
nabla9
Spending billions in basic research that investigates the causes of Alzheimer
without a potential patentable drug is not economically valuable for private
companies. If the cause is found it might not require expensive new drug to
cure. This research should be funded by the governments.

~~~
vikramkr
Basic research already is mainly funded by governments. The research in this
article is an attempt at a drug being developed by a private company, which is
seperate from research that investigates the cause of Alzheimers disease.

Once the root cause is discovered, if it somehow needs no drug or device
intervention to be treated, then great! Otherwise, the private sector would
step in to take those drugs to market and pay for those trials then.

------
CrankyBear
Nothing but bad news.

------
tylerjwilk00
What's the next best guess for a target now that the amyloid hypothesis seems
to be a failure?

------
downerending
tldr: No effect for the two antibodies tested.

