
The amyloid hypothesis on trial - cschmidt
https://www.nature.com/articles/d41586-018-05719-4
======
WhompingWindows
There is a conceptual framing for this hypothesis: that beta-amyloid plaques
are akin to the garbage left in the stadium after a big match. The garbage
itself is not the cause or raison d'etre of the stadium and its activity, yet
it is a negative and fixable side-effect of the main event. I'm sure those who
support the tao-hypothesis or some of the other more fringe hypotheses would
be in favor of such an explanation.

It's not simply that drugs have failed time and again for Alzheimers. It's a
very hard disease to come up with a treatment for. Here are some challenges:

1) It's a hard disease to detect in the earliest stages, where
preventative/slowing drugs would have the most effect. If your drug slows
decline by 30% but you start using the drug after 60% of the decline has
already occurred, your effect size will be much smaller.

2) The blood-brain-barrier is a strong obstacle in our anatomy that prevents
the passage of many potentially useful small or large molecules from general
circulation into the brain.

3) Our early-stage disease models, things from petri dishes to mice, are less
effective for choosing winners in this disease in particular. Maybe due to the
complexity of the human neurology, though TBH I'm not sure why this is.

4) Even if you reduce beta-amyloid or other biomarkers, if you can't slow the
disease progression/symptoms, then why is your drug useful? It's much harder
to provide the slowing or reduction of cognitive decline than it is to simply
clean up the beta-amyloid plaques. 4) is a specific case of the general use of
"biomarkers" or "surrogate endpoints" \- you need to measure SOME outcome,
it's hard to do for cognitive diseases, so you find something measurable and
look at that, though the linkage to symptoms is not totally clear in many
cases.

~~~
JamesBarney
#3 is because rats don't get Alzheimer's.

So all of our models are pretty artificial. And we build our rat models off of
our disease assumptions, like injecting rats with beta amyloid because we
assume that's the primay cause of brain dysfunction.

But it's looking more and more like that's wrong and beta amyloid is not the
central player in Alzheimer's but just one of many. With Tau/insulin
resistance/herpes/glial dysfunction/neuroinflammation playing important rules
as well.

~~~
subcosmos
Phosphorylated Tau may also play into the herpes story quite well. It
regulates microtubule stability, and herpes viruses traffic on those
microtubules to hop from one nueron to the next :

[https://medium.com/@InfinoMe/cholesterol-have-we-shot-the-
me...](https://medium.com/@InfinoMe/cholesterol-have-we-shot-the-
messenger-a3f5dfeba09)

------
tim333
I thought we'd cleared this up on HN last week with 'Alzheimer's risk 10 times
lower with herpes medication'
[https://news.ycombinator.com/item?id=17540094](https://news.ycombinator.com/item?id=17540094)

and subcosmos's comment "Right on the heals of the recent publication that
shows that beta-amyloid in the brain specifically wraps around HerpesViral
particles in order to prevent them from spreading!" (1st comment on the
above).

There seems evidence the amyloid is a body defence against viral infection,
mostly herpes 6&7.

~~~
corndoge
hacker news continues to push forward the state of alzheimers research one
comment at a time

------
alejohausner
I just read in the NYT about an amyloid-clearing drug called BAN2401 that just
reported results of Phase 2 trials (which test the safety and efficacy of a
drug). The article starts by singing the praises of the drug, which
substantially reduces amyloid scores. However, it then cautions that the
drug's ability to slow down cognitive decline was small.

This supports the OP: amyloid may not be the culprit. In a phase 3 trial, the
drug may not pan out.

source: nyti.ms/2JWjznT

~~~
hcknwscommenter
the drug's ability to slow down cognitive decline was small but statistically
significant and dose dependent. It is a huge deal. It is also interesting that
the drug selectively targets protofibrils. This is interesting because A/Beta
peptide is difficult to target because there is so much of it. Fibrils are
difficult to target because they are insoluble. Selectively targeting
protofibrils means the drug binds an accessible target and will not be
titrated out by A/Beta peptide.

------
krob
I've read some interesting news about how people giving people with Alzheimer
given a regular dose of coconut oil, maybe due to also some findings about how
this could be related to a type 3 diabetes, maybe the lack of ketones in the
blood, maybe the brain needs alternative energy sources, or the fat provided
by those foods provides a nutrient pathway that is currently dormant or
unblocks the neuronal damage in their brain. I'm not any kind of expert, but
I've been reading about people who gained some benefit / therapeutic value
from doing that. Saw someone post this which was interesting,
[https://www.ncbi.nlm.nih.gov/pubmed/24244584](https://www.ncbi.nlm.nih.gov/pubmed/24244584)
so the claim is, maybe damaged metabolism using glucose, and the body needing
to switch to ketone, but if someone has a compromised metabolism, say being
insulin resistant, this practically shuts down ketone distribution, it also
can be found to have heart implications for the future, but if the brain
switches to needing fatty acids, and insulin prevents this, it might help
understand how Alzheimer progresses and gets worse over time.

~~~
jdpigeon
As much as 'coconut oil cures Alzheimer's' sounds like quackery, there is some
pretty interesting evidence towards metabolic dysfunction being a major
contributor to the disease. It even got mentioned in the article.

------
dang
Recent and related:
[https://news.ycombinator.com/item?id=17444214](https://news.ycombinator.com/item?id=17444214).

Also, this submission was in response to
[https://news.ycombinator.com/item?id=17617054](https://news.ycombinator.com/item?id=17617054).

------
rossdavidh
It all sounds very interesting, and I can totally believe that it might not be
amyloid plaques that are the cause. I also believe we should fund multiple
lines of study. BUT, I also had this odd feeling of deja vu while reading it,
and eventually I realized that it sounded like some of the early HIV-skeptics,
when the HIV hypothesis had been around for years but no effective treatments
had been found yet.

------
tyu100
This is a really great article outlining the current state of research in the
field. It'd be nice to pin canonical articles like this every time a disease
is discussed.

------
jger15
Are there any good Twitter Lists for Alzheimer's research?

------
mhkool
Too many companies want to cure a disease with a drug. It is understandable
since a drug can be patented and the company can make a profit. Unfortunately
this means that diseases that do not require a drug never get cured.... Unless
you name is Dr Dale Bredesen. Dr Bredesen has a methododoly instead of a drug
to reverse Alzheimer. He has published about it and reverses Alzheimer in 9
out 10 patients and is currently doing new studies with a larger number of
patients. TL;DR go to bed at 10 PM, do stress management, exercise a little,
eat well and take supplements (blood tests determine which ones), and take a
couple of other substances that our body needs, Alzheimer's disappears in less
than 4 months.

~~~
rpedela
While sleep, exercise, healthy food, etc may certainly prevent or delay the
onset [1], once you have Alzheimer's, it is too late. This is like telling
someone with gangrene that all they need is neosporin, a fresh bandage, and
rest. Except it is too late for that once you have gangrene, your only options
are antibiotics or amputation.

1\.
[https://www.ted.com/talks/lisa_genova_what_you_can_do_to_pre...](https://www.ted.com/talks/lisa_genova_what_you_can_do_to_prevent_alzheimer_s)

~~~
mhkool
you did not get it. Dr Bredesen does reverse Alzheimer in 9 out of 10
patients. No theory or BS here.

~~~
rpedela
Oh I get it. I have heard the same stuff about cancer, heart disease, and
every other major disease. And yet the people who take the natural route end
up dying sooner on average. Once a disease progresses to a certain point, diet
and exercise stop working as a treatment because the disease has already done
too much damage.

Is it possible that there is a natural cure for Alzheimer's? Given we don't
know the cause yet, sure it is possible. But one study with 10 people is not
enough evidence to claim there is one. If you simply said "hey I found this
interesting, published study that suggests there may be a natural treatment",
then you probably wouldn't have been down voted to hell. Instead you asserted
that there is a natural treatment with very little evidence.

~~~
mhkool
ok, you do want to get it. This doctor publishes data about 10 patients that
are made up.

~~~
rpedela
The study was not a double-blind, placebo trial which means the positive
result could have been because one of the following:

1\. Patients didn't actually have Alzheimer's. Given the only definitive test
for it is a brain exam after death, this is possible.

2\. There was a placebo effect.

3\. There was a therapeutic effect better than placebo.

You are assuming #3 but we can't draw that conclusion yet. Even the authors of
the study aren't claiming #3.

~~~
mhkool
[https://markets.businessinsider.com/news/stocks/ahnp-
precisi...](https://markets.businessinsider.com/news/stocks/ahnp-precision-
health-launches-the-recode-report-1027405376)

~~~
rpedela
What does that prove?

