
Is the Alzheimer's “Amyloid Hypothesis” Wrong? (2017) - daddy_drank
https://www.theatlantic.com/health/archive/2017/02/alzheimers-amyloid-hypothesis/517185/
======
themgt
Frightening thought: if (at least some cases of) Alzheimer's really is
something akin to "Type III Diabetes", the planet and especially the USA can
expect absolutely skyrocketing numbers as today's obese adults age.

[1] [https://newsnetwork.mayoclinic.org/discussion/mayo-clinic-
mi...](https://newsnetwork.mayoclinic.org/discussion/mayo-clinic-minute-is-
alzheimers-type-3-diabetes/)

[2]
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2769828/](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2769828/)

~~~
LinuxBender
If T2D can be reversed with fasting (to purge the pancreas of fat), does that
mean we could test things like Acetyle-L-Carnitine in larger dosages in the
brain to affect T3D? Or perhaps a variant of 2-hydroxypropyl-beta-
cyclodextrin? Has anyone tried experimenting in this area?

Or is this a viral condition as others in the thread have mentioned? Perhaps
these are not mutually exclusive?

~~~
trendia
The amyloid, T3D, and viral hypotheses still don't explain why cholesterol,
obesity, air pollution, lack of sleep, and sedentary liftestyle positively
correlate with Alzheimer's and high caffeine intake and regular exercise
negatively correlate with it.

~~~
subcosmos
They do, if you consider the recent findings that many viruses have evolved to
exploit our colesterol synthesis and transport machinery to spread, it becomes
clear that many diseases of aging may have a viral cause :
[https://medium.com/@InfinoMe/senescence-links-between-
heart-...](https://medium.com/@InfinoMe/senescence-links-between-heart-
disease-genomics-and-aging-fa78bde773da)

Rhinovirus, the cause of the common cold, binds to vLDL receptors. vLDL
incidentally being the primary risk factor for cardiovascular disease
[https://www.ncbi.nlm.nih.gov/pubmed/12857919](https://www.ncbi.nlm.nih.gov/pubmed/12857919)

Influenza requires the cholesterol transport system to bud and spread
[http://news.mit.edu/2017/cholesterol-helps-flu-virus-
escape-...](http://news.mit.edu/2017/cholesterol-helps-flu-virus-escape-
through-host-cell-membrane-1120)

Hepatitis C virus relies on APO-E, our favorite alzheimers gene, to flourish,
and APO-E genotype predicts if you will get liver cancer from Hep-B
[https://goo.gl/images/Hev5ev](https://goo.gl/images/Hev5ev)

T2D, CVD, and obesity, being characterized by hypercholesterolemia and
mitochondrial dysfunction, are illnesses that are supportive of viral
infections. They also promote AGE formation, which activates the innate immune
system through a variety of RAGE receptors, Galectin-3 being potentially a
central axis as it is also part of the senescent phenotype.

~~~
inciampati
You tied together a lot of threads that I've been loosely aware of here. Nice
post. I hope we a have the chance to elucidate what of these links is relevant
and actionable.

~~~
subcosmos
I'm very confident in the future. What a time it is to be alive.

------
User23
Derek Lowe, of Things I Won't Work With fame, has an interesting post on the
subject too:
[http://blogs.sciencemag.org/pipeline/archives/2018/06/22/alz...](http://blogs.sciencemag.org/pipeline/archives/2018/06/22/alzheimers-
and-infectious-disease-for-real)

------
comboy
Somebody on HN recommended "Why do we sleep" by Matthew Walker a few weeks
ago. There are references in this book strongly linking lack of sleep to
Alzheimer's (diabetes too btw). Maybe somebody else can dig them up I don't
have the book at hand, but I echo that previous commenter sentiment: if you
are only going to read one book this year - make it this one.

~~~
rcjones
Excellent book! I'm only halfway through and it's already influenced the way I
treat sleep. Among the most important takeaways is that diet, exercise, and
sleep are commingled (as is their effect on disease and disease progression.
Diet and exercise affect sleep quality; sleep quality affects dietary cravings
and the ability to exercise; and so on. When one of these three pillars (diet,
exercise, sleep) is strengthened/compromised, the others may be
strengthened/compromised. By simply choosing to do things during the day that
will improve your sleep quality at night, you're checking many of the boxes of
a healthy lifestyle.

~~~
amelius
Would you also think that this book is interesting for people with a normal
sleep pattern?

~~~
jeffdavis
There's a lot of stuff in there, and it is very compelling, but there is
really only one take-away from it:

Get lots of sleep.

The book is mostly helpful for people who try to "optimize" things or
rationalize why they don't need to follow the rules. He debunks all of the
excuses.

If you already get enough sleep, then you don't need the book.

------
exhilaration
This comment from two months ago (when Carl Kasell died) was very interesting:

 _it is not for want of trying. Eli Lily bet the farm and lost, and they
aren’t alone._ _At this point, we’re beginning to think previously unthinkable
thoughts like “what if the hypothesis the last 20 years of research was based
on (beta amyloid plaques)is just totally wrong”._

 _we’ve made drugs that reduce plaques. they don’t ameliorate the disease._

[https://news.ycombinator.com/item?id=16863945](https://news.ycombinator.com/item?id=16863945)

~~~
nonbel
>"we’re beginning to think previously unthinkable thoughts"

What made it so previously unthinkable? AFAIK, there was a rough correlation
between presence of these plaques and certain symptoms (by "rough" I mean some
people with the AD symptoms have no detectable amyloid beta plaques, others
without AD symptoms have a lot). Then a bunch of studies where they figured
out how to get amyloid beta to kill cells in a dish or make animals sick (or
at least p-hacked such).

Was there ever a definitive prediction derived from this hypothesis that was
then tested on new data? What is it that makes people have such strong belief?

~~~
jcranmer
Well, the hypothesis was tested on data... that data being drugs to reduce
amyloid plaques, which have only recently been found to not work to ameliorate
Alzheimer's.

The amyloid hypothesis looks to be an open-and-shut case of "correlation does
not imply causation." The problem is, we don't know what actually causes
Alzheimer's, and for the longest time, the amyloid plaque correlation was the
only thing that looked like it could be a cause. On top of that, actually
testing these hypotheses takes a long time, especially if you take the not-
unreasonable attitude that tackling them after on its onset (i.e., before it's
readily detectable) may be too late.

~~~
jamesblonde
This is far from the whole story. The pathology of alzheimers as predicted by
the Amyloid Hypothesis is (year 0) imbalance in the production, (year 10-30)
deposition of abeta causes Tau and other downstream complications that are
symptomatic. Existing clinical studies started way too late, after the
appearance of significant sympthoms - at least mild cognitive impairment.

Personally, i take curcumin supplements, as it is known to bind to abeta even
in the cerebrospinal fluid, then it gets cleared out over the blood brain
barrier. If the abeta hypothesis is true, high dose curcumin should help delay
its onset.

Another thing to do is get your genome sequenced, even with 23andme. If you
have apoe4, you should, IMO, take curcumin.

~~~
nonbel
Fyi, I have no idea if your regimen (or any) of curcumin is good for you or
not but amyloid beta may be protective in some way:

>"Mice with excess beta-amyloid survived longer than the controls and had less
bacteria in their brains. Mice lacking beta-amyloid (from the genetic removal
of APP) died more often from infection."

[https://www.nih.gov/news-events/nih-research-
matters/alzheim...](https://www.nih.gov/news-events/nih-research-
matters/alzheimers-protein-may-have-natural-antibiotic-role)

~~~
jamesblonde
Curcumin won't clear out all abeta. Just bind to some and clear it. It also
dampens anti-inflammatory pathways (e.g., mild inhibitor of TNF-alpha
production). I see the cost-benefit being overall positive for medium-dose
curcumin (like 500mg-1g/day).

~~~
tim333
There is quite a lot of somewhat fuzzy evidence for curcumin helping eg. this
[https://www.telegraph.co.uk/science/2016/05/20/eating-
curry-...](https://www.telegraph.co.uk/science/2016/05/20/eating-curry-may-
help-fight-off-dementia-new-study-suggests/)

> 96 participants aged between 40 and 90 over 12 months.

>In tests of verbal and memory skills, those taking the dummy pill suffered a
decline in mental function after just six months that was not observed in
those who took curcumin

At least it has no negative side effect and tastes good in its chicken korma
form.

------
reasonattlm
The continued failure of efforts to remove amyloid by immunotherapy is
provoking a lot of diversity in theory in the Alzheimer's community. This is
economics 101: theorizing is cheap, running trials is expensive. Expect to see
more of the cheap thing than the expensive thing.

The challenge in Alzheimer's disease is most likely that it has several
mechanisms that are all of similar importance to degeneration. Get rid of one
of them and benefits are obscured by the others.

The most likely list is amyloid aggregation, tau aggregation,
neuroinflammation (covering microglial dysfunction, persistent infection),
energy metabolism issues (covering mitochondrial aging, loss of capillary
density, etc), and vascular dementia.

So therapies are needed that can address many of these issues at once. An
example is the approach of restoring drainage of cerebrospinal fluid, e.g. at
Leucadia Therapeutics. That should reduce all metabolic waste in the brain by
restoring a normal sink for amyloid, tau, and anything else that might be an
issue along the way.

The amyloid hypothesis seems unlikely to be wrong; there is extensive evidence
for amyloid aggregation to cause tau aggegation to cause neurodegeneration. It
just isn't the only problem: certainly vascular dementia (present to a
clinical level in 30%+ of Alzheimer's patients) is severe enough to question
whether it is a major problem in those trials that reduced amyloid and failed
to greatly improve dementia. The other big plausible issue is that amyloid is
the early stage of Alzheimer's, while tau is the later stage - so messing with
amyloid levels is not the way to go for late stage, severely impacted
patients. Still has to be done, but it if picking only one, then tau clearance
is a better bet.

~~~
jamesblonde
Good summary, but i don't agree with your analysis. The end-game will be early
diagnosis of abeta over-production, IMO. You will then treat that and you
won't get alzheimers. Few will transition to Tau degeneration, and it's so
much harder to fix. I don't think pharma will go big on Tau like they have
with abeta. The blood tests for over-production of abeta are almost here - I
expect them to be routine every few years for people over 50.

------
jcranmer
I like Derek's take on it:
[http://blogs.sciencemag.org/pipeline/archives/2018/06/12/an-...](http://blogs.sciencemag.org/pipeline/archives/2018/06/12/an-
alzheimers-statement)

> If there is any way left to send our ourselves full-tilt into another failed
> amyloid trial, our pledge to you is that Lilly will find it. ... we have our
> beloved wall, which we shall never forsake. Higher velocity! More power!
> Once more into the concrete, my friends! Who’s with me?

------
tibbon
Sadly, no mention of microglia as a possible cause. I can't explain it myself,
but someone who was close to me was researching this extensively and was often
frustrated by the over-focus on amyloid.

~~~
jayzee44
I agree. Microglia should be where a lot of the focus should be moving. From
my limited recent research on microglia and AD, it seems that plaque build up
is actually a symptom that is perhaps caused by dysfunctional microglia, which
normally phagocytoze plaques when functioning properly. Microglia secrete all
kinds of neurotoxins and cytokines that mediate the inflammatory response. It
is highly plausible that progressive damage to microglial function induces a
pathological state where the microglia become destructive to the neuronal
enivronment.

------
vajrabum
Not everybody has focused on amyloids other approaches are being explored as
well. Here's one example that's focused on a bacteria:

[https://www.bizjournals.com/sanfrancisco/news/2018/05/31/alz...](https://www.bizjournals.com/sanfrancisco/news/2018/05/31/alzheimers-
disease-cortexyme-verily-infection-ad.html)

------
clumsysmurf
What if Alzheimers / dementia is cause by air pollution?

[http://www.sciencemag.org/news/2017/01/brain-pollution-
evide...](http://www.sciencemag.org/news/2017/01/brain-pollution-evidence-
builds-dirty-air-causes-alzheimer-s-dementia)

A new study also investigates air pollution's role in diabetes

[https://medicine.wustl.edu/news/air-pollution-contributes-
si...](https://medicine.wustl.edu/news/air-pollution-contributes-
significantly-to-diabetes-globally/)

~~~
t3po7re5
Also found this which looks at urban vs rural rates:
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5056321/](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5056321/)

------
hprotagonist
considering that another two trials washed out since this article was written,
“yes” seems an ever-more plausible and tragic answer.

~~~
aantix
What does “washed out” mean? What were their conclusions?

~~~
hprotagonist
Washing out means that a clinical trial is halted for lack of efficacy. It
means the drug candidate in question is safe to ingest, but also doesn't work
to treat the condition it was designed to treat. "work" is defined as having
met or exceeded predefined clinical endpoints; e.g., "cognitive assessment
improves by x% on average in a cohort of Y thousand patients", or "blood
cholesterol levels reduced by Z%" or whatever.

It's important and sad to note, too, that the clinical targets of most modern
alzheimers drug candidates are comparatively low bars. We're not shooting for
a cure, we're shooting for things like "reliably slows down cognitive decline
by 6 months", and we can't even do that.

------
dawhizkid
When will the medical community take nutrition science seriously? Why don't
medical students take courses in diet and nutrition?

There is so much evidence that Alzheimer's is closely linked to lifestyle
(specifically diet) and the same lifestyle changes that can stop/reverse Type
II diabetes like a ketogenic diet + intermittent fasting is likely highly
effective in reducing onset of Alzheimers in old age.

~~~
bluejellybean
Medical students and nurses do take diet and nutrition courses. I'm in a
prereq nutrition class right now...

~~~
dawhizkid
And yet the first answer to type II diabetes is insulin therapy and other
drugs and not "immediately stop eating sugar and refined carbs"

~~~
mrestko
No it isn't. The Practice Guidelines from the American Association of Clinical
Endocrinologists are summarized in this PowerPoint presentation from their
website.[1] It is not intended for lay consumption, but you can clearly see
that there is a large emphasis on diet changes and weight loss. However, as I
mentioned in another comment, the reality in practice is that many people are
either unwilling or unable to change their lifestyle sufficiently to reverse
the condition.

Even before being diagnosed with a disease there are huge returns to regularly
exercising and staying fit. You feel better, look better, have more energy,
sleep better, the list continues. A doctor saying, "you need to lose weight
and exercise, it could help with your diabetes," is a relatively small
motivator compared with all of the other benefits.

1\.
[https://www.aace.com/files/aace_algorithm_slides.pptx](https://www.aace.com/files/aace_algorithm_slides.pptx)

------
eganist
Shockingly nothing anywhere in these comments about the potential ties between
herpes (HSV1 specifically) and Alzheimer's:
[https://scholar.google.com/scholar?q=alzheimer's+hsv](https://scholar.google.com/scholar?q=alzheimer's+hsv)

Is this a fringe theory?

~~~
IAmGraydon
I believe you would expect a correlation between percentage of population with
HSV1 and percentage with Alzheimer’s in each country. No such correlation
exists.

~~~
eganist
Some of the theories seem to hinge on HSV1 and ApoE4
([https://scholar.google.com/scholar?q=hsv1+apoe4](https://scholar.google.com/scholar?q=hsv1+apoe4))
both being necessary to substantially drive up the risk. One example:
[https://www.sciencedirect.com/science/article/pii/S019745800...](https://www.sciencedirect.com/science/article/pii/S0197458006000807)

I don't currently have access, but it'd be nice if someone who did could crack
into the statistics of some of these.

------
alfon
A related article that I enjoyed:
[https://news.harvard.edu/gazette/story/2017/05/devastating-c...](https://news.harvard.edu/gazette/story/2017/05/devastating-
chain-of-events-found-in-alzheimers-path/)

------
djsumdog
Is the Amyloid Hypothesis related at all to Prions?

Is there any research or drug research going into Prions and Alzheimer's?

~~~
2bitencryption
seeing as the worst forms are purely hereditary, that would seem unlikely. but
what do I know.

------
leemailll
I only skim reading researches in Alzheimer's, a thing that I suspect is that
plagues are a late stage sign for the disease. And to ameliorate it is a bit
like thinking that to cure age spots can reverse aging. They are the result of
the disease, not the initial factor.

------
EamonnMR
There's always the Tau hypothesis (ie it could be a tauopathy.) That would not
require exotic explanations like a virus or Diabetes.

------
shadowtree
Well, the fight is not over yet.

Biogen has Aducanumab in phIII trials. Pretty big bet for them.

~~~
shadowtree
well, and their results they just published are indeed encouraging. Nice bump
on their stock.

------
dsego
What happened to aducanumab? Wasn't that promising?

