
Alzheimer’s Drug Failure Leaves Scientists Seeking New Direction - shadykiller
https://www.bloomberg.com/news/articles/2019-03-22/alzheimer-s-drug-fails-and-scientists-ask-is-it-time-to-move-on
======
melling
Healthcare costs for Alzheimer’s is going to be astronomical.

[https://www.alzheimers.net/research-spending-vs-annual-
care-...](https://www.alzheimers.net/research-spending-vs-annual-care-costs/)

Finding a cure or delaying symptoms by a decade would save a lot of money.

Let’s add $10 billion to the federal research budget and add a motivated czar
to oversee the research. Wonder if Bill Gates has a few extra cycles.

~~~
buboard
Presuming Bill Gates has track record in finding cures?

~~~
ineedasername
Bill Gates, with the B&MGF, has a decent track record of finding and boosting
low-cost solutions to chronic and systemic issues. Basically, choosing where
to focus resources to the best effect. I'm not saying he'd revolutionize this
field, but there are worse choices than someone with his track record.

~~~
buboard
I disagree; steering basic science needs more than money to do it, and is
different from finding low cost solutions. BG also has some spectacular,
costly failures like in education

~~~
bsder
I'm no Gates Foundation fan, but their unlike every other group that attempted
to tackle educational issues, they were relatively honest about good _and_ bad
and they documented it.

The problem is that they found what everybody knows but doesn't want to admit.
The current public school system is about optimal for the amount of resource
being spent. There is no mythical "pile of waste" that you can magically draw
from.

They found that focused resource does help outcomes, but in far less
proportion than the increase. If you want 5% improvement in achievement, you
need closer to 25% increase in resource--and it needs to be sustained over
years. More teachers that are better qualified is a good idea, but that is
also the most expensive choice. And, your most effective option is to spend
almost all your resource on the lowest achievers. All of these are highly
politically unpalatable in the US.

~~~
specialist
_"...optimal for the amount of resource being spent."_

Belated reply, catching up on my reading.

This is a very interesting point.

I live in a largish school district. I've long believed, but cannot prove,
that it's just too big. eg Scale matters. Everyone I've ever met who has ties
to the district agrees with me.

I know the CFO. He crunched some numbers, comparing cost per student and
outcomes. Although he wouldn't share the data with me (political suicide), he
related that the it's a bathtub distribution.

So, I believe, but cannot prove, there's an optimal range for most
organizations, and education reformers would get a lot of mileage out of
correct sizing their districts.

------
fraggle222
Brush your teeth (and gums): [https://www.perio.org/consumer/alzheimers-and-
periodontal-di...](https://www.perio.org/consumer/alzheimers-and-periodontal-
disease)

------
ncmncm
The present generation of Alzheimer's researchers has a big, big problem. The
best evidence now points to infection as the cause, but they are not
infectious-disease specialists. It takes a long, long time to become an
infectious-disease specialist, and there are lots already. What will they do
when it turns out they have none of the skills needed to advance the study and
treatment of Alzheimer's?

The present generation of Alzheimer's patients has a big problem, too. Grants
for research into Alzheimer's are controlled by the present generation of
researchers, who have no particular desire to learn that Alzheimer's is an
infectious disease. So, negligible work is going into establishing an
infectious-disease etiology, never mind effective treatment. Publications
supporting an infectious-disease cause of Alzheimer's are, likewise, not
especially welcomed by established Alzheimer's referees.

The herpes-family observations go back twenty years, and are only now gaining
traction. The gingivalis observations are more recent.

This is an area where one wealthy donor could make an enormous difference that
might improve the lives of millions in a very short time.

~~~
est31
Science has always had the problem of the establishment fighting new
theories/insights. Max Planck once said:

> A new scientific truth does not triumph by convincing its opponents and
> making them see the light, but rather because its opponents eventually die,
> and a new generation grows up that is familiar with it.

Science has been able to deal with this problem for a long time.

~~~
ncmncm
Halting progress for several decades, and blighting the careers of its best
people until the old guard dies is not "dealing with it". That is actively
failing to deal with it.

------
ineedasername
I'm surprised that a range of existing drugs with neuroprotective capabilities
haven't received more attention. The cynic in me says it's because many of
them are cheap generics that have little financial upside for large
pharmaceuticals.

As an example, a range of anticonvulsant drugs exhibit neuroprotective
effects. Depakote appears to be the best studief of the lot for this, but
that's not saying much.Something like lamotrogine has similar results with
lower side effect profile. These are widely used drugs for diseases like
epilepsy, but they are also used for a wide range of mental health diseases
where psychosis and dementia are issues because they are very effective in
those areas as well. A nice bonus in treating another disease with similar
neuro symptoms.

This probably wouldn't be front-line treatment, but alongside amyloid reducing
medications could form a powerful combination. The biggest obstacle might be
the side effects, but judicial use in the earliest stages or in high risk
poulations would probably be useful. The problem is right now the data is
limited to very small studies or anecdotal case studies of individual patients
that were treated off label.

~~~
radicalbyte
> The cynic in me says it's because many > of them are cheap generics that
> have > little financial upside for large > pharmaceuticals.

The patent is for problem + solution. You can patent many solutions for one
problem and also a solution for many problems.

If they prove, say, that vitamin C stops Alzheimer's then they can patent it
for that usage.

You see this a lot in cancer treatment and it makes a lot of sense. In a
proper functioning system (i.e. not the USA±) it's a pretty decent solution.

± Seriously, the system there is designed so all in theory competing
components are incentivized to work against consumer interests. Same thing
with the housing market pushing house prices (5% interest on 500k is more $
then 5% on 200k, house sellers/older owners think they're rich but only
benefit when they sell and downsize; only winners are lenders and real estate
investors).

~~~
busyant
> If they prove, say, that vitamin C stops Alzheimer's then they can patent it
> for that usage.

Here is an article discussing this approach:

[http://stm.sciencemag.org/content/6/248/248fs30](http://stm.sciencemag.org/content/6/248/248fs30)

I call them "use patents" but I am not sure if that is an official term or
just a colloquialism.

~~~
radicalbyte
I just asked my wife (who's a pharmacist). She says that it's indeed true that
drugs companies basically ignore existing drugs because it's not worth the
costs to prove that they work even though they can officially patent them for
new usages.

Here's an example:
[https://en.wikipedia.org/wiki/Pregabalin](https://en.wikipedia.org/wiki/Pregabalin)

That's an epilepsy treatment which also worked for nerve damage. They weren't
allowed to dispense the generic for nerve problems. However in practise the
prescriptions don't include the reason so in practise they provided the
generic.

------
graeme
Read an interesting anecdote on amyloids in Why We Sleep. During a certain
sleep phase, the brain tissues change size and open up pathways for
cerebrospinal fluid to pass this. This washes out amyloids.

Over time with age and with brain damage, older adults lose the ability to
generate this type of sleep, and so there is less cleaning.

Does anyone know any more about this? It seems plausible that the cause could
be partly due to a loss of this sleep cleaning function. Indeed lack of sleep
is correlated with alzheimers.

But that's just a book anecdote. I'd be curious to read more.

~~~
holowire
I am currently reading Why We Sleep as well, and Matthew Walker's research on
the topic is really interesting to consider within the larger constellation of
approaches to Alzheimer's—particularly in context of the dietary/metabolic
angle.

The neural maintenance that occurs during sleep, the body's circadian
mechanisms and quality of diet all seem to be highly complementary and
ultimately point towards a more holistic and fundamental understanding of the
disease (or brain physiology in general). It's been demonstrated pretty
comprehensively that quality of diet and timing of eating have a profound
effect on how well the body functions as a whole, so the sleep component seems
to be an important thread in tying all of these approaches together.

------
fasteo
One alternative theory: Alzheimer as a metabolic disease.

"We conclude that the term “type 3 diabetes” accurately reflects the fact that
AD represents a form of diabetes that selectively involves the brain and has
molecular and biochemical features that overlap with both type 1 diabetes
mellitus and T2DM."

[1]
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2769828/](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2769828/)

~~~
pjkundert
Significant impact in 30 days. Without changing diet to reduce glucose. Can’t
achieve 1mmol/L of Ketones in the blood, though, without a Ketogenic diet. The
brain _lights up_ in the PET scan on a Ketogenic diet:

[https://youtu.be/OU26epaihmw?t=1469](https://youtu.be/OU26epaihmw?t=1469)

~~~
mft_
Wasn't that PET scan showing ketone _uptake_? So it showed that brains can use
ketones... but nothing about the activity or ability of the brain otherwise?

~~~
pjkundert
The researcher claimed to have observed declining energy use for years before
symptoms occurred, showing decreasing energy consumption leading to cell death
regardless of fuel availability, finally leading to Alzheimer’s symptoms.

Provision of ketones alone reversed this energy starvation. The PET scan
literally lit up like a Christmas tree — turned from all blue/black to red!

It was near the end of the presentation...

If neural cellular degeneration is the target of any Alzheimer’s management
strategy, wouldn’t dramatic energy consumption declines over decades before
cell death, and reversal of these declines after a short treatment be of
specific interest?

------
djsumdog
Could alzheimer's be more like cancer, where there are several variants and
several causes? It seems like beta amyloid were looked at because they produce
similar protein manifolding to prions. Other comments on here mention herpes
(which is incredibly common. I've never had cold-sores, but dated enough
people who have where I may just have it and not present, and it can't easily
be tested for since it produced very similar antibodies to chickenpox).

~~~
hunta2097
I think this may be the case for many brain-related illnesses. My son is
severely autistic and through schools etc I know a lot of autistic children
and adults. They are all very different but still labelled as "autistic
spectrum".

I think there are many causes with many similar symptoms, which is why no-one
has discovered a common cause.

~~~
mattkrause
This is definitely true for autism. It’s clearly somewhat heritable, but no
one has found _a_ gene or mutation that all people with autism share. Study A
picks out this gene from one set of families, Study B picks out a totally
different gene (and can’t replicate A’s findings).

Alzheimer’s is a little odd in that most (maybe all) patients seem to have the
plaques. Removing the plaques seems to do nothing though so it might be a side
effect of something else going wrong.

------
nobodyandproud
There's a novel theory that herpes is the culprit for a significant number of
Alzheimer's patients.

This line of thought was originally discounted, under the (mistaken) belief
that the blood/brain barrier made this impossible.

~~~
hackandtrip
(I'm not an expert) Isn't this evidence correlated to the presence of beta-
amyloid in the brain and the increased time required to clean them with
herpes? As far as I read it, the evidence that beta-amyloid are a cause and
not the consequence of Alz is not there. Also, I think that making such a
statement for institutions needs solids theory, because it could effect a
major part of population

------
nabla9
I think more money should be directed towards tools, sensors and technology
that can be used so map and study brain and biochemistry in general, and not
just particular pathologies. Expansion microscopy, optogenetics and deep brain
stimulation via temporally interfering electric fields are good examples of
that. The surprising result that you can clear amyloids from the brain (only
in transgenic mice) with 40 Hz light therapy is good example of surprising
findings you get when you build new tools.

~~~
dcbadacd
"I'm going for my biannual brain plaque checkup" will be a sentence I won't be
surprised hearing. I think it's just a matter of time when we figure out
brains need a bit of human-assisted maintenance just like teeth.

------
dawhizkid
I'm taking every preventative measure I can at a young age to reduce chance of
Alzheimer's later in life, starting with low carb intake (+ no sugar) and IF.

I can't think of anything more depressing than working your whole life so you
can retire only to go into retirement and be diagnosed with Alzheimer's.

~~~
ams6110
News flash: we're all going to die, and time flies. At the typical retirement
age of 65, most people have 10 or 15 years left.

I'd advise a sensible diet and enjoying life while you are young. Don't spend
time ruminating about what might kill you when you're near the end of your
life regardless.

~~~
AQuantized
Life expectancy is around 20 years at 65 in most developed countries.

~~~
ams6110
Fine. Point being, 20 years sounds like a long time when you're 25. When
you're 55 or 60, and reflect on how fast that time went by, 15 or 20 years
doesn't sound like very long. Certainly not enough time to make up for a
lifetime of denying yourself life's pleasures thinking you're going to make up
for it when you're old.

Edit to add: none of us are guaranteed anything. You could get cancer and be
dead at 40. Or younger. Avoiding reckless risks is one thing. Thinking you
really have much control over diseases you might get in 40 years from now is
another.

------
tonetheman
I watched two people get it side by side... It felt like I was watching them
catch a cold. It is only anecdotal but it feels like it was a virus or
something catching.

------
antiviral
What if the presence of beta amyloid is not the cause of Alzheimer’s but
rather the symptom? In that case, these drugs should be ineffective.

It would be interesting to see how brain function continues to be impaired
even while the beta amyloids are suppressed using these drugs, helping us get
to the real process.

~~~
jnurmine
Disclaimer: I am not a doctor, just try to follow up on big things impacting
many people.

According to my understanding of the amyloid cascade hypothesis, the amyloid
beta accumulation is not a cause but indeed a symptom (of gene
mutations/something). Then, the amyloid beta basically clumps up and other
mechanisms happen and neurons get damaged and this collective damage is known
as Alzheimer's Disease.

So the amyloid beta is just one link in the chain.

Even with a complete removal of that link (removing/reducing amyloid beta),
one cannot expect the disease to be reversed, since removal of something in-
between does not revert the already occured damage. But accumulation of new
damage might slow down. Coupled with improved early detection even this would
be very helpful to many people.

As far as I know, some modest slowing down was observed in some of the
clinical trials. This could mean the amyloid cascade hypothesis isn't
completely wrong.

Now, what I found really, really interesting is that first Biogen gets ca. 20
% of its market value vaporized after the aducanumab (a joint venture betwen
Biogen and Eisai). This is nearly 20 billion USD. Then, Eisai informs that
they still go forward with another substance called BAN2401.

The BAN2401 also targets amyloid beta, but in a different way than others
(protofibrils).

So... I'm thinking here that this is either a genius move or a really dumb
one. It cannot really be anything in-between. I honestly hope it'll be a
genius move.

~~~
copperx
> 20 % of its market value vaporized after the aducanumab

You're missing a few words here. Was it "the aducanumab trial failed"?

~~~
jnurmine
Yes, you are correct, thank you!

------
neonate
[https://outline.com/rfdTx9](https://outline.com/rfdTx9)

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kobieyc
This book
[https://www.amazon.com/dp/0735216207](https://www.amazon.com/dp/0735216207)

~~~
JPLeRouzic
I read it, it is interesting but it tells only a way to mitigate the disease,
not to cure it.

And I would love if there were independent studies that could confirm
Bredesen's writings (I do not say there are none, just that I am not aware of
them).

------
mrnobody_67
Ultrasound to break up plaques in the brain:
[https://www.fusfoundation.org/diseases-and-
conditions/neurol...](https://www.fusfoundation.org/diseases-and-
conditions/neurological/alzheimers-disease)

