
Scientists Fix Genetic Risk Factor for Alzheimer’s Disease in Human Brain Cells - po
https://gladstone.org/about-us/news/scientists-fix-genetic-risk-factor-alzheimers
======
epmaybe
I'll take a stab at explaining this. Neuroscientists and biomedical
researchers, feel free to chime in with corrections.

In biomedical researchers, the strength of evidence of your data correlates
with how close it is to modeling the human body. So, in general, strength goes
as follows:

Animal cell cultures < animal tissue < _in vivo_ animal models <= human cell
culture < human tissue < in vivo human trials (phases 1-3)

In this study, the researchers studied the ApoE4 subtype of the ApoE protein
(involved in fat metabolism). The gene coding for this protein has been
associated with greater risk of getting Alzheimer's disease then other
subtypes, so it has been a target of study for a while now.

These researchers cultured brain cells that were differentiated from stem cell
lines. Here's how they did it:

Skin from Alzheimer's patients and healthy patients (so apoe4 vs apoe3
containing cells) -> induced back to stem cell precursors -> differentiated
into neurons

What they found was the following:

-neurons with apoe4 had production of Alzheimer's hallmarks (Tau phosphorylation, ABeta, neuron degeneration)

-neurons with apoe3 had less to none of these changes.

-editing the apoe4 gene to apoe3 prevented the changes from occurring.

-gettig rid of the apoe4 gene completely prevented the changes from occurring.

-giving a drug that changed the protein structure from apoe4 to apoe3 prevented the changes from occurring.

~~~
epmaybe
I'm shamelessly pulling all of this from the paper abstract, which you should
find here:
[https://www.nature.com/articles/s41591-018-0004-z](https://www.nature.com/articles/s41591-018-0004-z)

As for what this means: it's exciting, and if these researchers can prove that
the drug is safe in animals and humans they can probably proceed with trials
on Alzheimer's patients with the apoe4 gene.

But that's the thing: this discovery, while cool, is relevant to only some of
the patients dealing with Alzheimer's that have the ApoE4 gene. This isn't a
unifying mechanism to how Alzheimer's occurs in all patients, as it doesn't
tackle the problem of patients with apoe3 getting Alzheimer's. Nonetheless it
is still relevant especially for early onset, which is more strongly
associated with this gene.

~~~
zitterbewegung
Hopefully the results can be generalized to other experiments? Possibly the
techniques they used?

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maho
There was another interesting publication about Alzheimer's Desease last week:
It appears to be possible to detect the misfolded amyloid‐β protein in a blood
sample many years before symptoms develop:

[http://embomolmed.embopress.org/content/early/2018/04/04/emm...](http://embomolmed.embopress.org/content/early/2018/04/04/emmm.201708763)

~~~
ekianjo
Interesting but not sure there is a clear benefit of knowing ahead of time
when there's no treatment available. Knowing how you will end will
significantly affect your outlook on life.

~~~
amp108
My mother has Alzheimer's, and I have the ApoE4 gene. Knowing is better.

The only other options are (a) knowing after it's too late to do anything, or
(b) knowing at the exact moment science makes a discovery. Since we can't know
(b) ahead of time, we're left with either knowing ahead of time, or too late.

Knowing sucks, but it sucks less than any other option.

~~~
monetus
The only counter argument to this I could imagine would be the one I often
hear used for other brain abnormalities; i.e. if the knowledge of a potential
health problem instigates a mental health issue, ignorance could be better.

I subscribe to your opinion, however.

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aaavl2821
This is a nice article and is a great example of a few technological advances
that are making now an incredible time to start a biotech company: massive
increase in genomic data and advances in biology (in this case stem cells) to
enable better modeling of whether things will work in humans

It costs up to $2.6B to develop a drug. The majority of this is not out of
pocket spend on developing the drug, but the cost of risk -- all the money
spent on drugs that end up failing. The biggest driver of the cost of failure
is failing in Phase 2. Phase 2 trials are the first test of whether a drug is
effective in humans. Prior studies look at animal or cellular models of
effectiveness, or safety in humans. It can cost $50-100M+ to get to phase 2

Genomic data is one of the most cost efficient ways to predict whether a drug
will work in humans. certain mutations, like apoe4, are strongly correlated
with disease risk and prognosis. Of course this does not imply causality, but
researchers can tease this out with established models. Clinical trials of
drugs based on genetic markers have greatly increased odds of success

Genetic biomarkers also enable smaller studies -- rather than study big
heterogenous population to find a signal, you can do so with a smaller
homogenous population.

This is all very important for Alzheimer's, a field where trials are big and
expensive and failure is the norm

The other advance is the ability to easily create neural cells from skin
cells. As the paper says, mice are very different than humans, especially
neurologically. But it's hard to study human neurons in the lab. The ability
to turn skin cells into stem cells and then into other cells enables this
(previously only embryonic stem cells were available). So researchers can
perform experiments to determine causation in a model that is much better
predictor than typical mouse models

There has been a lot of work in cancer developing genetically targeted drugs,
but it is not as common in other fields. Part of the challenge is getting
enough data, and part of it is that data alone isn't enough, you really need
the biological hypothesis to come first

------
rrggrr
Relevant link concerning attenuating Alzheimer's by a fat rich diet:
[https://www.mdedge.com/clinicalneurologynews/article/145220/...](https://www.mdedge.com/clinicalneurologynews/article/145220/alzheimers-
cognition/fueling-alzheimers-brain-fat)

------
exhilaration
Does anyone know if the genetic testing companies like 23 and Me tell you if
have the apoE4 gene mentioned in the article?

~~~
simulate
[Edited to remove incorrect, outdated info about apoE4 data]

23andMe offers information on ApoE4 now that they have FDA approval. You can
also use Promethease to get additional information on SNiPs if you want.
Here's how.

1\. Get a DNA analysis from 23andMe or similar.

2\. Download your raw genetic data. If you use 23andMe, you can download your
raw genetic data here:
[https://you.23andme.com/tools/data/download/](https://you.23andme.com/tools/data/download/)

3\. Upload your data to [https://promethease.com/](https://promethease.com/)

Before you do this, you might want to visit ApoE4.Info and consider what you
will do with the information once you have it.
[https://www.apoe4.info/wp/thinking-about-
testing/](https://www.apoe4.info/wp/thinking-about-testing/)

~~~
fredfl
This is wrong info. 23andMe has reinstated the Alzheimer’s report as of last
year.

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chiefalchemist
"Scientists have been unclear about why apoE4 is so much more damaging to
brain cells than other versions of the protein."

Without a solid why, doesn't this constitute correlation, and not cause?

I'm curious where the line gets drawn, and why that's so.

~~~
amelius
The first step is often to notice a correlation. The causation was found here:

> Treating human apoE4 neurons with a structure corrector eliminated the signs
> of Alzheimer’s disease, restored normal function to the cells, and improved
> cell survival.

The actual mechanism is not necessarily important for a treatment to be
successful.

~~~
chiefalchemist
Yes. But what about unintended consequences? What if this cures a symptom but
creates something else?

~~~
Unkechaug
It's definitely a roll of the dice but I'd venture to say that, aside from
constant pain and suffering, pretty much anything else is better than
Alzheimer's.

~~~
chiefalchemist
I agree. It makes sense.

This was probably not the best example given the context. None the less,
without a clear and proven why any "cure" could be risky.

~~~
amelius
> None the less, without a clear and proven why any "cure" could be risky.

The "why" is not as important as you might think. There are many drugs for
which we don't know _why_ they work, but we have clinical trials to test for
their effectiveness and safety.

And clinical trials are more important than knowing the "why". For example, if
you know why a drug inhibits such and such genes, then that is nice to know,
but that doesn't tell you what other effects the drug has.

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mrfusion
Isn’t this also groundbreaking because we never previously know why apoe4
contributed to Alzheimer’s. What the mechanism was?

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Andorin
Alzheimer's is not a neuron disorder. This paper should not have been
published.

~~~
mattkrause
Care to elaborate?

I know there are theories that it's linked to inflammation (etc), but it
clearly has _some_ effect on neurons. It's not clear whether reversing those
effects also reverses the disease (the anti-Abeta antibody stuff has been
disappointing), but given that neurons are.....important for cognition, it
doesn't seem totally insane to think that they are somehow involved in AZ too.

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devit
Seems to have already been known in 1993, according to Wikipedia?

"The best known genetic risk factor is the inheritance of the ε4 allele of the
apolipoprotein E (APOE).[45][46]" where [45] is from 1993.

What's new? Am I misunderstanding something?

~~~
codeulike
They know more about what happens at the protein level, and they can fix it by
adding compounds that fix the errant protein

------
bawana
really scary. Can you imagine the CIA create a small molecule that interferes
with ApoE3 to give and ApoE4 phenotype?! Inducing dementia in terrorists and
then allowing them to return home??!! or Inducing dementia in suspected spies?
or inducing dementia on political dissidents?

Or can you imagine the use of this small molecule (which btw is undetectable
in the blood) for nefarious political purposes? Have the democrats already
used it on our president??!!

~~~
krapp
>Inducing dementia in terrorists and then allowing them to return home??!! or
Inducing dementia in suspected spies? or inducing dementia on political
dissidents?

I mean... none of that would actually stop the terrorists, spies or
dissidents. It wouldn't be any better than, say,getting stabbed with a ricin
tipped umbrella[0].

>Have the democrats already used it on our president??!!

No, unfortunately, he's just like that.

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

