
A woman with a rare genetic mutation that has protected her from dementia - grzm
https://www.nytimes.com/2019/11/04/health/alzheimers-treatment-genetics.html
======
gzer0
Quick summary of the findings:

\- Patient had a PSEN1 E280A mutation, which predisposes you to a 99.9% risk
of developing early-onset Alzheimer's.

\- Patient was expected to have Alzheimer's by 50. She is currently 70, with
very little signs of cognitive decline. Although she has large amounts of
amyloid proteins (hallmark of Alzheimer's) it has not reduced her cognitive
capacity.

\- Patient had two copies of the APOE3ch gene variant. _The study indicates
this mutation was primarily responsible for protecting the patient from
Alzheimer 's._

\- Imaging tests showed she did have large amounts of amyloid protein
deposits, but the amount of tau tangles, was relatively low.

\- Experiments have shown this APOE3ch gene variant reduces ability of APOE to
bind to certain sugars called heparin sulphate proteoglycans (HSPG). APOE <->
HSPG binding has been implicated as one mechanism that may contribute to
amyloid + tau protein deposits.

~~~
raducu
Could someone use CRISPR to inject two copies of APOE3ch in regular
Akzheimer's patiens?

Sorry if this sounds silly, I have just a very rough understanding of
genetics.

~~~
youdontknowtho
I was wondering the same thing. Again, sorry if this is obviously a weird
question, but I also have a layman's understanding of genetics.

------
RocketSyntax
It could actually be an additional regulatory de novo mutation or epigenetic
mutation that is preventing the expression of that mutated gene.

Despite what people below say, understanding the pathways involved is
significant because drugs can be made to replicate the same biological effect
to block the disease. This is what biopharma looks for.

------
gardenfelder
Nytimes did a piece in 2017 about a similar situation [1] about studying the
Tsimané [2] and the Tsimané Project [3]; it's a different slant on Alzheimer's
but, with such a complex issue, we need to federate and examine all such
views.

[1][https://www.nytimes.com/2017/07/14/opinion/sunday/alzheimers...](https://www.nytimes.com/2017/07/14/opinion/sunday/alzheimers-
cure-south-america.html) [2]
[https://en.wikipedia.org/wiki/Tsiman%C3%A9](https://en.wikipedia.org/wiki/Tsiman%C3%A9)
[3]
[http://tsimane.anth.ucsb.edu/index.html](http://tsimane.anth.ucsb.edu/index.html)

~~~
sriacha
Thanks for that. The interplay between human parasite evolution is
fascinating. Here's a good paper I read some years back about helminth
infections and the beneficial effect on autoimmune disorders (among other
things) [1].

[1]
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1618732/](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1618732/)

------
neonate
[http://archive.is/HF7Nh](http://archive.is/HF7Nh)

------
thelittleone
This make me curious about mutations and human evolution.

By 50 years of age she has past her (natural) maternal age. So it's not like
women with that mutation would bear more children.

How would such a mutation help her lineage? But that same question, more
broadly, how do mutations that benefit people past their child bearing age
factor into human evolution?

I suppose mentally healthy grandparents are able to spend more time with
grandchildren freeing up the parents to be more productive. They can also pass
down wisdom, techniques that could benefit grandchild.

~~~
chrisamiller
> How would such a mutation help her lineage? But that same question, more
> broadly, how do mutations that benefit people past their child bearing age
> factor into human evolution?

To oversimplify a bit, you can think of most mutations as neutral, in terms of
reproductive fitness. People (and populations) accumulate them all the time,
just by chance. Occasionally, one that was previous neutral becomes beneficial
when the environment changes - say, when it confers immunity to a virus, or
helps with synthesizing an amino acid that's in short supply. This is why
having a big population with lots of variation is beneficial and why
bottlenecks hurt the viability of a species.

------
huac
I wonder if one of the major pharma companies will develop an anti-dementia
drug from this finding, and then if she (or her family) will see any of the
billions in revenues they'll make.

~~~
echelon
They won't earn anything.

This might lead to discovering a receptor or metabolic pathway mechanism for
attack, but the mutation isn't a part of any solution that will be distributed
to patients.

This mutation is merely a suggestion for a gradient in solution space to
explore.

In case you're thinking that this variant of the gene can be introduced into
Alzheimers patients, that is impossible. You can't safely deactivate metabolic
pathways at runtime in a single cell, much less a whole organism. And
especially not in a critical organ such as the brain. And how would you
introduce the new gene and ensure that the correct dosing is delivered? This
type of thinking stems from a lack of familiarity with biochemistry, the
molecular biology of genetics, and cell physiology.

~~~
gzer0
You must not be familiar with the drug Onasemnogene abeparvovec. This is
administered for spinal muscular atrophy patients. Patiens with SMA have a
mutation in their SMN1 gene which causes decreased SMN protein.

Onasemnogene abeparvovec is a biologic drug consisting of AAV9 virus capsids
that contains a SMN1 transgene along with synthetic promoters. Upon
administration, the AAV9 viral vector delivers the SMN1 transgene to the
affected motor neuron, where it leads to an increase in SMN protein.

The point is, while research innovation regarding gene therapy, CRISPR CAS9,
etc takes time and money, it IS indeed possible. Your post suggests a type of
thinking that stems from an abundance of ignorance.

~~~
mattkrause
> stems from an abundance of ignorance.

Ouch. In their defense of their 'ignorance' of gene therapy, Zolgensma was
_just_ approved this spring, it's literally one of two in vivo gene therapies,
and it's only approved for kids < 2, which is a developmentally special sort
of group.

On the other hand, they're almost certainly correct that there's no straight
path from this one patient to a therapy. For SMA, we've known about the
affected genes for nearly 30 years
([https://www.ncbi.nlm.nih.gov/pubmed/2320125](https://www.ncbi.nlm.nih.gov/pubmed/2320125)).
The pathways are not totally trivial--there's some weirdness involving
alternative splicing--but it's not impossible to wrap your head around what
goes wrong. For AZ, we have _no_ idea. Untold amounts of blood and treasure
have been sunk into the idea that plaques were the problem, and despite some
promising initial data, that hasn't panned out[0]. This _is_ exciting because
it suggests a new set of pathways to explore. The rest is hype and
speculation: I'd be gobsmacked if there were a viable therapy in the next ten
years.

[0] Or maybe not. Biogen seems to be taking yet another whack at it.

------
Merrill
Not paywalled - "Colombian woman’s genes offer new clues to staving off
Alzheimer’s" \- [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)

------
rkagerer
While I'm loath to endorse any sort of widespread "big data" on our genetics,
I can't help but wonder what other gems we might glean if metrics like genes
and medical outcomes of everyone ever born were somehow made _safely_
available to researchers.

(Maybe some kind of decentralized and anonymized project with voluntary
participants? Some googling found
[https://www.labiotech.eu/features/blockchain-control-
genomic...](https://www.labiotech.eu/features/blockchain-control-genomic-
data/))

~~~
dekhn
This can't currently be done. Taking the US as an example, if your data is in
EMRs, it's possible for researchers to access your data, but it depends on
what you consented to. Obtaining additional consent- for example by mailing a
letter to everybody in an org's EHR system- isn't super-effective because most
people don't respond to these requests.

Orgs like GA4GH are trying to change consent forms for people who voluntarily
take part in research so that other researchers can pull the EMR data and
aggregate it for other research. This would only apply to people in the
future, we don't normally have such open consent forms right now.

Personally I think it's unlikely that large orgs would agree to decentralized
systems. Instead, they would run this on a major cloud provider using standard
cloud features like encryption and IAM, as well as standard de-identification
techniques.

In principle, if we had a single global database of billions of patients with
both high dimensional data (genomes, images) and labels (medical outcomes such
as "got flu again"), a lot could be done, but researchers have to be extremely
careful. Most folks aren't trained to deal with big data and will immediately
attempt to do all sorts of testing that is prone to false positives (data
dredging/p-hacking is very common in medical fields, and it gets worse as you
have more data).

Note that ultra-large GWAS studies are being done, on datasets with millions
of patients, and the results are interesting; you can explain, for example,
variance of height using genomic variation data, up to a limit (height is only
partially determined by our genome, as is true of effectively any large-scale
coarse-grained phenotypic trait).

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kempbellt
Very clickbaity title. Suggest a change to: "Rare genetic mutation protects
this woman from dementia", or something more descriptive.

~~~
dang
We've switched to that phrase from the subtitle.

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rpmisms
Yet another exception to an incurable disease. This happens all the time.

~~~
yitchelle
Please don't put a downer on this as it gives hope to those whose is suffering
or have close one who is suffering.

~~~
harry8
Really? Please don't prick the clickbait bubble? That is the /exact/ emotion
that makes us be exploited by this clickbait. And it /is/ clickbait. Bringing
it back to reality is what most of us need and actually want. Being taken
advantage of becuase you would literally clutch the tip of a sword as somoene
drowning is just really horrible. You clutch the sword and they let it go as
you've served your purpose and they couldn't stop you drowning anyway. It's
_vile_.

