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A woman with a rare genetic mutation that has protected her from dementia (nytimes.com)
296 points by grzm 13 days ago | hide | past | web | favorite | 39 comments

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.

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.

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.

So this isn’t apoe2? It’s some novel mutation of apoe3?

Correct. The APOE3ch alteration falls within a region of the APOE3 protein. Specifically, the article talks about APOE3 R136S or 'Christchurch' (APOE3ch) mutation.

A more indepth analysis of the patient's mutation and mechanism(s) of action:


I never realised that the APOE variant bound heparin sulfate (HS). HS is actually a cool molecule (glycan) from the perspective of its ability to encode information in its pattern of sulfation.

The signals can be mixed and the precise binding partners for a single molecule can be programmed in. How this is all regulated, and the extent this happens in nature is still being worked out.

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.

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... [2] https://en.wikipedia.org/wiki/Tsiman%C3%A9 [3] http://tsimane.anth.ucsb.edu/index.html

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/

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.

> 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.

I remember reading something where they explained that cultures where they kept the grandmothers around tended to have better outcome for both the mother and the baby when their daughters gave birth.

It isn't really surprising, when you think of it, and it's probably just one of many examples where aging better, past child bearing age, improves the chances of a lineage.

Your last paragraph is likely the crux of it. When people die “young” in low information societies, received wisdom has tremendous survival value.

It doesn't, that's why not everybody has that gene; if Alzheimers was something you developed as a teen, I'm sure that mutation would spread and soon everybody would have it.

Maybe we could use that gene in the future on patients at the onset of regular Alzheimers.

It would be interesting to see if, in a few thousands years, these traits do somehow manage to get passed down. There is a good chance that traits that help with things like Alzheimer's wouldn't be as likely to get passed down because of reasons you've mentioned. Or we might be able to treat it with other therapies as science outpaces evolution as far as longevity goes.

Humans are in a very unique place with our sentient minds and understanding of the world. It'd be nice if we could compare ourselves to other species, but we haven't found any yet, and they're likely to be billions of light years away, or extinct, or both.

I agree.

One thing that strikes me is how many go undocumented - including mutations that cause HIV immunity.

I think it's incredibly interesting that perhaps 5000 years from now some mutations would be well established - but that we aren't aware of now (as they happen).

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.

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.

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.

> 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). 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.

> You can't safely deactivate metabolic pathways at runtime in a single cell

While I generally agree with your sentiment that it would be remarkably difficult to genetically modify the brain tissue of an adult, you have no idea if your statement is true or not.

In fact, this is the whole point of CRISPR and similar forms of "gene therapy." Yes. You probably can't modify the genome of all cells in a large multi-cellular organism like us, but there may be ways of modifying selected/important tissues.

> This type of thinking stems from a lack of familiarity with biochemistry, the molecular biology of genetics, and cell physiology.

This is not warranted either.

Thats absurd. She neither created nor detected the mutation. I agree that dna patents should not exist though. We share so much of it.

She, or her parents, literally created the mutation they're researching.

"Accidentally" as part of a natural process for sure. But that doesn't take away the validity of them being the creators of it.

Understood- what if, after developing the drug you find these mutations occur spontaneously elsewhere in the world population- do all those people also get a cut?

Figuring how to do this is non-trivial.

Agreed. Doesn't mean "too hard, thus ignore" is the right approach though. ;)

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...

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...)

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).

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

We've switched to that phrase from the subtitle.


Please read the article.

> Researchers have found a woman with a rare genetic mutation that has protected her from dementia even though her brain has developed major neurological features of the disease.

> She, like thousands of her relatives, going back generations, was born with a gene mutation that causes people to begin having memory and thinking problems in their 40s and deteriorate rapidly toward death around age 60.


Is there really no way to report posts/users for spam on here?

How do you report spam

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

It’s very interesting from a scientific standpoint. Finding conditions like this can give valuable insight to causality of the different symptoms. You just can’t test all possible mutations to asses their effect.

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

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.

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