One man's rare Alzheimer’s mutation delayed its onset | Hacker News Reader

One man's rare Alzheimer’s mutation delayed its onset

nature.com

177 pointsdeepzn57 comments

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Really frustrating there is no open access to this paper.

I carry four (as far as I know) rare and low frequency homozygous minor allele SNPs in RELN:

rs39335(G;G)

rs3914132(C;C)

rs7696175(C;C)

rs4298437(T;T)

And guess what? I have Bipolar Disorder Schizoaffective type and my therapists keep telling me I have Aspergers.

This gene seems to bind to zinc, and a deficiency of zinc is also found in Alzheimer's.

https://www.jneurosci.org/content/41/13/3025#:~:text=Inflamm....

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3010690/

https://alzres.biomedcentral.com/articles/10.1186/s13195-021...

Zinc has helped me in many ways.

Since the mutation is a GAIN OF FUNCTION mutation, more zinc means less risk of Alzheimer's.

It is open access though, and linked at the bottom of the article:

https://www.nature.com/articles/s41591-023-02318-3

Thanks, still cannot fine the SNP for the RELN-H3447R mutant though...

I believe it is rs201731543

Found it by going to the list of all alleles of that gene (https://ensembl.org/Homo_sapiens/Transcript/Variation_Transc...) and looking for one that changes the 3444th amino acid from an H to an R

Thank you! Too bad 23andMe does not pull that SNP.

Can you recommend a zinc supplement? Preferably NSF or Mayo tested?

Zinc Sulphate is the hospital approved form. But zinc picolinate will work well too.

I take zinc sulfate. 220 mg with 50mg of elemental zinc.

That is rather high and may cause side effects for most people.

(Those are: tingling in fingers, vivid dreams, and especially bad nausea and stomach pain. Also higher testosterone and dramatically higher sex drive, though maybe you like that.)

I agree, and I don’t recommend anyone take zinc before getting their zinc levels tested. Or if they know they have genetic issues with zinc and zinc deficiency.

But the side effects from the zinc could be from a deficiency as well.

If you are low in serotonin and dopamine and take zinc, it will increase these, and since you were low for so long, the reaction to higher levels will be more pronounced. The increase in serotonin is usually what causes stomach upset, and diarrhea.

So it’s probably better for people who haven’t taken zinc who are deficient to start slowly.

...Zinc can increase dopamine? I wonder what it would do to someone with ADHD.

Probably help some of them:

https://www.nature.com/articles/s41598-021-94124-5

B6 increases dopamine so that might play a role as well.

How did you find these alleles?

I uploaded my 23andMe raw data to promethease.con and searched for the gene.

> For nearly 40 years, neurologist Francisco Lopera at the University of Antioquia in Medellín, Colombia, has been following an extended family whose members develop Alzheimer’s in their forties or earlier. Many of the approximately 6,000 family members carry a genetic variant called the paisa mutation that inevitably leads to early-onset dementia.

Does he, like, tell them? Do they tell people they're dating? It's not clear how this perpetuates.

I remember a podcast where I believe a lady could smell Alzheimers (or possibly Dementia) years before it showed any symptoms. I have no idea how real it is, but the ethical dilemma is similar. She decided never to tell anyone if my memory is correct

Found it! The ethical question isn't in the transcript as far as I can see, maybe my memory deceived me - https://www.npr.org/2020/03/23/820009335/invisibilia-an-unli...

Yeah, she could smell Parkinson's. I believe it. Dogs can smell all sorts of things humans cannot, and it is possible that a human mutation could grant her such a gift (or curse).

My wife and I smell different scents with differing sensitivities, so I can believe it. (I still remember the smell of roaches from when I was a young child.)

https://www.npr.org/sections/health-shots/2020/03/23/8202745...

But then one day, about 10 years into the marriage, when Les was 31, he came home, and strangely, Joy says, he smelled different. "His lovely male musk smell had got this overpowering sort of nasty yeast smell," she says.

This smell observation has prompted the development of predictive tests for Parkinson's. New results eight days ago.

https://pubs.acs.org/doi/10.1021/acscentsci.2c01468

https://www.smh.com.au/national/nsw/how-smelly-t-shirts-and-...

> But then one day, about 10 years into the marriage, when Les was 31, he came home, and strangely, Joy says, he smelled different.

This is interesting by itself. It suggests that part of the onset of Parkinson's involves a large, rapid change taking place somewhere.

There’s evidence that Parkinson’s, Alzheimer’s may be due to viral infections or brain inflammation, and the plaques are evidence of the damage.

So possible that process begins suddenly. Whatever the cause you’re right that is quite interesting

Yesterday an article was published showing a strong link with trichloroethylene. Apparently some of Fort Bragg's drinking water was contaminated with it and the incidence of Alzheimer's among soldiers being present there was way high.

I can smell asparagus in pee so easily, no one else in the house can though - it's so funny and interesting.

I can smell coffee, not sure how common that is, I have never asked anyone. :D

Very

Really! My piss must really stink then... bzzzzz

IIRC for asparagus it's a common mutation to be able to smell it or not.

Asparagus, coffee, modafinil are all so easy to detect as smells in urine. Weird that some can't.

She actually says that telling it is the better idea [1]:

> She told BBC Scotland that not knowing Les had Parkinson's put her family in a "negative spiral".

> "What if we did know?," she said

> "It would have changed things dramatically.

[1] https://www.bbc.com/news/uk-scotland-47627179

People can choose to give a blood sample for the study, but they are not being told if they carry the mutation. I’m unclear if they even tell people they have found through the genealogical tree (that did not provide a blood sample) that they are part of it.

The Spanish speaking podcast Radio Ambulante covered the story few years ago. Here’s an English transcription of it https://radioambulante.org/en/transcripcion/the-paisa-mutati...

> they are not being told if they carry the mutation.

I would want to know.

With new drugs released in the past year for Alzheimers after more than 20 years. It's exciting that we may be beginning to understand this disease.

Also excited to see how LLM's and DL/AI can help accelerate research by reducing menial tasks for researchers and scientists as well as by contributing to drug discovery. https://medicalxpress.com/news/2023-05-scientists-ai-drug-al...

How far are we from being able to simulate every molecule and folding in our body, tell a neural net what the desire outcome is and have it point out everything that prevents the desired outcome and what to do about it in a way that also doesnt prevent the desired outcome

Here's an interesting paper that looks at blood plasma protein contents and uses bioinformatics processes including learned models to identify plausible biofeedback pathways responsible for protein concentrations deviated from baseline. It's not what you are asking for, but it's the closest thing I've seen to date:

Plasma Proteome of Long-covid Patients Indicates Hypoxia-mediated Vasculo-proliferative Disease With Impact on Brain and Heart Function (Preprint)

https://assets.researchsquare.com/files/rs-2448315/v1/8043bd...

An excerpt:

> In Fig. 7A, hierarchical clustering heatmaps reflect the levels of neurological markers across the patient groups (markers have been curated by OLINK). The values of the PEA expression levels were hierarchically clustered based on Pearson correlation algorithms. Markers selected through the above methodology were investigated for functional annotation using tools from the GSEA platform and MSigDB data positories (Fig. 7B). This latest analysis demonstrated that functional clusters were formed around leukocyte migration, positive immune signals, glial cell differentiation, neurogenesis and MAPK regulatory modules. Taken together, these pathways predict a possible brain-blood barrier dysfunctionality grounded on cell proliferation. Graphs in Fig. 7C illustrate the expression levels of individual markers from the functional groups presented in Fig. 7B. One of the highly expressed markers, was the amyloid precursor protein (APP; Supplementary Fig. 10) which is known to be a pathognomonic marker for both Alzheimer disease and brain inflammation [61–65]. Additional markers for brain dysfunction include JAM2 (endothelial tight junctions protein), SNAPIN (a mediator of neuronal autophagy-lysosomal function in developing neurons), KCNH2 (potassium channel), S100A14 (involved in cell motility adhesion and growth), KIAA0319 (language impairment biomarker), and IROR1 (a receptor tyrosine kinase like orphan receptor 1, which regulates neurites growth in the central nervous system having also WNT-signaling pathway functions, and being crucial for the auditive apparatus maintenance).

Incredibly far. Simulating all of that would be egregiously wasteful and extremely unlikely to provide actionable results.

I'd guess about 0.1% complete.

Still a ways off but AlphaFold is a big step in that direction.

These new drugs, or something else? https://www.science.org/content/blog-post/are-anti-amyloid-a...

I didn't read earlier about the backlash, but yes, I was talking about these-https://www.bbc.com/news/health-63749586

But I see there are side effects as well (Thanks for pointing it out) -https://www.axios.com/2023/05/15/alzheimers-drugs-patients-r... -https://www.science.org/content/article/scientists-tie-third...

It's good then that we now have another solution to tackle this like mentioned in OP, such as targeting reelin or APOE. And if anti-amyloids, or reducing amyloids are only a part solution. Hopefully, the findings keep continuing to cure Alzheimers.

I read a little more In The Pipeline than I should, and understand a little less of it than I should.

Which drug are you thinking of? Because the recent one that was approved was both highly controversial because the efficacy is extremely questionable[1] and the entire theory of disease is in question as well [2].

[1]: https://www.npr.org/2021/06/07/1003964235/fda-approves-contr... [2]: https://www.nbcnews.com/science/science-news/alzheimers-theo...

> and the entire theory of disease is in question as well [2].

The entire theory of Alzheimer's is not resting on that research. Nobody believes in amyloids exclusively because of it.

Yes these anti-amyloid drugs announced recently. I wasn't aware of the controversy. Hopefully, this period is the start of more fruitful discoveries.

They may be thinking of the one approved even more recently [0], of which I am unaware of any controversy.

[0] https://www.theguardian.com/society/2023/may/03/new-alzheime...

Yes, this too. This one though appears to have some side effects of brain swelling as mentioned in the article.

Though the one announced in 2021 made the headlines and appeared to be more of a success than it was. You could say a new drug being approved after 20 years is still a relative success (it does have some statistically significant results which led it to being approved).

The beta-amyloid debacle will persist as one of the most fatal mistake the scientific community, and a single individual's deceit created.

If you're referring to the (likely) falsified research of Sylvain Lesné, my understanding is that researchers universally agree that it was not central to the beta-amyloid hypothesis, and therefore didn't change much. The story appears to have been widely mischaracterized in the press, even by Science, who broke the story.

“The fact that the man stayed mentally healthy for so long despite the many amyloid plaques in his brain suggests that Alzheimer’s is more complicated”. Given researchers still think is amyloid/tau related but still don’t understand why, you don’t say. Is like saying the universe is more complicated than that

It suggests the plaque is a symptom rather than a cause.

But any researcher whose life's work has been tackling the plaque isn't going to like that.

> It suggests the plaque is a symptom rather than a cause.

I will profess that the plaque is actually protective and not just "a symptom".

That is why this man had no issues even though he had so many plaques.

I searched for Reelin protein and found related articles where rats benefited as well.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3166788/

https://www.frontiersin.org/articles/10.3389/fncel.2020.0028...

Is Reelin commercially available?

It might be low Reelin that protects them. That is the function of must genetic mutations, to slow down the enzyme. So taking Reelin might make you worse.

Zinc might increase reelin activity though.

https://pubmed.ncbi.nlm.nih.gov/10192793/

It might be that high reelin is protecting but I cannot tell from this study yet what the mutation does.

ADDING:

Found it. It is a GAIN OF FUNCTION mutation, which means more Reelin will help curb Alzheimer's. And to me that means more zinc will help as well.

https://www.nature.com/articles/s41591-023-02318-3

RELN-COLBOS is a gain-of-function variant showing stronger ability to activate its canonical protein target Dab1 and reduce human Tau phosphorylation in a knockin mouse. A genetic variant in a case protected from ADAD suggests a role for RELN signaling in resilience to dementia.

These molecular systems are deeply complex and will depend on cascades of interactions. Hang tight. The only generic neuroprotective supplement I can recommend is niacinamide (vitamin B3, non-flushing). See:

https://pubmed.ncbi.nlm.nih.gov/28209901/

(yes, in mice! but now in clinical trials for glaucoma and looking good. And yes, glaucoma is not AD, but many/most forms of neurodegenerations are associated with high mitochondrial stress/dysfunction).

I was wondering what non-flushing meant, and I found this, apparently the non -flushing vitamin B3 is just barely absorbed: http://www.dpic.org/article/professional/niacin-facts-flushi....

wow, you really like dismissing pretty obvious evidence that zinc plays a role in Alzheimer's.

It is not complex, it is simple. I believe it is a metabolic disease caused by metabolic disease and genetic risk. That will be unique for everyone, but for most people I feel the answer will be poor zinc handling.

And Niacin is all you can come up with? Did you know we make niacin if we have enough B6 and B2?

Feels like a "lot" of things help rats for whatever reason though

No, not in any way useful in therapeutics yet. It is a large gene and protein. Delivery to the right cells and neurons in adult humans is well beyond state-of-the-art. But we may be able to mimic its effects with small molecules.

https://www.ncbi.nlm.nih.gov/gene?Cmd=DetailsSearch&Term=564...

Isn't these kinda of data points we often miss if we look at correlations in big datasets? They often get dismissed as an a anomaly.

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