[HN Gopher] One man's rare Alzheimer's mutation delayed its onset
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One man's rare Alzheimer's mutation delayed its onset
Author : deepzn
Score : 102 points
Date : 2023-05-16 18:09 UTC (4 hours ago)
(HTM) web link (www.nature.com)
(TXT) w3m dump (www.nature.com)
| deepzn wrote:
| 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...
| dllthomas wrote:
| These new drugs, or something else?
| https://www.science.org/content/blog-post/are-anti-amyloid-a...
| deepzn wrote:
| 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.
| dllthomas wrote:
| I read a little more In The Pipeline than I should, and
| understand a little less of it than I should.
| onepointsixC wrote:
| 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...
| astrange wrote:
| > 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.
| deepzn wrote:
| Yes these anti-amyloid drugs released recently. I wasn't
| aware of the controversy. Hopefully, this period is the start
| of more fruitful discoveries.
| yieldcrv wrote:
| 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
| charliea0 wrote:
| I'd guess about 0.1% complete.
| zamnos wrote:
| Still a ways off but AlphaFold is a big step in that
| direction.
| photon12 wrote:
| 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).
| dekhn wrote:
| Incredibly far. Simulating all of that would be egregiously
| wasteful and extremely unlikely to provide actionable
| results.
| fsiefken wrote:
| 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?
| robwwilliams wrote:
| 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...
| FollowingTheDao wrote:
| 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.
| robwwilliams wrote:
| 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).
| psb wrote:
| Feels like a "lot" of things help rats for whatever reason
| though
| jiggywiggy wrote:
| 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.
| astrange wrote:
| > For nearly 40 years, neurologist Francisco Lopera at the
| University of Antioquia in Medellin, 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.
| FollowingTheDao wrote:
| 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.
| panax wrote:
| It is open access though, and linked at the bottom of the
| article:
|
| https://www.nature.com/articles/s41591-023-02318-3
| FollowingTheDao wrote:
| Thanks, still cannot fine the SNP for the RELN-H3447R mutant
| though...
| elsherbini wrote:
| 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_Trans
| c...) and looking for one that changes the 3444th amino
| acid from an H to an R
| jamiek88 wrote:
| Can you recommend a zinc supplement? Preferably NSF or Mayo
| tested?
| FollowingTheDao wrote:
| 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.
| astrange wrote:
| 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 to the point
| it annoys your spouse.)
| ycombinete wrote:
| How did you find these alleles?
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