8 ms·

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

177 points by deepzn 3y ago

FollowingTheDao 3y ago
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=Inflammatory%20lifestyle%20factors%20increase%20the,evidence%20for%20this%20is%20limited https://www.jneurosci.org/content/41/13/3025#:~:text=Inflamm.... https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3010690/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3010690/ https://alzres.biomedcentral.com/articles/10.1186/s13195-021-00931-3 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 3y ago
  It is open access though, and linked at the bottom of the article: https://www.nature.com/articles/s41591-023-02318-3 https://www.nature.com/articles/s41591-023-02318-3
  - FollowingTheDao 3y ago
    Thanks, still cannot fine the SNP for the RELN-H3447R mutant though...
    - elsherbini 3y ago
      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_Transcript/Table?db=core;g=ENSG00000189056;r=7:103471789-103989658;t=ENST00000428762 https://ensembl.org/Homo_sapiens/Transcript/Variation_Transc...) and looking for one that changes the 3444th amino acid from an H to an R
      - FollowingTheDao 3y ago
        Thank you! Too bad 23andMe does not pull that SNP.
- jamiek88 3y ago
  Can you recommend a zinc supplement? Preferably NSF or Mayo tested?
  - FollowingTheDao 3y ago
    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 3y ago
      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.)
      - FollowingTheDao 3y ago
        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.
        LoganDark 3y ago
        ...Zinc can increase dopamine? I wonder what it would do to someone with ADHD.
        FollowingTheDao 3y ago
        Probably help some of them: https://www.nature.com/articles/s41598-021-94124-5 https://www.nature.com/articles/s41598-021-94124-5 B6 increases dopamine so that might play a role as well.
- ycombinete 3y ago
  How did you find these alleles?
  - FollowingTheDao 3y ago
    I uploaded my 23andMe raw data to promethease.con and searched for the gene.
fsiefken 3y ago
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.ncbi.nlm.nih.gov/pmc/articles/PMC3166788/ https://www.frontiersin.org/articles/10.3389/fncel.2020.00285/full https://www.frontiersin.org/articles/10.3389/fncel.2020.0028... Is Reelin commercially available?
- FollowingTheDao 3y ago
  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/ 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 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 3y ago
    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/ 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).
    - carlmr 3y ago
      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-flushing#:~:text=Q%3A%20What%20about%20%22no%2D,does%20not%20produce%20any%20flushing http://www.dpic.org/article/professional/niacin-facts-flushi....
deepzn 3y ago
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-alzheimer.html https://medicalxpress.com/news/2023-05-scientists-ai-drug-al...
- yieldcrv 3y ago
  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
  - photon12 3y ago
    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/v1/8043bdbc-0b70-4ef5-8090-521214158396.pdf?c=1673979999 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).
astrange 3y ago
> 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.
- anitil 3y ago
  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-unlikely-superpower https://www.npr.org/2020/03/23/820009335/invisibilia-an-unli...
  - ronyeh 3y ago
    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/2020/03/23/820274501/her-incredible-sense-of-smell-is-helping-scientists-find-new-ways-to-diagnose-di 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.
    - femto 3y ago
      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://pubs.acs.org/doi/10.1021/acscentsci.2c01468 https://www.smh.com.au/national/nsw/how-smelly-t-shirts-and-ai-helped-unlock-secret-to-detecting-parkinson-s-disease-20230510-p5d7bm.html https://www.smh.com.au/national/nsw/how-smelly-t-shirts-and-...
jiggywiggy 3y ago
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.
m3kw9 3y ago
“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
- bratbag 3y ago
  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.
  - FollowingTheDao 3y ago
    > 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.

177 points by deepzn 3y ago

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=Inflammatory%20lifestyle%20factors%20increase%20the,evidence%20for%20this%20is%20limited https://www.jneurosci.org/content/41/13/3025#:~:text=Inflamm.... https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3010690/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3010690/ https://alzres.biomedcentral.com/articles/10.1186/s13195-021-00931-3 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 3y ago
It is open access though, and linked at the bottom of the article: https://www.nature.com/articles/s41591-023-02318-3 https://www.nature.com/articles/s41591-023-02318-3
- FollowingTheDao 3y ago
  Thanks, still cannot fine the SNP for the RELN-H3447R mutant though...
  - elsherbini 3y ago
    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_Transcript/Table?db=core;g=ENSG00000189056;r=7:103471789-103989658;t=ENST00000428762 https://ensembl.org/Homo_sapiens/Transcript/Variation_Transc...) and looking for one that changes the 3444th amino acid from an H to an R
    - FollowingTheDao 3y ago
      Thank you! Too bad 23andMe does not pull that SNP.
jamiek88 3y ago
Can you recommend a zinc supplement? Preferably NSF or Mayo tested?
- FollowingTheDao 3y ago
  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 3y ago
    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.)
    - FollowingTheDao 3y ago
      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.
      - LoganDark 3y ago
        ...Zinc can increase dopamine? I wonder what it would do to someone with ADHD.
        FollowingTheDao 3y ago
        Probably help some of them: https://www.nature.com/articles/s41598-021-94124-5 https://www.nature.com/articles/s41598-021-94124-5 B6 increases dopamine so that might play a role as well.
ycombinete 3y ago
How did you find these alleles?
- FollowingTheDao 3y ago
  I uploaded my 23andMe raw data to promethease.con and searched for the gene.

fsiefken 3y ago

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.ncbi.nlm.nih.gov/pmc/articles/PMC3166788/ https://www.frontiersin.org/articles/10.3389/fncel.2020.00285/full https://www.frontiersin.org/articles/10.3389/fncel.2020.0028... Is Reelin commercially available?

FollowingTheDao 3y ago
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/ 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 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 3y ago
  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/ 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).
  - carlmr 3y ago
    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-flushing#:~:text=Q%3A%20What%20about%20%22no%2D,does%20not%20produce%20any%20flushing http://www.dpic.org/article/professional/niacin-facts-flushi....

deepzn 3y ago

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-alzheimer.html https://medicalxpress.com/news/2023-05-scientists-ai-drug-al...

yieldcrv 3y ago
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
- photon12 3y ago
  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/v1/8043bdbc-0b70-4ef5-8090-521214158396.pdf?c=1673979999 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).

astrange 3y ago

> 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.

anitil 3y ago
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-unlikely-superpower https://www.npr.org/2020/03/23/820009335/invisibilia-an-unli...
- ronyeh 3y ago
  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/2020/03/23/820274501/her-incredible-sense-of-smell-is-helping-scientists-find-new-ways-to-diagnose-di 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.
  - femto 3y ago
    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://pubs.acs.org/doi/10.1021/acscentsci.2c01468 https://www.smh.com.au/national/nsw/how-smelly-t-shirts-and-ai-helped-unlock-secret-to-detecting-parkinson-s-disease-20230510-p5d7bm.html https://www.smh.com.au/national/nsw/how-smelly-t-shirts-and-...

jiggywiggy 3y ago

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.

m3kw9 3y ago

“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

bratbag 3y ago
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.
- FollowingTheDao 3y ago
  > 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.