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Scientists Fix Genetic Risk Factor for Alzheimer’s Disease in Human Brain Cells
- deleted 9y ago[deleted]
- chiefalchemist 9y ago"Scientists have been unclear about why apoE4 is so much more damaging to brain cells than other versions of the protein." Without a solid why, doesn't this constitute correlation, and not cause? I'm curious where the line gets drawn, and why that's so.
- amelius 9y agoThe first step is often to notice a correlation. The causation was found here: > Treating human apoE4 neurons with a structure corrector eliminated the signs of Alzheimer’s disease, restored normal function to the cells, and improved cell survival. The actual mechanism is not necessarily important for a treatment to be successful.
- chiefalchemist 9y agoYes. But what about unintended consequences? What if this cures a symptom but creates something else?
- amelius 9y agoWell, lots of people don't have the apoE4 morphism, and have the normal apoE3 version. So fixing the gene could have other bad consequences in theory, but probably not as bad as Alzheimer's.
- ianai 9y agoI’ve personally learned about many medications without a known functional path, but with eons of use. As for side effects, those are often similarly documented. You’re basically pointing at a part of the medical field.
- JoeAltmaier 9y agoIt will; chemistry is complicated. But you won't have Alzheimer's. So life is tough choices, but lacking any clear downside its a chance lots of us would take.
- ekianjo 9y agoThat's why we have Phase I trials.
- mattkrause 9y ago...and preclinical work. These are exciting results, but tons of additional work is needed before this goes anywhere near an actual human.
- Unkechaug 9y agoIt's definitely a roll of the dice but I'd venture to say that, aside from constant pain and suffering, pretty much anything else is better than Alzheimer's.
- chiefalchemist 9y agoI agree. It makes sense. This was probably not the best example given the context. None the less, without a clear and proven why any "cure" could be risky.
- amelius 9y ago> None the less, without a clear and proven why any "cure" could be risky. The "why" is not as important as you might think. There are many drugs for which we don't know why they work, but we have clinical trials to test for their effectiveness and safety. And clinical trials are more important than knowing the "why". For example, if you know why a drug inhibits such and such genes, then that is nice to know, but that doesn't tell you what other effects the drug has.
- deleted 9y ago[deleted]
- maho 9y agoThere was another interesting publication about Alzheimer's Desease last week: It appears to be possible to detect the misfolded amyloid‐β protein in a blood sample many years before symptoms develop: http://embomolmed.embopress.org/content/early/2018/04/04/emmm.201708763 http://embomolmed.embopress.org/content/early/2018/04/04/emm...
- ekianjo 9y agoInteresting but not sure there is a clear benefit of knowing ahead of time when there's no treatment available. Knowing how you will end will significantly affect your outlook on life.
- StavrosK 9y agoMaybe that is the benefit.
- exhilaration 9y agoKnowing ahead of time would allow you to make sure that you put your affairs in order well ahead of time, set up long term care options, restructure your investments and property holdings. I think the knowledge would be very valuable.
- sgc 9y agoAs well as increase your exercise, mental stimulation/effort, and social life, which have been shown to help reduce the effects of the disease. Not all people heading towards Alzheimer's will walk the same path. Not even close.
- amp108 9y agoMy mother has Alzheimer's, and I have the ApoE4 gene. Knowing is better. The only other options are (a) knowing after it's too late to do anything, or (b) knowing at the exact moment science makes a discovery. Since we can't know (b) ahead of time, we're left with either knowing ahead of time, or too late. Knowing sucks, but it sucks less than any other option.
- devit 9y agoSeems to have already been known in 1993, according to Wikipedia? "The best known genetic risk factor is the inheritance of the ε4 allele of the apolipoprotein E (APOE).[45][46]" where [45] is from 1993. What's new? Am I misunderstanding something?
- codeulike 9y agoThey know more about what happens at the protein level, and they can fix it by adding compounds that fix the errant protein
- epmaybe 9y agoI'll take a stab at explaining this. Neuroscientists and biomedical researchers, feel free to chime in with corrections. In biomedical researchers, the strength of evidence of your data correlates with how close it is to modeling the human body. So, in general, strength goes as follows: Animal cell cultures < animal tissue < in vivo animal models <= human cell culture < human tissue < in vivo human trials (phases 1-3) In this study, the researchers studied the ApoE4 subtype of the ApoE protein (involved in fat metabolism). The gene coding for this protein has been associated with greater risk of getting Alzheimer's disease then other subtypes, so it has been a target of study for a while now. These researchers cultured brain cells that were differentiated from stem cell lines. Here's how they did it: Skin from Alzheimer's patients and healthy patients (so apoe4 vs apoe3 containing cells) -> induced back to stem cell precursors -> differentiated into neurons What they found was the following: -neurons with apoe4 had production of Alzheimer's hallmarks (Tau phosphorylation, ABeta, neuron degeneration) -neurons with apoe3 had less to none of these changes. -editing the apoe4 gene to apoe3 prevented the changes from occurring. -gettig rid of the apoe4 gene completely prevented the changes from occurring. -giving a drug that changed the protein structure from apoe4 to apoe3 prevented the changes from occurring.
- epmaybe 9y agoI'm shamelessly pulling all of this from the paper abstract, which you should find here: https://www.nature.com/articles/s41591-018-0004-z https://www.nature.com/articles/s41591-018-0004-z As for what this means: it's exciting, and if these researchers can prove that the drug is safe in animals and humans they can probably proceed with trials on Alzheimer's patients with the apoe4 gene. But that's the thing: this discovery, while cool, is relevant to only some of the patients dealing with Alzheimer's that have the ApoE4 gene. This isn't a unifying mechanism to how Alzheimer's occurs in all patients, as it doesn't tackle the problem of patients with apoe3 getting Alzheimer's. Nonetheless it is still relevant especially for early onset, which is more strongly associated with this gene.
- zitterbewegung 9y agoHopefully the results can be generalized to other experiments? Possibly the techniques they used?
- exhilaration 9y agoDoes anyone know if the genetic testing companies like 23 and Me tell you if have the apoE4 gene mentioned in the article?
- pilom 9y agoYou can always take the test from 23andMe and then take your data to https://www.promethease.com/ https://www.promethease.com/. That's what I did and it told my my apoE status. They will tell you all the things that 23andMe is not legally allowed to as they are just looking up what is known in SNPedia. That said, the 23andMe test has unknown (or at least unpublished) false positive and false negative numbers for that gene so take any result with a giant grain of salt and if you're really worried about it, pay the real money for a real test.
- hgbrian 9y agoIt is published: https://www.accessdata.fda.gov/cdrh_docs/reviews/den160026.pdf https://www.accessdata.fda.gov/cdrh_docs/reviews/den160026.p...
- simulate 9y ago[Edited to remove incorrect, outdated info about apoE4 data] 23andMe offers information on ApoE4 now that they have FDA approval. You can also use Promethease to get additional information on SNiPs if you want. Here's how. 1. Get a DNA analysis from 23andMe or similar. 2. Download your raw genetic data. If you use 23andMe, you can download your raw genetic data here: https://you.23andme.com/tools/data/download/ https://you.23andme.com/tools/data/download/ 3. Upload your data to https://promethease.com/ https://promethease.com/ Before you do this, you might want to visit ApoE4.Info and consider what you will do with the information once you have it. https://www.apoe4.info/wp/thinking-about-testing/ https://www.apoe4.info/wp/thinking-about-testing/
- fredfl 9y agoThis is wrong info. 23andMe has reinstated the Alzheimer’s report as of last year.
- bawana 9y agoreally scary. Can you imagine the CIA create a small molecule that interferes with ApoE3 to give and ApoE4 phenotype?! Inducing dementia in terrorists and then allowing them to return home??!! or Inducing dementia in suspected spies? or inducing dementia on political dissidents? Or can you imagine the use of this small molecule (which btw is undetectable in the blood) for nefarious political purposes? Have the democrats already used it on our president??!!
- krapp 9y ago>Inducing dementia in terrorists and then allowing them to return home??!! or Inducing dementia in suspected spies? or inducing dementia on political dissidents? I mean... none of that would actually stop the terrorists, spies or dissidents. It wouldn't be any better than, say,getting stabbed with a ricin tipped umbrella[0]. >Have the democrats already used it on our president??!! No, unfortunately, he's just like that. [0]https://en.wikipedia.org/wiki/Georgi_Markov https://en.wikipedia.org/wiki/Georgi_Markov
- aaavl2821 9y agoThis is a nice article and is a great example of a few technological advances that are making now an incredible time to start a biotech company: massive increase in genomic data and advances in biology (in this case stem cells) to enable better modeling of whether things will work in humans It costs up to $2.6B to develop a drug. The majority of this is not out of pocket spend on developing the drug, but the cost of risk -- all the money spent on drugs that end up failing. The biggest driver of the cost of failure is failing in Phase 2. Phase 2 trials are the first test of whether a drug is effective in humans. Prior studies look at animal or cellular models of effectiveness, or safety in humans. It can cost $50-100M+ to get to phase 2 Genomic data is one of the most cost efficient ways to predict whether a drug will work in humans. certain mutations, like apoe4, are strongly correlated with disease risk and prognosis. Of course this does not imply causality, but researchers can tease this out with established models. Clinical trials of drugs based on genetic markers have greatly increased odds of success Genetic biomarkers also enable smaller studies -- rather than study big heterogenous population to find a signal, you can do so with a smaller homogenous population. This is all very important for Alzheimer's, a field where trials are big and expensive and failure is the norm The other advance is the ability to easily create neural cells from skin cells. As the paper says, mice are very different than humans, especially neurologically. But it's hard to study human neurons in the lab. The ability to turn skin cells into stem cells and then into other cells enables this (previously only embryonic stem cells were available). So researchers can perform experiments to determine causation in a model that is much better predictor than typical mouse models There has been a lot of work in cancer developing genetically targeted drugs, but it is not as common in other fields. Part of the challenge is getting enough data, and part of it is that data alone isn't enough, you really need the biological hypothesis to come first
- Andorin 9y agoAlzheimer's is not a neuron disorder. This paper should not have been published.
- mattkrause 9y agoCare to elaborate? I know there are theories that it's linked to inflammation (etc), but it clearly has some effect on neurons. It's not clear whether reversing those effects also reverses the disease (the anti-Abeta antibody stuff has been disappointing), but given that neurons are.....important for cognition, it doesn't seem totally insane to think that they are somehow involved in AZ too.
- rrggrr 9y agoRelevant link concerning attenuating Alzheimer's by a fat rich diet: https://www.mdedge.com/clinicalneurologynews/article/145220/alzheimers-cognition/fueling-alzheimers-brain-fat https://www.mdedge.com/clinicalneurologynews/article/145220/...
- mrfusion 9y agoIsn’t this also groundbreaking because we never previously know why apoe4 contributed to Alzheimer’s. What the mechanism was?
- throwawaymanbot 9y agoCouldnt crispr just snip these genes out?