Scientists Fix Genetic Risk Factor for Alzheimer’s Disease in Human Brain Cells
gladstone.org
gladstone.org
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.
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.
From the paper itself, this is what the researchers say: "These findings warrant further development of ApoE4 structure correctors and, ultimately, testing in clinical trials." So it looks like they want to move forward clinically.
One of the most widely used methods of "target validation" (determining a molecules / genes causal role in disease) is the knockout mouse model. Basically delete the gene of interest in the mouse and see what happens. This is great for determining causality if a gene. However, mice are different than humans.
Genomics allows us to observe "human knockouts / knockins ". This provides very strong evidence that a gene is implicated in disease. Apoe4 is an example, but the canonical example is pcsk9
I also want to quibble a bit with your "strength ranking": it dramatically understates the value of in vivo experiments in animal models. Animals do differ from humans in some known--and presumably other unknown--ways, and this has certainly caused issues in the past. For example, the subjects in the CB28-SuperMAB trial all became seriously ill despite successful tests in rabbits and monkeys.
However, a major advantage of in vivo data is that it can give you a "whole organism" perspective on a possible treatment. This ensures that the therapy is targeting the actual condition (cognitive deficits) and not just a biomarker/side effect/epiphenomena. As an analogy, you want to actually fix a car's engine, instead of just turning the radio up until you can no longer hear the misfires. The Alzheimer's field has had issues with this before. ABeta is associated with Alzheimer's disease. While it's possible to reduce Abeta levels (e.g., with an antibody), this does not seem to have much effect on the mental symptoms.
http://embomolmed.embopress.org/content/early/2018/04/04/emm...
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.
I subscribe to your opinion, however.
Eventually, she had to be moved to a nursing center where the health care costs are astronomical.
Of course no one wants to hear this news early, but in terms of preparations that can be made by family members, the earlier the knowledge the better.
When a family member is struck with an illness it does not just affect the individual, but rather the whole family.
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
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.
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/
3. Upload your data to 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/
If you are CC genotype for marker rs7412 AND marker rs429358 your status is APOE4.
Note that there are several other markers/genotypes that can reduce risk, but research appears to point to APOE4 status having the most impact. Also be aware that genetic reports could always have errors due to chance, operational errors, or problems with original research.
I made a script to examine the raw text dump from 23andMe. See the README for a list of interesting genes to check.
23andMe does have the raw data you can look up. You can use the raw explorer on the site or download the data to text and then examine it.
Recently they just got permission in the US to do some health screening again and now they let you opt in to a Alzheimer health section.
I find looking at the raw data to be easiest.
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.
> 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.
This was probably not the best example given the context. 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.
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.
"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?
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??!!
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.