I'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.
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.
That's a great summary, but I'll add one point. You could argue (and many people do) that strong genetic correlation (of one gene / mutation with disease) paired with in vitro / animal elucidation of causation is the second highest "level of evidence", second only to clinical trials. This is the core thesis of "precision medicine" and has radically improved success rates of science, drugs and startups
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
That's a decent summary of the paper, though it's important to note that the "structure corrector" is, at this point, more of a "compound"--there's a lot more work to be done before you'll be able to pick some up at CVS.
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.
I mentioned in a later comment that the researchers stated in the article that the small-molecule drug needs more work before human trials.
I think you and another commenter are correct in that in vivo animal models should be higher up in that ranking, especially since I have seen human cell culture evidence not line up with in vivo experiments.
Good overview. Does this mean that the next steps to confirming/expanding these findings would be to reproduce this result in neuron cells, rather than skin cells which were differentiated to neuron cells? What are the next steps required to move further up the evidence chain?
I'm not entirely sure. It seems, from the paper, that mouse models do not share the same phenotype with humans, so animal tests may not be all that helpful, except for some safety data. I'm not sure they will be able to culture actual human neurons from tissue, as that was only recently accomplished back in 2017.
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.
I'm not so sure it's a great time at all. Most alzheimer's drugs have failed dramatically. vTv Therapeutics is the most recent I think. They had a Phase 3 drug trial end early due to futility, and their stock tanked hard. In one day I think it lost 70% of its value.
Alzheimer's drugs have not been successful, but in general it is the best time ever to start a biotech company. Returns in biotech VC the last 5 years are better than tech, more IPO and big M&A (three $8-12B startup acq in last 4-6 months) even with 1/5 the funding of software, tons of great science out there, massive amounts of capital ($4B venture funding to startups in Q1)
As far as I'm aware the majority of failing biotech companies have very broadly targeted Amyloid beta (apparently because they thought it was a good risk tradeoff). A narrow focus on APOE4 could be a wiser strategy. I could even see gene therapy playing a role.
There 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:
Interesting 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.
My 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.
The only counter argument to this I could imagine would be the one I often hear used for other brain abnormalities; i.e. if the knowledge of a potential health problem instigates a mental health issue, ignorance could be better.
Knowing 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.
As 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.
As mentioned above, the main benefit could be for the family members. When my grandmother was diagnosed it took our family completely by surpise. She lived in another state and my elderly grandfather was the only one around to take care of her.
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.
This 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
[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.
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.
You can always take the test from 23andMe and then take your data to 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.
In addition to 23andMe, Rhonda Patrick has a website FoundMyFitness [1] where you can link your 23andMe account, and generate additional reporting on your 23andMe data, including info on APO-E3/E4 such as risk factors and dietary/lifestyle advice.
The 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.
Well, 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.
It'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.
> 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’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.
It 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.
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.
really 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??!!
>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??!!
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.