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Comment by mjfl | Hacker News Reader

As someone who does research in biology and therapeutics, it seems to me that Alzheimer's research is such a dismal field. We don't have a good idea of what causes it, not only do we not have good animal models, we have misleading animal models which reflect some of the traits of Alzheimer's but nothing translates to humans. There was this mouse model they made which developed these plaques like in Alzheimers and they found they could clear them with brain stimulation pretty well - but trying it in humans there was no effect.

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> There was this mouse model they made which developed these plaques like in Alzheimers and they found they could clear them with brain stimulation pretty well - but trying it in humans there was no effect.

Rinse and repeat many times over, I think. This dynamic is what pushed me away from the field in general, the knowledge that I could spend my whole career working on a mouse model that there's reason for only tepid confidence in.

There’s a Twitter feed dedicated to this caveat

https://mobile.twitter.com/justsaysinmice?lang=en

For diseases where the causal mechanism is known very well, mouse models aren't that bad: Rett syndrome, hemophilia, spinal muscular atrophy.

It gets to be a problem where the disease is poorly defined and the cause is unknown: Alzheimers, schizophrenia, ADHD, etc.

It is very important that people have this discrimination power and not jump to "All of this is bad" or "All of this is good".

Also in a lot of cases it’s the best we’ve got. You might be able to use monkeys but even that doesn’t change a lot of the problems. If you move from animal models you aren’t going to suddenly be able to start experimenting on humans.

Very good point. I always considered that Twitter profile as tongue-in-cheek, rather than being outright dismissive.

Do you know if there are new ideas or techniques to go around that issue ? With printed tissue and new computational means .. I was hoping new roads would emerge.

Hopefully :) it's been 10 years and I haven't kept up on the topic.

Some of this has to do with the funding incentives in academic AD research. NIH continues to dump money into mouse and even more ridiculously Drosophila (fruit fly) models of Alzheimer’s. I am all for basic research but for this disease, if we have learnt one thing, it is that the success of a therapeutic in animal models is nearly 100% predictive of its failure in humans. The funding incentives need to change for meaningful change in the clinic.

Do you think that the "organ on a chip" method could help?

Having tiny human brains (or brainlets) would be a closer model than using any animal, or not?

Missing a lot of signals from the in vivo context - for example taking a naive approach to organoids typically means you’re going to be missing vascularization, which is essential for the architecture of the brain in vivo.

Also typically organoids present as very immature brains, whereas Alzheimer's patients sort of have "maximally mature" brains.

I’m not an expert, but suppose Alzheimer’s onset and progression is affected by the gut-brain axis. There’s no way for an organoid to capture that.

Yes, also hormones controlling e.g. sleep, which is essential for brain function.

> Do you think that the "organ on a chip" method could help?

Can we even reliably diagnose Alzheimer's based on brain tissue alone? If so, what do we look for?

I think tau protein is a correlate?

As far as I know, it can only be tested post-mortem but there is some research related to detecting it with blood tests.

Is there a paper on that? I'm so interested.

is Alzheimers akin to Depression in the sense its a umbrella term/abstraction?

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