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Chemical clears Alzheimer's protein and restores memory in mice (nature.com)
452 points by coris47 on Dec 17, 2015 | hide | past | web | favorite | 138 comments



This is heartening news; if not a cure, at least it suggests a promising avenue for future research into this terrible condition.

This LiveScience[1] article is an easily read summary that also mentions a critique of the approach.

Given the unfortunate history[2][3] of falsified Korean scientific research, it would be prudent to withhold judgment until these results have been reproduced in other labs around the world.

1. http://www.livescience.com/53019-epps-chemical-washes-away-a...

2. http://www.nytimes.com/2009/10/27/world/asia/27clone.html?_r...

3. https://www.washingtonpost.com/news/to-your-health/wp/2015/0...


Ever since a family member was diagnosed with Alzheimer's, I've been paying attention to reports like these. Every other year, there is a paper about a major breakthrough, and surely a cure should be just around the corner any time now.

Every few years there is a paper that claims that we now finally know what causes the disease, and every time it's something different, and every time you never hear of a followup.

It's about 3 decades later now, and as far as I can tell, there is still no actual progress in the way of treatment. An alzheimer's diagnosis still means the same as it did in the 80's or in the 60's for that matter.

About this cure that is just around the corner. It came too late for my grandparents generation, it came too late for my parents' generation, it came too late for my generation, I wouldn't be surprised if it came too late for my children's generation. I don't believe in it any more.


When you realize that pretty much every disease and condition has similar papers written about it, you start to realize that the way we do medical research is pretty messed up.

Keep in mind that they still haven't really decided whether salt is bad for you or not, or what the real effects of dietary cholesterol are. Widespread conditions that should be much easier to research and understand than Alzheimer's are still very controversial.


you start to realize that the way we do medical research is pretty messed up.

The way the media reports on research (not just medical) is really messed up.


Both are true, IMHO, again returning to the dietary salt/cholesterol example. It is easy to point to peer-reviewed literature that backs up any point of view you want to take.

The scientific community needs to get its own act together before criticizing the popular media. Few other scientific disciplines are less reliable than medical research, and even fewer are more important.


"The way the media reports on research (not just medical) is really messed up."

Might have something to do with wanting simple answers. I notice this happening on HN.

If I add a new post where it's a general science article I post both the general article and the original academic paper. HN readers choose the general over the technical article most times except when it comes to HN technical areas of interest. The level of reader understanding may influence article choice.


Yup, I feel that.


This seems like a pretty unfair generalization of Koreans. Assuming all scientists have the same shameful characteristics of a few doesn't seem very scientific, does it?


I think it's more of a generalization of the Korean scientific community, of which most Koreans are not a part.


It is an unfair generalisation in both cases. The wiki list of scientific fraud examples is very heavy on US examples.


What's the ratio of U.S. scientists to Korean scientists? 10:1 or so? I would expect to see 10x as many fraud cases in the U.S.

But there have been some doozies in Korean science, especially the stem cell guy who really embarrassed and shamed his country with the extent of deception he practiced. Brilliant, but also crazy.


where is that ratio pulled from? your ass?

My point is that it was a generalization against korean scientists and a few instances is not representative of an entire group. Your point seems to be that the korean instances are somehow higher profile, but if that was the case then UK research science would be the worst because the vaccine/autism scandal has probably had the most far reaching after effects and infamy.


Approximately 10x as many scientific documents produced in the U.S. as in S. Korea.[1]

Ratio of U.S. to ROK scientists is about 6:1.[2]

OK, so # of scientists isn't 10:1. But in terms of scientific activity, the U.S. is far and away more productive.

1. http://www.scimagojr.com/countryrank.php 2. http://chartsbin.com/view/1124


And I would still call it an unfair generalisation.

It's almost as if you are saying that some fraud is to be expected and is therefore fine when actually any fraud is wrong.



Wow, talk about cherry-picking. And those both resulted in jail time. How about the "unfortunate history" of falsified research in other countries?

https://en.wikipedia.org/wiki/Scientific_misconduct#Notable_...

Do you feel the same way about US scientific research?


If the research misconducts are from Japan, China and South Korean, they would immediately become the top news in the major media in USA. If they are from Western countries, well, most of them didn't even get mentioned in the same media. That is how unbiased these media are.

BTW, I am not even talking about Fox News and alike. NYT, you are in the list. The journalistic integrity of your articles has been dropping like a rock.


Here is what happened when someone was believed to have committed scientific fraud in the US: http://retractionwatch.com/2015/11/07/its-official-anil-pott...


It seemed like everybody's journalistic integrity was dropping like a rock.



This is one of the realities of scientific publishing. Certain countries (like China and Korea) churn or large quantities of falsified research.


I wish I could vote this down. What does this statement really add except reiterate what was said previously?


If it's a slow thing that happens with aging (as some research suggests) then this might also be an anti-aging treatment to a small extent in that it might restore a little bit of the health of a younger brain.


Wow, you can buy some EPPS (the chemical in the article) here for £39.20?

http://www.sigmaaldrich.com/catalog/product/sigma/54465?lang...

Looks interesting research but I'm sure this stuff probably can't be that good for you!


Pretty sure Alzheimer's isn't good for you, either.

I'd take any health risks over dementia, personally, and I'm sure most would, too. Looking forward to the FDA blocking this on "safety" grounds.


It's amazing to me that people are willing to experiment with an unapproved chemical that provides no proven benefit in humans, yet aren't willing to use human-proven therapies with known benefits such as statins.


Well, it's not for a sore knee. Is there anything more unapproved than an irreversible disease that destroys your mind in the space of a few years? It's not like cancer, from which you might be cured, or at least with which you can have a meaningful life until your eventual death. It is a slow motion process of erasure that is well on its way at the moment of the first diagnosis. Taking the wrong medicine could shorten your brain's life of how much, a year perhaps? Still worth trying.


Taking chemicals which haven't been made for human consumption and haven't been tested thoroughly could render you dead much faster than that.


Dead can to be honest be better than full blown Alzheimer's.


This. If there's a 10% chance it works and you don't die, I bet a lot of Alzheimer's patients would jump on it.


Some people go to Switzerland for specific chemicals to render them dead as fast as possible, since they see it as preferable to living with Alzheimer's.

Admittedly it seems like a bit of a gamble to just start popping drugs whether they've been studied or not, but people spend lots of money on "natural" supplements which are at least usually reasonably safe but are even less likely to work.


Alzheimer's is such an awful way to go, I can see how people would chance it.


When it comes to rapid onset dementia, that's a risk many people are willing to take.


Yes, obviously. But what about new chemicals where testing has been done, without significant observed damage? Is that considered safe after enough observations, or would a single fatality skew your risk-minimizing behavior?


If I was slowly losing my mind, I'd even try experimental drugs that came with a 20% chance of sudden death.

There's not much worse than having your mind die while your body is still alive.


But perhaps it has other nasty side effects, maybe another 20% to get instant dementia.

Just to pick another unrelated chemical example that is well known, 30ml of methanol will kill you but 10ml will make you permanently blind.


> 30ml of methanol will kill you but 10ml will make you permanently blind.

How is this relevant?


Presumably these "people" you speak of are actually different people (unless you have evidence of the parent choosing not to use statins?)

People tend to vary wildly in choices and opinions. Who knew!?


>> People tend to vary wildly in choices and opinions. Who knew!?

But some people think their choice or opinion is somehow the "correct" one and should be imposed on everyone ;-)


provides no proven benefit in humans

I know there's very good reason to be wary of mouse models, but in cases (as this appears to be) where the physiological mechanism of disease is both (a) understood and (b) the same from mouse to human, a little less skepticism may be warranted.


I think the point has more to do with side-effects than efficacy. Your argument misses this point entirely.


Not really. Side-effects aren't to be observed in a vacuum.

We should be far more concerned about side-effects of a drug intended to treat acne or erectile dysfunction than for drugs targeting life destroyers such as cancer and Alzheimer's.

At some threshold of disease viciousness, society (and the FDA) should relax substantially on the risk-aversion, because the patient is already facing the worst-case scenario.


>At some threshold of disease viciousness, society (and the FDA) should relax substantially on the risk-aversion, because the patient is already facing the worst-case scenario.

This is a fair point, but the rest... well ... still manages to miss the above argument. Side-effects aren't observed in a vacuum, but efficacy is still observed in laboratory conditions, so we really can't comment on whether (or how) this molecule affects other systems.


Mouse models are rapidly becoming obsolete as it's becoming easier than ever to model entire, differentiated tissues grown from red blood cell-derived adult stem cells.

It's also now possible to do clinically-useful testing of targeted treatments using genetically-edited control tissue cultures against unedited tissue cultures.

The point is that it's better to test something that is as close to the patient as possible, not guess with other species or even other people whom express genes differently.

FYI: making a new mouse models requires lots of chopping off heads of mice whom don't possess the desired gene. While transgenic, highly-edited living models might be nice, there's probably a more humane/simpler/reproducible way to do the exact same thing.


>>Mouse models are rapidly becoming obsolete as it's becoming easier than ever to model entire, differentiated tissues grown from red blood cell-derived adult stem cells.

No they aren't. Transgenic mouse models are a $billion industry. We do not understand biological mechanisms nearly enough to not use live animal models. We are not even able to recreate single cell organisms with our level of knowledge and engineering.

>>FYI: making a new mouse models requires lots of chopping off heads of mice whom don't possess the desired gene. While transgenic, highly-edited living models might be nice, there's probably a more humane and simpler way to do the exact same thing.

Ah, the real root of your argument. Do you even know what the word humane means? I work in a labroatory and the animals are treated better than the people. Yes, a lot of mice are killed.. but for a reason. You say there's probably a simpler way to do the exact same thing, but there simply isn't. I wish more people were actually educated in this matter, but emotional responses tend to get more results.


Not only that .... chopping off heads isn't how mice are terminated, from what I've been told by someone who worked in fetal development research on mice.


I always assumed that the sacrifice method depended on the research. You might liquefy them in a centrifuge, or pith them with a probe, or asphyxiate them in pure gaseous nitrogen, or flash freeze them in liquid nitrogen. Whatever makes sense for the study.

But if the animals in question are not part of the study at all, I don't see how it matters much. Maybe there's a little mouse guillotine. Maybe one person on the team owns a reptile pet that is very well fed. The reason why rodent models are used in the first place is that they're mammals, easy to care for, breed, and handle, and no one really cares if they die by the millions.

If they were outside the lab, they would likely get poisoned or crushed by snap traps. (That's better than what a cat would do.) Cuteness won't save you from my wrath if you eat my food and then poop in whatever you left behind. At least the ones that died in the labs had real jobs, instead of living hedonistic freeloader lifestyles inside someone else's couch.


Overcompensating by treating animals well isn't a valid rationalization for anything which comes next, regardless of benefit.


So the human lives saved would be the valid rationalization.


I work for the Stanford Med School, so where do you work?

But regardless, you're rationalizing your own biases and agendas on outdated techniques and racing to the bottom with a disrespectful, ad hominem approach. How pleasant and humane of you. Maybe you should look to the future instead of attacking what isn't in your narrow focus, because you come across as a troll.

Watch this, and learn something: https://youtu.be/ilVjSnE5t44


I think what you're responding to is NOT about willingness to experiment with unproven drugs, but rather a feeling of horror about dementia and Alzheimer's disease. These are awful afflictions that impact not just the victims but also their families.

That said, regardless of whether or not they're proven/approved/tested, drugs are never magic bullets. The ones used to treat the most serious chronic diseases always come with serious risks and profound side-effects. I don't expect that to change anytime soon.


Hippies often did the same thing. It's pretty dumb to just throw compounds in your body without having a guestimate about their effects.

In the future, medical clinicians won't have to guess as much because adult stem cells can now be created from red blood cells, allowing personalized medication with a petri model of actual patient tissue, to screen problems like interactions and allergies before administration.


The Cochrane report on statins confirms your claim: http://www.cochrane.org/CD004816/VASC_statins-for-the-primar...


There's a lot of subtlety when it comes to statins:

"Statins are beneficial, but some have questioned whether their benefits are due to their ability to lower cholesterol or to their anti-inflammatory effects, or both. There are two competing hypotheses, the LDL hypothesis and the statin hypothesis. A new study in The New England Journal of Medicine sheds some light on that controversy and tips the balance in favor of the LDL hypothesis."

https://www.sciencebasedmedicine.org/update-on-cholesterol-a...


Maybe they are not the same people?


I expect there is a Venn diagram that would cover this small subset of people that fulfill your 2 requirements but most people probably fall into one or the other.


Dementia is death a little bit at a time. At that point you really don't have much to lose by trying an experimental drug.


Many people are quite cynical about Big Pharma


How many of those people would trade the portfolio of medications available today for those available in 1955?


Nobody, of course. But would you prefer not to have drugs of dubious effectiveness marketed like consumer products? It's not an either or choice.


I would definitely prefer not to have chemical compounds that haven't been demonstrated effective marketed as consumer medical products. I'm not sure how that connects to the thread, though.


> demonstrated effective

While there are some drugs that are clearly effective, there are big problems in Big Pharma's approach to clinical trials, including burying half the trials' results and poor experiment design. And once a drug makes it to market, expanding that market without testing becomes a priority. Do you think Risperdal was a one-off, or is it a representative case study of how drugs are marketed by at least a major part of Big Pharma?


Yes, those people don't experiment with dangerous chemicals, instead they happily give their dollars to big placebo!


Being cynical about 'Big Pharma' does not mean that you support <insert pseudoscience/buzzword category here> placebos, and does not mean that you do not support honest scientific efforts.

For example, Ben Goldacre. He is cynical about 'Big Pharma', and has written about it in one of his books[0]. At the same time he appears to support efforts to open up private medical research -- he recently cofounded AllTrials[2] along with the BMJ, Cochrane, PLOS, and a few other high-profile reputable sources[3].

[0]: https://en.wikipedia.org/wiki/Bad_Pharma [1]: http://www.cochrane.org/ [2]: http://www.alltrials.net/ [3]: http://www.phc.ox.ac.uk/news/ben-goldacre-joins-oxford-unive...


Most people would take "be at risk of health problem" against "not lose your mind". The question (and the effect in both sides) are still worth asking


You would probably want some help administering it via intracerebroventricular injection.

(http://www.ncbi.nlm.nih.gov/pubmed/19558257)


Don't have the paper in front of me, but IIRC, the test dose ranged from 10mg/kg to 100mg/kg. A branch of the study looked for adverse effects at 2000mg/kg and found none. That indicates a very large therapeutic margin. Of course it's in mice, not people....


Edit: Ok, ok, I totally screwed that up. Damnit. Sorry, everyone. Grams aren't kilograms. The freaking base unit shouldn't have a prefix.

2000mg/kg = 2, right?

Like 2kg of medicine for every one kg of body mass? That seems impossible to consume. Even 0.1 kg/kg seems really, really high.

Or is mg here used for micrograms rather than milligrams? So it's actually 2000 μg/kg.


2000 mg is 2g (a kg is 1000g, or 1 x 10^6mg)

Have you worked on software for NASA Mars probes in the past?


Err.... NASA software, yes. No Mars probes yet.

Yeah, I know, I know.


I really need to be less sarcastic.


It was the perfect comment.


I concur entirely. You had ought to be ashamed of yourself.


2g of drug per kilogram of body mass. That's not the therapeutic dose, that's the safety limit.


2000mg = 2 grams not 2 kilograms. So it would be 2 grams per kilogram.

2kg = 20000000mg.

Hope that clears that up.


Wrong. 2000mg/Kg = 2g/Kg, two grams of the chemical per kilogram (1000g) of the subject. To give you an idea, that's 160g of chemical for an 80Kg human. Quite a lot, but nowhere near impossible to consume...


Actually it's just something between 0.8g and 8g, 160g is a safe limit, not the therapeutic dose.


> 2000mg/kg = 2, right?

No, 2000mg/kg = 0.002

> Like 2kg of medicine for every one kg of body mass?

No, 2g for every kg of body. And that's some safe limit, not therapeutic dose.

> Or is mg here used for micrograms rather than milligrams?

No, it's milligrams.


If you use this on someone else with Alzheimer's and they die or are injured, you will almost definitely go to jail. You could likely use it on yourself, but look at it as an extreme, it is still less bad than suicide I suppose... But you don't know what the side effects could be.

It kind of scares me that people think they can buy untested chemicals online and self-medicate with them. But then again I'm not into the whole "Bath Salts" scene which is all about that.


It kind of scares me that people with terminal or completely debilitating diseases don't have widespread access to whatever experimental treatments are available. Imagine watching yourself die and reading articles about promising treatments you are unable to obtain. That is scary.


There's a thin line between an experimental treatment with some potential merit being trialed on vulnerable people, and a mad scientist just trying things "to see what will happen."

A lot of terminal people have, historically, had pretty terrible things done to them on the guise of "well they were going to die anyway!"

I for one welcome medical and academic oversight of experimental treatments. Terminal people are especially in need of protection as they will grasp to any hope no matter how slim or misguided.


The line is even thinner when it is some issue that impacts a persons ability to reason. An old person who is mentally all there can make an informed decision if they think the offered treatment is an actual attempt at a cure or some mad scientist's plaything, but someone with dementia is far less able to reason about such.


If you haven't seen it already, I highly recommend The Knick, a show about a doctor in the early 1900s, directed by Steven Soderbergh. It deals with these kind of issues.


An additional issue: While I am interested in an experimental drug and have no issues with its risk of death, my children / wife / family may choose to hold the drug liable in the case I die. I could make it as clear as possible that I would not hold the drug liable but if I die those words don't matter.


>It kind of scares me that people think they can buy untested chemicals online and self-medicate with them.

It kind of scares me other people would presume to dictate what I can and can not put into my own body.


In mice the curative dose was 20x smaller than anything that brought on toxicity. We can only hope people respond similarly.


Shows 137.50€ here :D


4,265.99 CZK ~ 157.82 EUR (Czech Republic)


$175 here (Netherlands Antilles, Bonaire)


Same (137.50€) from Italy


143.50€ here... (Spain).


158 euro here. (Morocco) maybe a pricing algorithm that increases price based on demand?


Or based on the existence of positive research papers ;)


If you go digging around you'll find dozens of other similar results in the past five to ten years for dozens of various compounds, some of which produce larger effect sizes than this one. This is nothing to get excited over.

It is interesting the way in which various groups leap upon some research reports but not others. The challenge is always having the context for the broader state of research to understand whether it is meaningful or new or not.

The present mainstream view of Alzheimer's is that amyloid (and tau) clearance is the way to go. Immunotherapies are the most developed tool, but that is so far proving to be hard - it is too early to say whether failures in clinical trials are because it is hard or because amyloid clearance isn't as useful as thought in this condition. Which could be for any number of reasons including that amyloid-related biochemistry is the problem, but clearing a particular variant or stage of its aggregation doesn't touch that problem area.

Amyloid levels in the brain are in fact highly dynamic on a very short timescale. That Alzheimer's develops slowly supports the view that the condition is a slow degeneration of natural clearance mechanisms, such as the filtration performed by the choroid plexus, or the more recently investigated peristaltic passage of fluid out of the brain by other channels. E.g.:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4245362/

On that latter point, the Methuselah Foundation just a few days ago seed funded a startup company that will investigate whether reversing the degeneration of peristaltic fluid passage with aging will improve clearance and thus stop the progression of Alzheimer's. It's based on as yet unpublished work by Doug Ethell at GCBS Western who presented at Rejuvenation Biotechnology 2015 ( http://www.sens.org/files/conferences/rb2015/RB2015-Program.... ), and has the merit that it should be a fast failure if the theory is wrong, unlike many of the other efforts in Alzheimer's research.


Just because I agree with most of your points and there seem to be some overexcited responses to the OP, here are two papers for anyone interested, summarising Aβ and tau [0] and some failures of Aβ therapies [1].

[0] http://www.nature.com/nrn/journal/v12/n2/abs/nrn2967.html [1] http://www.nature.com/nrneurol/journal/v9/n12/full/nrneurol....


The title is "EPPS rescues hippocampus-dependent cognitive deficits in APP/PS1 mice by disaggregation of amyloid-β oligomers and plaques" and it does not say that it reduces memory, it says "EPPS reduces Aβ-aggregate-induced memory deficits in mice" but they also say that "We observed substantial rescue of working memory deficits in Aβ-infused mice by EPPS treatment".

Of course this is only small part of the paper and I have no training to appreciate it more.


I'm not an expert either, but as far I can see:

The diagramme showing how much memory is recovered is figure one. White is before the administration of the "Alzheimer's protein" (AB protein), black is without the new clearing chemical, blue is with it, and then the different blue columns showing different concentrations. Fig 1c is prophylactic treatment (clearing molecule administered before, during and after the AB protein), Fig 1d is clearing molecule administered alongside AB protein. The impairment seems to more or less recover fully back up to where it was originally, in all four combinations of timing and clearing molecule concentration.

But bear in mind:

* The mouse model for Alzheimer's seems to be very, very simplified - as far as I can see they literally inject big doses of these proteins directly into the brain in order to induce Alzheimer's like symptoms, that doesn't mean this is equivalent at all to the complex chemical processes underlying Alzheimer's. AB proteins are observed in Alzheimer's patients, but they are also observed in healthy patients, and other proteins are also seen in Alzheimer's patients, some of which are recently thought more likely to be the underlying driver of the disease.

* All of this occurs over a very short period of time. Someone who has developed symptoms of Alzheimer's will have had the disease process occurring for many years beforehand. Recovery a few days after administration of the protein doesn't mean that damage would be recoverable years later.

Edit: I'm actually just looking at the first experiment, they also do longer term trials with a mouse model which has been genetically altered to over-expresses the AB protein. Arguably this is still a very over-simplified model, but it does more to address the time question. They say Alzheimer's symptoms usually develop at 5 months, then they administer the clearing molecule at 10.5 months for 3 months. Those experiments shows about half the deficit being recovered relative to normal age-matched mice.


Yeah, good highlight. My skim seems to indicate it means working memory too. That's a different concept than the kind of memory lapses most people associate with Alzheimer's--more about holding information in your head long enough to process in a subsequent step or file in long-term storage.

It's one of the major deficits in ADHD, to the extent that clarifies what the effects might be.


it's a great day for mouse health


Relevant West Wing dialog:

MARGARET

Let me ask you this...Red meat has been found to cause cancer in white rats. Maraschino cherries have been found to cause cancer in white rats. Cellular phones have been found to cause cancer in white rats. Has anyone examined the possibility that cancer might be hereditary in white rats?

DR. GRIFFITH

Let me tell you something, I'm not 100% sure we've ruled that out.


Reminds me of a lecturer I had in a neuroscience class that informed us that "no one really checked whether all neurons had the same constants as the ones from the giant squid, but just assumed they did" (or something similar). Apparently anyone who thought of it assumed that something so blindingly obvious would already have been examined by someone else. It took decades before the error was found.


You say that tongue in cheek, but as a non-scientist, I've always wondered how much "mouse science" ultimately translates to humans. My guess is it's very low, but knowing a percentage would help me better understand how to proceed reports like this.


It depends on what kind of science it is. Mice are very very similar to humans at a chemical level. They have a similar genome, their bodies are basically the same as ours, they have the same organs, the same blood, the same cells, and the same chemical processes happen in those cells. They are just a bit smaller and arranged in a different way. That explains why scientists use mice as models for humans at all. However, with diseases that happen mostly in the elderly like Alzheimer's and cancer it's not so clear. Mice die at a young age, before those diseases really happen. Mice have to be genetically manipulated to develop those diseases. The development of those artificially caused diseases may not be the same as the development of those diseases in humans. The mice also still have a young body despite having the disease. This makes healing them a lot easier.


Mice are ~30% similar genetically to humans, so a surprising amount of transfers. Rats are a bit more similar IIRC, but mice breed quicker so it's easier to do bigger studies...

Source: Used to work in mouse research on addiction (alcohol, cocaine, nicotine, etc).

Edit: This link gives even more specifics on the similarity: https://www.genome.gov/10001345 -- 30% is probably accurate, but in terms of function, it's even higher.


30% similar? Didn't we find that bananas share 50% of genes with humans?


that would explain a lot



If it were that low, we would not use them as models.

Also bear in mind that mouse models are merely part of a large set of animal models that we use: https://en.wikipedia.org/wiki/List_of_model_organisms#Verteb...


We can also make older mice young again:

http://www.businessinsider.com/scientists-make-old-mice-youn...

The real problem with medicine is that there's no easy way to have "agile" and rapid iteration in humans. Drugs, for example, take decades and billions to get to market.


You have a good point. Keep in mind that this is a mouse model of Alzheimer's disease. That is, these mice have a genetic defect that causes similar changes to that seen in human Alzheimer's disease. These mice do not have the same disease as in humans.


I am having an epiphany. Maybe this "Alzheimer protein" is supposed to be the brain's defenses to something much worse. Maybe this protein is a "reaction" similar to skin rashes when it absorbs poison ivy's urisol.

If Alzheimer was simply a deficiency of nutrients, I wouldn't think this way, but if it really is a protein that "can be cleared", why did it get there in the first place?


I wish I had more time to follow up on this but I'll write what I can think of.

Your core question is a good one and fundamentally raises the question of causality (which came first, the A-beta or Alzheimer's disease, AD? See ref. 1 for a 'simple' discussion).

Interesting evidence comes from people with genetic mutations that decrease the levels of the precursor to A-beta (the protein associated with Alzheimer's plaques). People with these mutations are less likely to develop AD, suggesting that A-beta is related to the root cause of AD. The OP supports this evidence, as removing A-beta plaques ameliorates some memory loss.

As a final, unrelated note, I don't know much dermatology but I haven't gotten the sense that our response to uroshiol is considered protective. Unlike A-beta, uroshiol is directly causative of its associated clinical symptoms[3].

1. http://www.mayoclinic.org/diseases-conditions/alzheimers-dis... 2. http://www.ncbi.nlm.nih.gov/pubmed/22801501 3. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC294319/


>Maybe this "Alzheimer protein" is supposed to be the brain's defenses to something much worse.

What could possibly be worse? What are we seeing from non-Alzheimer sufferers that's so terrible? I don't think there's any evidence here that there's some benefit to it. Its a horrible disease.

My dad went from occasional forgetfulness to completely falling apart in less than two years. He would get lost routinely, couldn't remember names, had no idea what time or day it was, and developed sundown syndrome where once 6pm hit he completely went mad. He would be angry at nothing and scream at the mirror. He would rant and ramble about his past or strange conspiracy theories. Towards the end, he lived in some weird nightmarish state almost all the time. Sundown syndrome became his norm. He died of cancer before it progressed past that point, but man, this disease is not just losing memories. It pretty much destroys your brain and acute dementia has a link with immune system dysfunction, so it eventually kills you, usually by pneumonia.

I doubt there's any benefit. Evolution isn't this wonderful process. Its a lot of crap thrown at the wall and enjoying the stuff that works and dealing with what doesn't. There's no mastermind or clockmaker here. There are a lot of things that go wrong with human health that has no benefit.


What I understood from the PopSci that passes HN every now and then is that the 'Alzheimer protein' is just some normal protein that the brain makes during normal operation every day. In your sleep the brain contracts and 'flushes it out' somehow, but over the years the protein accrues and you suffer dementia. Obviously that's super oversimplified and probably wrong, my source being skimmed over PopSci and all.

Since dementia is a disease that happens at a late age, there doesn't need to be a reason why it is there. It happens a long time after reproduction, so its effect on evolution is minimal, worse it could even be evolved as a mechanism to curb older specimens in the species.


There's a growing body of evidence that Alzheimer's is really just "Type 3 Diabetes":

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2769828/


I'm not an expert, but human lifespans have only risen to relevant heights very recently. It's simply not enough time for it for evolution to kick in.


Average life expectancy is a commonly misunderstood (and widely misrepresented) concept. We hear things like "Humans really only lived into their 40s in the Stone Age," or what have you. This is untrue.

Average (arithmetic mean) life expectancy was a lot lower because it was heavily skewed by infant mortality. Up until very recently, many more babies died within their first few years of life. We've dramatically improved our ability to produce and distribute food and medicine, which has had a profound effect on infant survivability. But we haven't actually lengthened the average life expectancy of an adult who survives the first few years of childhood by all that much.

Point is, plenty of people have been living into their 70s, 80s, and 90s for as long as we've existed as a species. That said, the prevalance of diseases like Alzheimer's might be a fairly modern aberration, perhaps owing to lifestyle, environmental, and dietary factors.


"That said, the prevalance of diseases like Alzheimer's might be a fairly modern aberration, perhaps owing to lifestyle, environmental, and dietary factors."

Also somewhat owing to the recognition of Alzheimer's as a disease state (coincident with amyloid beta plaques) rather than just part of "getting old". The difference between "more prevalent" and "better identified" is difficult to determine.


That's a totally fair point.


Many more people are living in to their 70's, 80's and 90's than previously in human history. While our lifespan may not have increased much, the proportion of people reaching the extreme ends of our lifespan continues to rise. It's not just about infant mortality (not to mention death from childbirth).


"Many more people are living in to their 70's, 80's and 90's than previously in human history."

Correct, though largely (not entirely, but very largely) because the proportion of people living past age ~3 has skyrocketed. Correct for that factor, and our life expectancy is actually lower than it was in, say, mid-Victorian England.

(Note, as well, that I'm referring to life expectancy and not, say, the potential maximum human lifespan).


For evolution, what is important is that you survive and have good health long enough to have offsprings. The vast majority of people, even in modern times, have their children before 50 years old (because women have this hard limit in their fertility). So there was never an evolution pressure to make our body function propertly after that time.


Children who don't have extended family, such as grandparents, to care for them are more likely to die, either of of predators (if parents are out hunting) or of hunger (if parents stick around to protect their children).


Wow, they've prevented Alzheimer's in healthy mice, and restored memory function to sick Alzheimer's affected mice. The treatment is non-toxic at ridiculous levels too.


There have been at least 3 previous solutions for AD in mice which have never panned out in humans.


Source?


Actually its more like 300 treatments that haven't panned-out...

‘Too much good news’ – are Alzheimer mouse models trying to tell us how to prevent, not cure, Alzheimer’s disease?

https://www.ncbi.nlm.nih.gov/pubmed/?term=20542579


I would like to point out that the main study described in this article is not the "inject aggregated amyloid beta fibrils" that is described first. That study was a preliminary study that prompted the main study which uses genetically altered mice.

The test for alzheimers for the first study (previously reported but summarized again) was to quantify how much the mice deviates from solving a maze that they have been trained to solve.

In the first they injected amyloid beta aggregates into mouse brains and found that EPPS administered orally at 30 mg/kg and 100 mg/kg restores the ability of the mice to efficiently solve the maze.

Next they tested toxicity quantified the amount of EPPS that passes the brain/blood barrier. For toxicity they found no signs of toxicity at 2000 mg / kg (20x dosage). For blood/brain barrier, as you go up in blood concentration you should go up in brain concentration if there is a good penetration from blood to brain. If the barrier is high then you immediately get high blood and low brain concentrations. The point where there is no longer a significant increase in brain concentration when increasing blood concentration is used to determine effective dosage concentrations. They found that at 100 mg/kg they were starting to see increased blood/brain ratios so they targeted 10-100 mg/kg for the next study.

MAIN STUDY (which included identifying the dosage level) used mice that were engineered to "get Alzheimer's" starting around 5 months of age because they produce a human gene (transgenic) that is a precursor to form the AB plaques. This transgenic model is established and the mice showed the expected amyloid beta plaques and had difficulty solving the maze at 10.5 months as expected.

Starting at 10.5 months they gave oral doses of EPPS at 10 mg/kg and 30 mg/kg and monitored maze solving along with several additional tests: likelihood to freeze when presented with negative input (fear conditioning) and ability to find hidden platforms when swimming (water maze). Both tests improved significantly to the wild-type (no Alzheimer's) level when taking EPPS. They also did dose dependency at .1 1 and 10 mg/kg. There was a steady improvement at higher doses.

They also took slices of the mouse brain and tested whether or not the neurons responded differently to electrical stimulation. They found no difference in wild-type (WT, non-genetically altered) or transgenic (TG, altered) response to electrical stimulation with and without EPPS. This hints at no difference in neural activity with or without EPPS. They also gave EPPS to WT for the behavioral tests and did not see a difference (although that was not shown in the behavioral test figures).

They also took slices of the brain and stained them with a fluorescent dye to show the Alzheimer's associated plaques. There is a significant quantifiable reduction in plaques in the treated mice.

They used several other techniques to confirm that they were actually AB plaques and they disaggregated by a specific site of activity. I won't go into those specifics, but to say that this was a VERY well designed and executed study across multiple lines of inquiry and all of the lines of inquiry point to the same conclusion:

EPPS rescues hippocampus-dependent cognitive deficits in APP/PS1 mice by disaggregation of amyloid-b oligomers and plaques

And that's why it's a Nature article.


Excellent summary for those of us without enough will or ability to read the original article. Thank you, good sir.


A slightly unrelated question; are there any companies out there that are working on a replacement for mouse models in disease research?

I'm think more in terms of computer simulation?


Yes, but it's incredibly complicated.


Perhaps Pinky can now stop asking Brain what it is they will be doing tonight!


BUT it makes for pet chimpanzee super smart and and ruins human civilization, setting up en epic battle between apes and men.


Ginkgo Biloba [1] is very solid at helping preventing Alzheimer's, even in some cases slowing it down when it's already occurring. Lots of research on the benefits of Ginkgo. Yet most don't know about it.

[1] https://duckduckgo.com/?q=ginkgo+biloba+alzheimer+site%3A.ed...



Quotes to save the clicks...

> The dietary supplement Ginkgo biloba was found to be ineffective in reducing the development of dementia and Alzheimer’s disease in older people

> The GEM study—the largest of its kind to date—was a randomized, double-blind, placebo-controlled clinical trial of 3,069 community-dwelling adults aged 72 to 96,

> Compared with placebo, ginkgo did not lessen cognitive decline. Researchers found no evidence of an effect on cognitive decline in general, or on memory, attention, visual-spatial construction, language, or executive functions. There were no differences by age, sex, race, education, or baseline cognitive status.


Major studies of ginkgo show minimal, if any, benefits.[1] It has not been proven that there are "very solid" benefits of this substance, thus far.

http://www.mayoclinic.org/diseases-conditions/alzheimers-dis...


Well, I guess everyone loves ideas that re-enforce their own personal beliefs, instead of looking [1] up [2] the various [3] studies that prove this, all you had to do was click through five links and you'd have enough information to dismantle these very common, but unscientific, perspectives. No worries. I'll do the work for you guys since many are just lazy. Here are a handful [4, 5] of sources.

It's pretty clear that Gingko DOES work. Low doses (120mg), don't. But that's why I linked to the plethora of research to look into the matter.

Finally, source four just makes me laugh because it's clear as day from UMM, that Gingko does work. Also, there are many many more sources that speak to the benefits of Gingko for cognitive repair and slowing down decay. Please don't limit this discussion to the five I listed, hence why I originally linked to search results.

Sources (with brief snippets of importance):

[1] http://www.ncbi.nlm.nih.gov/pubmed/26268332 "Ginkgo biloba is potentially beneficial for the improvement of cognitive function, activities of daily living, and global clinical assessment in patients with mild cognitive impairment or Alzheimer's disease."

[2] http://www.ncbi.nlm.nih.gov/pubmed/12244890 "Metaanalysis in the indication--demential disorders--comparing Ginkgo biloba versus acetylcholinesterase inhibitors have shown a similar clinical efficacy of both therapy regimens with an additional drug safety benefit for Ginkgo. Due to the clinical efficacy the WHO accepted Ginkgo biloba as an antidementiv drug and add it in January 2000 into the recent ATC-Classification Index."

[3] http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0072541/ "The studies showed that people who took the higher dose of the ginkgo extract (240 mg per day) were better able to perform daily activities again, like doing household chores or washing themselves."

[4] http://umm.edu/health/medical/altmed/herb/ginkgo-biloba "Ginkgo is widely used in Europe for treating dementia. At first, doctors thought it helped because it improves blood flow to the brain. Now research suggests it may protect nerve cells that are damaged in Alzheimer disease. Several studies show that ginkgo has a positive effect on memory and thinking in people with Alzheimer disease or vascular dementia."

[5] http://www.ncbi.nlm.nih.gov/pubmed/12519586 "Overall there is promising evidence of improvement in cognition and function associated with Ginkgo. "




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