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(Reposting again since it wasn't noticed ~1.5 months ago.)
This paper looks really good.
Amyloid beta has long been implicated in Alzheimer's. Now they've found a way to trigger the disease by generating amyloid in the liver and shown that it can reach the brain (by crossing the blood brain barrier). This setup was shown to trigger the disease. It's a very plausible mechanism that worked end-to-end and seems to fit all of the observational evidence we've gathered.
The paper: Synthesis of human amyloid restricted to liver results in an Alzheimer disease–like neurodegenerative phenotype
https://journals.plos.org/plosbiology/article?id=10.1371/jou...
Abstract:
Several lines of study suggest that peripheral metabolism of amyloid beta (Aß) is associated with risk for Alzheimer disease (AD). In blood, greater than 90% of Aß is complexed as an apolipoprotein, raising the possibility of a lipoprotein-mediated axis for AD risk. In this study, we report that genetic modification of C57BL/6J mice engineered to synthesise human Aß only in liver (hepatocyte-specific human amyloid (HSHA) strain) has marked neurodegeneration concomitant with capillary dysfunction, parenchymal extravasation of lipoprotein-Aß, and neurovascular inflammation. Moreover, the HSHA mice showed impaired performance in the passive avoidance test, suggesting impairment in hippocampal-dependent learning. Transmission electron microscopy shows marked neurovascular disruption in HSHA mice. This study provides causal evidence of a lipoprotein-Aß /capillary axis for onset and progression of a neurodegenerative process.
We knew amyloid beta was highly associated with Alzheimer's. We've been studying this for decades.
The researchers noticed amyloid beta was found in lipoprotein complexes (fat+protein), then experimentally modified the liver to produce it. The protein leaks out of the liver and causes neurodegeneration.
Insight into how blood Aβ increases risk for AD comes from findings that in humans, greater than 90% of blood Aβ1–40 and 97% of the particularly pro-amyloidogenic Aβ1–42 is associated with plasma lipoproteins [3], principally the triglyceride-rich lipoproteins (TRLs) of hepatically derived very low-density lipoproteins (VLDLs) and of postprandial chylomicrons [4,5]. Direct evidence of a peripheral TRL-Aβ/vascular risk pathway for AD comes from studies in preclinical models, which show that cerebral capillary amyloid-angiopathy, a common early neurovascular pathology of AD, may be a consequence of parenchymal extravasation of TRL-Aβ.
This implicates fatty acids originating from the liver migrating (extravasation). And they just experimentally reproduced this.
Some quotes from the linked article:
“This study,” he added, “shows that exaggerated abundance in blood of potentially toxic fat-protein complexes can damage microscopic brain blood vessels called capillaries and, thereafter, leak into the brain, causing inflammation and brain cell death.”
“[Changes] in dietary behaviors and certain medications could potentially reduce blood concentration of these toxic fat-protein complexes, [subsequently] reducing the risk for Alzheimer’s or [slowing] down the disease progression,” he concluded.
This would suggest that liver health and diet can play a factor in disease development.
Of course there's the chance that this is just a really good "biologically plausible" mechanism that looks good on paper, but might not naturally occur outside of this experimental setup. There will need to be much more research to either prove or rule this out.
This looks exciting though.
I'm curious how this squares up with the failure of drugs targeting beta-amyloid plaques. Despite some of these drugs being very effective at clearing Aβ plaques, they don't seem to ever achieve any significant benefit in clinical trials.
Reading Derek Lowe, you'd get the impression that the beta amyloid hypothesis is a formerly exciting thing of the past with a disastrous track record.
>the relentless failure in this area, when amyloid plaques seemed for so long to be the most likely causative agent for the disease, is really something that makes you question things.
>Add in the additional complete failures for every other attempt at the amyloid mechanism (secretase inhibitors, for example) and you start wondering if amyloid really is a cause of the disease or not
Now Wikipedia is more optimistic:
>The "amyloid hypothesis", that the plaques are responsible for the pathology of Alzheimer's disease, is accepted by the majority of researchers but is not conclusively established.
I'm curious to see what comes out of this study, it's a very encouraging result. But it's hard to resolve this conflict of the mechanism looking great on paper, and completely failing in trials.
From what I got from skipping over the study, this isn't about beta-amyloid itself, but "triglyceride-rich lipoprotein" amyloid beta _complexes_.
The amyloid beta plaques may be not cause, but symptom of the disease. Maybe the TRL-A-betas are causing the damage, get metabolized and after that the protein separates and then accumulates in the brain? The study states, the TRL-A-beta are causing inflammation, which they attribute for disease progression rather than A-beta plaque formation.
> ...the findings presented in this study nonetheless support a now large body of evidence that demonstrates that the genesis of plaque is not the initiating trigger for neurodegenerative processes to be initiated, but rather, may be consequential. This study provides evidence that more subtle chronic interactive effects of peripheral metabolism of TRL-Aβ with the cerebrovasculature may be sufficient to potentially cause AD.
So, clearing up A-betas may be just flushing the "damage logs".
> _This study provides, for the first time, direct evidence that hepatic expression of genes leading to the synthesis of human-Aβ is causally associated with corruption of the NVU, with cell death and brain atrophy realised. [...] Consistent with the hypothesis of increased neurovascular insult as a consequence of hepatic synthesis of TRL-Aβ, PET findings clearly demonstrated an age-associated increase in [Pittsburgh compound] uptake. We suggest that this was indicative of the marked abundance of amyloid-rich lipofuscin aggregates distributed within brain parenchyma and within vessel lumen._
They definitely seem to lean into the neurovascular damage angle. I.e. liver produces amyloid-beta complexes, high levels of which result in neurovascular damage, resulting in lipids making it through and accreting in the brain.
Which makes sense, as if your capillaries are less functional, how would you body clear plaques from a difficult to reach organ (the brain)?
It's also possible that something which causes the liver to synthesize amyloids is the causative agent in alzheimers. In which case the amyloids may be a by-product.
I only have a passing understanding, so forgive me if I get some of this wrong, but my understanding is that the beta amyloid hypothesis is "disproven" from the perspective that removing beta amyloid that has built up doesn't seem to resolve the symptoms. That is different than it isn't a causal link in the chain though.
For example (making this up) I don't think we have disproven that beta amlyoid build-up causes inflammation, which actually causes the brain damage via a process that continues even once the beta amyloid is gone.
As I recall, several studies have also shown that people can have high levels of amyloid-beta plaques (ABPs) in the brain and not show any signs of dementia.
Between the two outcomes (ABPs exist but there's no decline, and ABPs are removed but dementia persists), the prevailing interpretation is that ABPs _alone_ do not cause Alzheimer's. They seem to arise along with the cognitive loss, though not cause it.
Tau deposits and associated neurofibrillary tangles have also been implicated in dementia, but also can be absent in those with the disease, so they too are not directly causal.
Everything you said is still consistent with the beta amyloid theory. The plaques don't cause dementia, they are supposed to lead to damage.
Once dementia sets in, there is no turning back, the neuronal network has been damaged enough and you can't replace neurons (not most of them)
Dementia is the main symptom of Alzheimer. And there are other causes of dementia, too.
What I find puzzling if the plaques are a link in the chain (as opposed to a symptom), isn't so much that beta-amyloid drugs stop short of outright resolving the symptoms, but that they don't seem to affect the progress of the disease.
To continue with your example, if beta-amyloid was a major source of inflammation, and inflammation caused the damage, it'd seem reasonable to expect that removing the plaques would result in slowed cognitive decline.
Strangely, this does not seem to happen in clinical trials.
Could it be that the amyloid-beta plaques are just a by-product of the same thing that is causing the damage in the first place?
> [Changes] in dietary behaviors and certain medications could potentially reduce blood concentration of these toxic fat-protein complexes, [subsequently] reducing the risk for Alzheimer’s
What would be some recommended changes in dietary behaviors if this link were also verified in humans?
avoid oxidized lipids and especially oxysterols
very good primer:
https://csroldsite.wordpress.com/2013/03/04/oxysterols-the-t...
How do you relate this to the study at hand? Oxysterol isn't mentioned once.
I don't even disagree or something, but your advice seems rather automatic than based.
The study used atherogenic diets as offense. So all the consensus on heart health seems to apply: LDL bad; salt bad; cholesterol bad; saturated fats bad - inflammation bad.
In mice.
Oxysterols seem to stimulate amyloid beta formation in the liver and even in the brain directly:
> We have shown that patients with AD have increased brain levels of 27-hydroxycholesterol, which may affect the production of beta-amyloid.
https://pubmed.ncbi.nlm.nih.gov/16866910/
tl;dr avoid fried foods :<
chicken is more susceptible to lipid oxidation than beef or pork. lower temperature cooking methods are preferable.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5055878/
There have been several studies done showing that a healthy keto diet can reduce or even reverse Alzheimers symptoms in many patients. Just do a quick Google or YouTube search, lots of content on the subject.
Not exactly what they hint at in this study...
> In wild-type (WT) C57BL/6J mice, a saturated fatty acid (SFA)-enriched diet was found to strongly stimulate biosynthesis and secretion of TRL-Aβ, concomitant with a reduction in cerebral capillary endothelial tight junction proteins, blood-to-brain extravasation of TRL-Aβ, and marked neurovascular inflammation [6]. In contrast, mice fed unsaturated fatty acid–rich diets had no evidence of exaggerated TRL-Aβ secretion and capillary integrity was unremarkable [6,7].
...
> Moreover, synergistic effects of TRL-Aβ with exaggerated central nervous system (CNS) synthesis of human Aβ are also suggested by the findings of accelerated amyloidosis in amyloid precursor protein/presenilin 1 (APP/PS1) mice maintained on atherogenic diets [9].
Not saying keto is inherently an atherogenic diet, but surely saturated fat and salt isn't exactly avoided by most followers.
> Just do a quick Google or YouTube search, lots of content on the subject.
Yeah.......... sure. Content.
Here is an example of a ketogenic diet:
- 2 hard-boiled eggs for breakfast.
- 1 cup of walnuts or almonds or pecans as a snack.
- Eaten with a slice of sharp cheddar cheese (4g saturated fat).
- Always rinse the nuts to make them more palatable.
- This meal may be eaten twice a day.
- 3 tablespoons of chia seeds soaked in water, as a snack.
- Like a high fat/protein version of oatmeal.
- Peanuts and macadamia nuts as needed for hunger.
- Steamed vegetables (broccoli, kale, spinach, brussels, zuchini, tomatoes).
- Eaten with 8 tablespoons of olive oil.
- A very large serving of steamed vegetables.
- Salt/seasoning however you prefer.
- This is dinner.
Once a week, eat a cheeseburger. Or twice a week: rotisserie chicken and olive oil, or coleslaw and guacamole and chicken.
This high-fat, low carb diet can be maintained with no difficulty for decades. Also, it is an ideal diet for insulin-dependent diabetics.
It's cheap, healthy, and you won't be hungry.
Anyone reading this, please ignore it and learn about keto properly, not from a random comment from a green account on hacker news.
I’m not going to tell you anything else, because I too am a random commenter on hacker news - except please don’t take the comment as a good example of how to put together a keto diet.
Good points, but I would just add once I ate almost nothing but salad and salmon or sardines for two weeks and it completely transfigured my physiology in a way that continues to astound me. As a result of that my primary recommendation is that people experiment with the best diet plans they can find and try them in two week blocks to let changes set in.
> Always rinse the nuts to make them more palatable.
OK, I have to ask...what is this about? "More palatable" in what way?
You're not a real health nut unless you're activating your almonds
Buy some walnuts. Try rinsing them before eating, to wash away the walnut dust. You may find you prefer the taste after washing.
> - steamed vegetables (broccoli, kale, spinach, brussels, zuchini, tomatoes)
- eaten with 8 tablespoons of olive oil
I am not entirely sure that my body is ready to down half a cup of oil as part of a regular meal.
I think I read that Italians use something like 3oz/day of olive oil on average, aka 6 tablespoons. I wouldn't eat 8 tablespoons directly (lol) but if you just put a good amount on all your meats and vegetables it adds up a lot faster than you think.
The large serving of olive oil is small relative to the bulk of the steamed vegetables.
It's typical for ketogenic dieters to use vegetables as a carrier for olive oil, and for a large fraction of the day's calories to come from that oil.
Mice trials don't interest me much. Human trials of various diets for Alzheimer's have been done along with lots of individuals who have tested it on themselves or family members with positive results.
I can't find one of the more comprehensive studies I was looking at before, but a quick search pulls up this video which discusses a recent human trial which showed significant improvement on the keto diet (links to the study in description):
That looks like a 12-week keto diet, applied to 21 patients who already have AD. The measured results were cognitive scores on testing, which improved.
Consequently, it suggests someone who is already impaired due to AD may be able to improve symptoms from a keto diet (vs a low-fat one).
But the general consensus is that reversing or alleviating AD symptoms is a different task than preventing it in the first place.
The linked article here is talking more about the latter, and specifically for preventing non-hereditary AD.
If the diet can reverse the usual decline and ultimately cure the disease given enough time, surely that would imply it would also prevent onset, no?
I'll take a more detailed look into the other resources I've studied and post another reply in a few hours.
Alzheimer's research and drug development is littered with decades of ideas that were implied, but didn't bear out.
And nutritional research... well, there's a lot of money in food, and that's funded a lot of noise around the signals.
Thanks for re-posting, I'm not sure how I missed this research, and even in Australia as well (I'm Sydney based).
We're in sleep tech, building closed-loop SWO which of course has an impact on removal of beta-amyloids, but all the research I've seen to date has just not gone further than saying there is a "correlation" between Aß and Alzheimers.
I'm not sure this completely closes the loop on cause-effect, but it seems a very strong bit of evidence. Not sure how I missed it before, but thanks.
How do these findings line up with the controversy surrounding Aducanumab?
This also tracks with apoe4 carriers being at greater risk, as they are also at greater risk of raised cholesterol from dietary sources of saturated fat
A couple more studies related to the findings in the OP:
https://www.statnews.com/2021/10/11/mouse-experiments-with-o...
https://www.nia.nih.gov/news/study-reveals-how-apoe4-gene-ma...
It's also very suggestive that Vitamin D deficiency is associated with reduced choline metabolism in the brain:
https://pubmed.ncbi.nlm.nih.gov/3753932/
For those of us genetically predisposed to this disease, what dietary changes would theoretically result in a reduction of risk?
One option is to eat less of everything. This may sound dumb but in the current stone age understanding of nutrition and health, it is a reasonable option.
The only foods which are ‘definitely safe’ are leafy greens and cruciferous vegetables. Could probably add berries to that in moderation. Not saying that is all one should eat, what I mean is to eat less of everything else than baseline, to some caloric deficit. This excludes the few people who are underweight for whatever reason, and those with certain diseases.
> _The only foods which are ‘definitely safe’ are leafy greens and cruciferous vegetables_
If you have kidney disease, or are at risk for kidney stones, oxalates from excessive leafy greens can make either condition worse.
If you where in a constant state of caloric deficit you would constantly loose weight.
At every calorie level above starvation, there is an equilibrium weight associated.
(Metabolism (which drops with less weight) + Exercise - Intake) -> over time -> equilibrium weight.
So assuming you pick a low calorie diet for now, eventually you'd maintain at a skinny weight.. and maybe live longer. Maybe.
Doesn’t this just introduce a different risk that you lose a nutrient your body needs to prevent/fight against various health problems?
"leafy greens and cruciferous vegetables" Aren't these covered in pesticides? If you are looking for reasons to not eat:
https://www.nytimes.com/2006/10/31/health/nutrition/31agin.h...
https://www.kxan.com/news/simplehealth/dirty-dozen-which-fru...
Keep your vitamin D and choline intake high:
https://www.nia.nih.gov/news/study-reveals-how-apoe4-gene-ma...
https://pubmed.ncbi.nlm.nih.gov/3753932/
I am not a liver expert, but it seems like those kinds of compounds might be created by a malfunctioning liver, rather than specifically diet induced.
why is the liver malfunctioning? perhaps its a malfunction induced by diet?
Yeah or it could be a hormone producing organ like they hypothalamus, thyroid generating not enough/too much of a chemical, or unhealthy kidneys not pulling enough salt out of the blood causing the liver to become stressed, or, or or....
I'm sure if you do five whys on liver malfunction, you'll always be able to find that diet impacts structurally deficient organs eventually, but wether or not it is a significant contributor is always up for debate.
Minimally processed plant-based diets. People keep fighting it, but it always comes back as the optimal diet to healhty longevity.
Coffee and exercise have been shown to have protective effect (not sure how robust those studies are) which seems consistent with liver health/fat metabolism action…
Also nicotine.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1670208/
Do you know if it's the caffeine in coffee, or something else? (i.e. does decaf work?)
It doesn't seem like they draw any correlation to food intake since the mice were genetically modified to just emit the proteins from their livers.
My guess is healthy diet and exercise go a long way. Don't drink and avoid sugar (diabetes) both of which are damaging to the liver.
some would say saturated fat is the cause
the mechanism could be atherosclerosis
https://youtu.be/t-noCw4LsY4?t=168
linear correlation by country
https://youtu.be/Gel4vlG4Jbk?t=68
personally, i think something close to wfpb diet is the best for all things (except gaining weight).
What seems to be hinted at through this and other research out in the past 12 month:
Reduce fat intake.
It's not the cause, but the carrier of toxins across the blood-brain carrier. Reducing fat would reduce the rate of toxin build up. It's not a cure, nor does it tackle the genetic component, but way to prolong lifestyle.
Not sure what evidence you've been looking at; from what I've read the opposite is true: Keto diet can be an effective treatment for Alzheimer's.
https://m.youtube.com/watch?v=jK6-r1zWOI0
Bad news for the Keto dieters.
I don't think that fits. Someone following a strict keto or low-carb diet is typically going to have healthier levels of fat in their blood e.g. lower cholesterol. Add to that a greatly reduced risk of diabetes and if these findings prove true it may end up being another reason to adopt such a diet.
There are many dietary changes that can be implemented to decrease the odds of the disease occurring in those who are genetically predisposed. Look into a nutrition program that specializes in Alzheimer’s prevention.
For example:
https://amosinstitute.com/cognitive-health-program/
It's hard to say right now. It might be one possibility if this line of research pans out.
This is a potential mechanism that they've experimentally built and triggered. There's no guarantee this happens _in situ_ exactly as they've set up. There's also the chance that Alzheimer's is caused by various contributing factors.
This paper does look promising though, because they've triggered the disease from the liver using lipoproteins that have been observed.
I'd love for domain experts to weigh in.
So...if you're a mouse you should eat less sugar and less trans fat? (asking for a friend)
Title needs "in mice" appended to it.
_Using mouse models, researchers in Australia have identified one of the likely causes of Alzheimer’s disease. Some have dubbed the finding a “breakthrough.”_
Mice don’t get alzheimer’s.
Alzheimer isn’t a disease but a symptom of chronic viruses and bacteria.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6066504/
People with Alzheimer have been cured after taking antibiotics.
In that paper the authors suggest that 1) inflammation may _contribute_ to AD, and 2) the microbiome may be _a_ source of that inflammation.
Their conclusion: "Many experimental data support the involvement of a polymicrobial community in the pathogenesis of AD."
The authors do NOT claim that anyone has been cured of dementia by reducing inflammation or altering patients' microbiome. They suggest only that the microbiome and its role in inflammation may be worth further investigation.
In support your point the authors also state that :
It would be very optimistic to imagine that an antibiotic therapy may be administered and cure, or at least prevent progression of AD. It is clear, however that no antibiotic regimen has been developed to cure periodontitis which has a similar implication of chronic infectious microorganisms and biofilms.
The hypothesis is my own based on my own experience. Then I found out some researchers believe the same.
It’s just a one paper I quickly googled. There are more but I lack the energy to link them all.
Just google ‘alzheimer's infection theory’ if you want to dig deeper.
I've heard similar evidence for Alzheimer's being essentially type III diabetes.
I'm starting to think the causes can be multi-variate.