Scientists discover links between Alzheimer's disease and gut microbiota

I had to triple check the date because I was pretty sure that this was known before. Maybe it is simply the confirmation aspect of it?

Edit:

> Our findings reveal for the first time, that Alzheimer’s symptoms can be transferred to a healthy young organism via the gut microbiota, *confirming a causal role* of gut microbiota in Alzheimer’s disease ...

From: https://faculty.sites.uci.edu/kimgreen/bio/glucocorticoids-a...

Citing many papers

> One early event in AD is an increase in circulating glucocorticoids

You could sum up Alzheimer's as: Diet/Lifestyle + a congenital form of Cushing's syndrome and you have increasing glucocorticoids which imply downregulation of the PVN, less progesterone and low levels of Prolactin reducing oligodendrocyte reducing myelin sheaths. Add in APOE e4 without choline in the diet and you have accumulation of lipids to round it all out.

There is a reason why Omega 3 + B+D vitamins are talked about as preventative as they all reduce inflamation.

See this for example: https://www.grassrootshealth.net/two-nutrients-proven-stop-b...

Edit2: For the curious here is a larger brain dump on the topic with many more links when I had to untangle the pathway earlier this year while working on something else. https://www.reddit.com/r/DrWillPowers/comments/16ae4zy/alzhe...

Microbiome researcher here. As usual, when a microbiome paper reaches HN, I emerge to urge caution.

You should be extremely skeptical of the larger conclusions drawn from this paper. The biology of Alzheimer's disease (AD) is poorly understood, and the contribution of dietary and microbiome factors are extremely unclear. I think you should treat the evidence from this paper (and shared in this thread) as more like "fails to converge" than "I will use this data to update my priors".

I want to note, first, that the researchers should be commended on clearly communicating their procedures, crafting a well written paper, and doing some nice experiments (in figure 4 particularly). The main criticisms I have relate to the conclusions drawn, and then echoed in this HN thread.

1. The behavioral analysis was not conducted in a blinded way - the researchers doing the behavioral analyses knew if the rats were AD or non-AD groups. From supplement "The experimenter was blinded to the FMT human donor but not to the rat group." The degree to which rodent behavior reflects human behavior is unclear (I would argue very little) but you should definitely be skeptical of measures with significant subjectivity done without blinding.

2. The paper has many materially important assertions not backed by the data.

> However, at phylum level, Alzheimer’s patients had a higher abundance of Bacteroidetes (Fig. 1C) reported to comprise many pro-inflammatory species

A phylum is an extremely diverse group of microbes - the phylum Bacteroidetes contains microbes that likely diverged hundreds of millions of years ago (from their LCA). Claiming that an entire phylum is "pro-inflammatory" is not even wrong. The different Bacteroidetes found in humans can be "pro-inflammatory" or "anti-inflammatory" depending on a truly staggering number of factors (diet, what other microbes are there, host immune status, host epithelial integrity). To claim that it's clear that AD patients have more of a "bad phylum" exemplifies the strong claim X weak evidence of this paper.

> ...and a lower abundance of the phyla Firmicutes and Verruocomicrobiota, reported to produce beneficial metabolites.

Ahh yes, the beneficial metabolites of my favorite Firmicutes - Clostridium botulinum (most toxic metabolite known to man), Clostridium difficile (kills >20,000/year in the US), etc... Again, you can't paint with this broad a brush and have the conclusion mean anything.

> Importantly, a positive correlation was observed between the abundance of the health-associated SCFA producer Coprococcus and the MMSE score, and inverse correlations were detected between the abundance of the disease-associated pathobionts Desulfovibrio, Dialister and the MMSE score, supporting a microbiome signature for cognitive performance in Alzheimer’s disease.

Desulfovirbio has evidence of potential linkage to AD (a quick google found correlational, but no causal evidence). On the other hand, a quick google showed that other groups disagree about Dialister - Vogt et al 2017 (PMID: 29051531) find that Dialister is reduced in AD patients and the less Dialister you have, the worse your symptoms! Again, claims stronger (and in this willfully ignoring) than evidence.

3. The main data from this paper is generated in a standard fecal transplant experiment. In short, feces from AD patients is given to some rats, and feces from healthy donors (HD) is given to other rats. Figure 2-4 rely on this setup. These are not independent verifications or tests of the hypothesis "Do AD bacteria --> AD?". Any systematic difference between the feces with the AD label and the HD label could be causal for the results the authors see. This is a major confounder in all microbiome work. Behavioral changes associated with AD are going to change food intake and bowel habit, which in turn will substantially change microbial characteristics of the gut. Other than the microbes, there are a huge number of human derived proteins, metabolites, signaling molecules, viruses, etc in the stool. The researchers don't eliminate these, and their data would be consistent with this as an explanation just as much as the microbes. Even the best studies cannot create a design that blocks every confounder, but FMT paradigm suffers from a really large number of them and the authors don't address this. There are some experiments you can do - for example, you could culture the individual microbes you believe to be responsible for the AD pathology, introduce them into rats, and show the _microbe alone_ is enough to cause the disease (this resolves the last confounder cited). The authors don't do this. There are many other considerations in designing FMT experiments that I could quibble with (like why not germ-free animals - that is the standard rather than the microbiota depletion they do), but the main point is: any systematic difference in AD vs HD feces could cause the differences in rat physiology they observe.

4. Figure 2 is an excellent example of a broader phenomenon in microbiome papers: statistically significant results with extremely small effect sizes. Consider 2D-I. The authors show (for instance) that the mean water content of stool differs significantly in their AD- vs. HD-colonized rats. The effect size is maybe ~12%. Everything in 2G-I is smaller than this. Do we think that losing 12% of the water from feces is a part of the physiological cascade that leads to AD? While this could be true (or this could be evidence of some other underlying change being caused by the AD microbes) the effects are extremely small. I think it's much more likely that some other systematic difference in the feces (as outlined in 3) is causal for these small-scale changes seen.

This is similar to the data in Figure 3. Consider 3B - the AD microbiota induces a (significant) ~0.23% change in the "discrimination index". What size is that effect? It might be large, but considering there is no comparison to differences in whatever the human equivalent of this index is (if it even exists) I am going to guess it's more on the 'too small to be meaningful' side.

> These observations were further corroborated by correlating the clinical human donor profile to the Alzheimer’s behavioral readouts of the recipient rats. They test 50 different metadata correlations, don't correct for multiple hypotheses, and find one correlation at p<0.05 and one at p<0.08. This does not match the tone of that sentence.

5. Quoting from the paper: "Rats colonized with faecal material from Alzheimer’s donors exhibited no change in locomotor parameters in the Open Field Test (Supplementary Fig. 6A), no change in anxiety-related behaviours in the Elevated Plus Maze (EPM) (Supplementary Fig. 6B), or in antidepressant-like behaviour in the Forced Swim test (FST) (Supplementary Fig. 6C), indicating no specific effects of the Alzheimer’s human gut microbiota on comorbid features of Alzheimer’s disease in rats." So clearly whatever the effect of the microbiota is, it's not enough to trigger these measures of pathology. Does that suggest that the microbiota causes only some AD features? If you read their abstract "Our findings reveal for the first time, that Alzheimer’s symptoms can be transferred to a healthy young organism via the gut microbiota, confirming a causal role of gut microbiota in Alzheimer’s disease" they certainly don't qualify the result this way.

6. Figure 4 - there are some nice experiments here. They show differences in neuronal survival conditioned on AD or HD feces. There are microbial metabolites that affect neuronal survival that are certainly not linked to AD causally (e.g. the short chain fatty acids). Evaluate this in the context of point 3 above: the authors show differences in neuronal survival, but whether that is due to changes in AD patients microbiome that are _caused_ by the disease (e.g. they eat weird and get weird microbes that don't make short chain fatty acids) rather than _casual for_ the disease cannot be evaluated from this data.

7. Figure 5 has no evidence of microbial cause. The authors show that serum from AD patients injected into rats caused reduced neurogenesis. As outlined in point 3 above - this could be (and seems much more liekly to be) from any of the human-derived factors floating in the blood. They try to address this by saying "gut microbiota composition explains up to 58% of the variance of individual plasma metabolites" and citing a paper (PMID: 36151114) but this is a very misleading citation. First, the authors of the cited paper corrected that figure to 46%. Second, that figure is for a SINGLE metabolite, not the whole plasma metabolome. Quoting from the cited paper "We detected the largest variance explained (46%) for an uncharacterized common metabolite with the provisional identifier X-11850.". The gut microbiome makes a lot of chemicals, but your body makes many many more. The idea that gut-derived metabolites are the predominant thing in the bloodstream is...not correct. The authors similarly try to suggest with figure 6 that because the AD-transplanted rats show a different plasma metabolome, that means the serum injection experiment points to the microbes. This is not causal evidence, and it isn't a test of what they say it is.

Related, although it looks like different work:

Link between Alzheimer's disease and gut microbiota is confirmed (2020) - https://news.ycombinator.com/item?id=35202457 - March 2023 (19 comments)

Does anyone know if there is correlative data showing lower incidents of Alzheimer's among people who've had a GI reboot with antibiotics?

or how to find it?

Original published:

https://academic.oup.com/brain/advance-article/doi/10.1093/b...

I certainly hope they are going to replicate while knocking out one species of gut biota each time. Would be super helpful right?

Edit: Experiemental design

we establish indvidual colonies of each of the biota detected in our earlier work, we then recombine them in the ratios found in the original work and replicate the previous results.

We then creation combinations lacking a single organism from our mix and look for replication.

Finally we vary the percentages of the biota in our origianal mix and look to see if that affects our ability to replicate.

I wonder if simply taking antibiotics at some point, clearing everything out and repopulating the flora could help?

My guess is no - that something in the system is triggered by the fecal transplant but that gut flora isn't the main source, but it would be an interesting thing to look at. I'm not in this field and do not know how to mine this data or properly posit the question, but maybe something along the lines of: "How many people who have taken a strong antibiotic in the last 10 years get alzheimer's vs people who have not taken any antibiotics?" Seems like this data should be out there, right?

Maybe someone who works with this kind of data or research can weigh in. Can you imagine if the cure is that simple? Just take strong antibiotics at an early stage....!?!

As someone who used to research neurogenesis in rats - there isn't great evidence that adult mammalian neurogenesis occurs in humans, so don't assume that this will translate to humans.

It would be cool if you could create technology to diff a donor microbiota to a recipient microbiota in humans and check the causality.

The keto community already knows that Alzheimers is a metabolic disease.

Don't eat carbs, have an active livestyle = don't become insulin resistant and you won't get Alzheimers.

In the meantime I'll just keep watching how long researchers are going to dance around the bush until they finally get it...

I have a cousin studying the gut microbiome's role in mood, and it seems to play a role. I wonder if there are companies that specialize in creating tailored probiotics to help individuals struggling with mental diseases.

The vagus never is the super highway of the brain it appears. I also feel our parasympathetic nervous system is vastly understudied.

> For the first time, researchers have found that Alzheimer’s symptoms can be transferred to a healthy young organism via the gut microbiota, confirming its role in the disease.

I just read “I Contain Multitudes” by Ed Yong where this topic was unsure as there’s only a handful confirmed links to things like depression, obesity, etc. Now it is confirmed for Alzheimer’s. This is extraordinary.

I would bet that the root of both is diet. A diet that leads to Alzheimers will result in a certain kind of gut microbiota. I would guess that sugar and carbs generally, along with fiber, are the problem.

I thought it was gum disease? Or was it herpes?

how does antibiotic medication affect our gut microbiota generally, and our alzheimer’s disease risk specifically?

does this mean anal sex could theoretically transmit Alzheimer's?

If you look at the scatter graphs, it's not terribly impressive. Lots of overlap, and most of the results show no difference. The one that does show a large difference still has a lot of overlap in the scatter graph, and it seems to be some outliers that bring down the mean value.

It's kind of an extraordinary claim, which requires extraordinary evidence. This isn't that.

What interests me more is why HN users keep posting this study, and voting it to the top of the home page.

Are shady fecal transplant clinics a thing yet? Take these antibiotics for a week, then we’ll hose fecal matter from healthy, young, thin people into your intestines like a reverse enema. Move over sperm banks and blood banks, the poop bank is much easier. Only sorta joking.

It seems like they killed the gut bacteria with antibiotics, then transferred the bacteria from alzheimer's patients, causing symptoms.

I wonder if a second gut transplant from non-alzheimer's patients would reverse it?

Analysis of gut microbiota composition by bacterial 16S rRNA gene sequencing in a subset of Alzheimer’s patients (Supplementary Fig. 1A–E) revealed no significant change in alpha and beta diversities between control subjects and Alzheimer’s patients (Supplementary Fig. 1B–D). However, at phylum level, Alzheimer’s patients had a higher abundance of Bacteroidetes (Fig. 1C) reported to comprise many pro-inflammatory species,53 and a lower abundance of the phyla Firmicutes and Verruocomicrobiota, reported to produce beneficial metabolites.54 At the genus level, Alzheimer’s patients had on average a significant reduction in the relative abundance of Clostridium sensu stricto 1 and the short chain fatty acid (SCFA) butyrate-producing genera Coprococcus, which is associated with healthy ageing in general55 (Fig. 1C). In addition, similar to a previous report using a transgenic mouse model of Alzheimer’s disease,56 the relative abundance of the pathobiont genera Desulfovibrio was significantly increased in Alzheimer’s patients compared to cognitively healthy control subjects

Do we know which bacteria/microbiota is causing this? Any benefits from taking probiotics?

... in rats.

Holy crap. We really don't know anything, do we.