Can gut bacteria tell if Alzheimer's is developing?

One of the most amazing features of the human body is the gut-brain axis.  As we discussed last summer, microorganisms in the intestines have a signaling network with the brain such that the microorganisms exercise a significant level of control over what happens in the brain.  Bizarre, I know.  Nevertheless, good gut health contributes to good neurologic health.

Doctors often refer to "gut flora," meaning gut plants.  This hearkens back to the 1950s, in my late elementary school days, when the biological sciences were trying hard to sort all life as either plant or animal.  And they were trying hard to force fit bacteria into the plant kingdom.  That didn't work out very well.  It turns out that bacteria are more different from plants than plants are from animals.

And so more sophisticated folks will refer to "gut bacteria."  But that's not quite right either.  Many of the microorganisms in your gut are archaea.  Archaea are often referred to as bacteria, partly because, like bacteria, their cells have no nuclei.  They are the organisms that can live under extreme conditions, such as near volcanic vents on the sea floor.  They stain the glaciers on Mount Rainier pink, they allow goats to digest cellulose, and they give the hot water pools in Yellowstone their beautiful colors.  But there are ways in which they are significantly more different from bacteria than plants are from animals.

So we will refer to the gut microbiome and skip worrying about whether their citizens are plants, animals, bacteria, or archaea.  

Now since the gut microbiome plays such an important role in how the brain functions, it may also play a role in how Alzheimer's disease develops.  Therefore, logic says that you should be able to see the development of Alzheimer's disease somehow reflected in the gut microbiome.  Can you?  Maybe so.  

There was a new study published in the June 14, 2023 edition of the journal Science Translational Medicine, "Gut microbiome composition may be an indicator of preclinical Alzheimer’s disease."  As indicated in the title, the research explored the idea that Alzheimer's disease might be detected by analyzing changes in the gut microbiome during the preclinical phase of the disease.  This is before any symptoms develop.

The researchers studied 164 cognitively normal people, 49 of whom had evidence of preclinical Alzheimer's disease.  In other words, the 49 passed cognitive tests OK, but they had other evidence that the disease had already begun.  As we said in Beating the Dementia Monster, the preclinical stage normally lasts about 15 years, only ending when the first symptoms appear.  Usually it is simply undetected during that stage. 

So what did the research find?  "The gut microbiomes of people with preclinical Alzheimer's disease (indicated by altered brain amyloid and tau proteins) had a different composition from that of healthy individuals."  This means that examining fecal matter may turn out to be a less invasive method for diagnosing Alzheimer's disease than, say, the spinal tap that I underwent. 

On the other hand, if the blood tests we've been anticipating turn out to be as reliable as they appear, they may end up being the preferred diagnostic tool.  The gut microbiome researchers compared their approach to the spinal tap rather than the blood test.

Aside from perhaps using changes in your gut microbiome to diagnose Alzheimer's disease, some believe that supporting good gut health supports good brain health.  That may or may not be true, but I still do things thought to support the gut microbiome.  I eat yogurt (without all the sugar), fermented foods like kimchi, and fiber supplements.

This idea of resisting Alzheimer's disease by caring for your gut underscores something we've said before: this is an incredibly complex disease, and we just don't understand it well at all.

Interesting new insight on intermittent fasting

I've been a bit distracted and so haven't posted in a while.  I do hope everyone had a wonderful Christmas, Hanukkah, or whatever you celebrate.  This is a season of light and hope.

I have come across news on intermittent fasting that I thought was interesting.  It has to do with the gut-brain axis.  We've written before about the influence of the gut-brain axis on brain health.  Somehow, there is a two-way communication between microbes in the gut (bacteria and archaea) that regulates brain function.  Meaning that healthy gut = healthy brain.  Or something like that.

When we discussed intermittent fasting in Beating the Dementia Monster, it was credited by the sources I referenced with raising the level of brain-derived neurotrophic factor (BDNF) in the body.  BDNF not only repairs damaged brain cells, but it also prompts stem cells in the hippocampus to form new neurons.  BDNF is generated during sustained aerobic exercise, and so exercise is the most powerful tool in the Dementia Toolkit.

But, after reading an article in the New England Journal of Medicine, I was prompted to began a 20 hour/day (sort of) fasting protocol in 2020.  Intermittent fasting is not recommended for the elderly, because many of us have trouble maintaining an adequate weight.  But I am currently five pounds over where I want to be, and fasting appears to have been beneficial to me.  So I continue.

For the past year and a half or so, my memory and cognition have been tested weekly by researchers from the University of Washington's Alzheimer's Disease Research Center.  While I don't have access to their protocols for analyzing the data, I have no trouble telling that I'm doing just fine.  I've also found that I score best late in the morning, after some coffee, after the gym, but before eating anything.

So how do fasting, the gut-brain axis, and brain health intersect?  There was recent research from China published in the journal Frontiers in Cellular and Infection Microbiology finding an association between weight loss due to intermittent fasting and brain health.  The researchers correlated intermittent fasting, improvements in the health of gut microbiome (all those little things swimming around inside your gut), and brain health.  Long story short, intermittent fasting is good for the health of the gut microbiome, so the gut microbes do a better job of regulating brain activity.

Here's an article about the study from Newsweek -- a little easier reading than the journal article.  Most people do intermittent fasting for weight loss, so that's the context for the study.  But there are other reasons to fast, so I don't think the association with weight loss in either the Newsweek or journal articles are central to the phenomenon.  If you do all the things to support your gut, it will help your brain.  This Healthline article lists 10 things you can do to support your gut biome.  Notables include eating fiber, eating fermented foods (I eat kimchee and yogurt every day), eating whole grains, etc.

How does the gut-brain axis work?  It's pretty mysterious to me, but this passage from the Wikipedia article is interesting: 

"Chemicals released in the gut by the microbiome can vastly influence the development of the brain, starting from birth.  A review from 2015 states that the microbiome influences the central nervous system by 'regulating brain chemistry and influencing neuro-endocrine systems associated with stress response, anxiety and memory function.' The gut, sometimes referred to as the 'second brain,' may use the same type of neural network as the central nervous system, suggesting why it could have a role in brain function and mental health."  

Your body is truly amazing.

And more evidence that gut inflammation promotes Alzheimer's disease

We've written quite a bit about how events in the gut affect what happens in the brain.  I remain amazed at how bacteria and archaea in the gut (your gut microbiome) are mysteriously controlling what happens in your brain.

Sometimes they call it "gut flora," indicating plants growing in your gut.  Really?  This hearkens back to the 1950s and 1960s when they thought all life could be force-fit into a template of either animal or vegetable.  So bacteria were considered a strange kind of plant, and I'm not sure they even knew how different archaea was from bacteria. Today, we see things differently.  Archaea and a bacteria are each in their own "domains," while all of the other "kingdoms," perhaps five of them, are lumped into a third domain, the eukaryotes.  (Actually, how this is all organized depends on who you ask.  But this is how I taught it as a biology teacher.)

One of the things that goes wrong in the gut is inflammation.  What's important to us is that this inflammation involving the gut microbiome has long been suspected of influencing development and progression of Alzheimer's disease.  After all, Alzheimer's disease is known to be an inflammatory disease.  So inflammatory agents leaking from an aging gut are suspected of promoting inflammation in the brain.  So if these agents are released into the blood, how do they get past the blood-brain barrier to promote inflammation in the brain?  I can't find anyone with a good explanation for that. 

So why am I writing about this?  I came across a new study just published in the journal Scientific Reports, entitled "Gut inflammation associated with age and Alzheimer’s disease pathology: a human cohort study."  It describes research in which fecal matter of 125 participants was analyzed for the protein complex calprotectin which is known to be present when the intestines experience inflammation.  The presence of the proteins was then correlated in the test participants with markers for Alzheimer's disease.  This included cerebrospinal fluid analysis, PET scans, and cognitive and memory tests.  (Of course, I've been subjected to all of these diagnostic tests.)

What did they find?  The researchers wrote, "Calprotectin levels were elevated in advanced age and were higher in participants diagnosed with amyloid-confirmed AD dementia.  Additionally, among individuals with AD dementia, higher calprotectin was associated with greater amyloid burden as measured with PET. Exploratory analyses indicated that calprotectin levels were also associated with cerebrospinal fluid markers of AD, and with lower verbal memory function even among cognitively unimpaired participants. Taken together, these findings suggest that intestinal inflammation is linked with brain pathology even in the earliest disease stages. Moreover, intestinal inflammation may exacerbate the progression toward AD."  (The emphasis is mine.)

So what do we do with this?  From everything I've learned, it is most important to eat in ways that don't promote inflammation.  I stay away from foods that promote inflammation, primarily refined sugar and flour.  I also place importance on prebiotic and probiotic foods.  So I get a lot of fiber in my diet, and I eat fermented foods, like kimchee.  Also, yogurt.  And beans don't hurt.  Non-inflammatory eating is central to all of the brain-healthy diets we discussed in Beating the Dementia Monster; the MIND diet, the DASH diet, and the Mediterranean diet.

This just in: I had posted this entry and gone back to reading a book on intermittent fasting.  More on that book in a future post.  But what I read in a few minutes made me stop and return to this blog post.  I was able to stop the post just before it went out so I could add the following.  

I read in the book about a study with mice in which they took fecal matter from mice that had been undergoing intermittent fasting and implanted it in mice that had been sedentary.  The fasting mice had low inflammation, while the sedentary mice had high inflammation.  (Just like in people.)  This caused a remarkable reduction of inflammation in the sedentary mice.  The inference was that the gut microbiome in fasting mice has a different bacterial makeup than that of sedentary mice.  The bacteria in the fasting mice was anti-inflammatory, while the bacteria in the sedentary mice seemed to promote inflammation ... and disease.

Gut and Brain Redux

Perhaps there's a love-hate relationship between your gut and your brain.  On the one hand, it appears that microbes in your gut are controlling much of what goes on in your brain in mysterious ways.  That's called the gut-brain axis.  But at the same time, your "leaky gut" is killing your brain.  With respect to the latter, we've known for a long time that, as we age, the walls of the intestines are less able to contain the gut bacteria.  The bacteria leak out into the abdominal cavity and create inflammation throughout the body, including in the brain.  Much of our battle against Alzheimer's disease is to control inflammation, and gut bacteria becomes a major adversary.

How the gut bacteria makes its way to the brain is coming into sharper focus, and there's better information on how to put the brakes on that process.  (Spoiler alert:  It's a high fiber diet.)  My friend Teale sent me this article from Neuroscience News about new research findings on leaky gut and brain inflammation.  The researchers at the LSU Health New Orleans Neuroscience Center and the Departments of Cell Biology and Anatomy, Neurology, and Ophthalmology examined the culprit bacteria, Bacteroides fragilis.  This bacteria generates a neurotoxin known as BF-LPS.  At autopsy, it's found in the brain cells of Alzheimer's patients.  

How BF-LPS is able to cross the blood-brain barrier is not clear to me.  Perhaps it's a relatively small molecule, allowing it to cross both the intestinal membranes and the blood-brain barrier.  Recall that the blood-brain barrier allows smaller molecules to pass but screens out larger molecules and microbes.  But the intestinal membranes and the blood-brain barrier both weaken as we age.

When the BF-LPS reaches the brain, it not only causes inflammation, but it also inhibits the action of a protein called NF-L.  NF-L is important to the survival of neurons, and when its actions are inhibited like this, brain cells die, and the brain atrophies.  

So what can we do about this?  Control Bacteroides fragilis, so that it can't generate BF-LPS.  The design of your gut is such that it expects a certain fraction of what you eat to be dietary fiber.  I'd describe the situation like this.  If you're not eating enough fiber, your gut bacteria becomes unbalanced, and Bacteroides fragilis will generate a lot more BF-LPS.  So make sure you have a high-fiber diet.

How much fiber?  The USDA recommends that women up to age 50 consume 25 grams a day and men 38 grams.  Women and men over age 50 should consume 21 and 30 grams daily, respectively.  A medium-sized apple contains about 4.4 grams of fiber.

No cheese -- Why not??

When I speak to a group about lifestyle changes to prevent or slow the advance of Alzheimer's disease, I hear the loudest groan when I talk about diet ... notably when I say that the MIND diet rules out cheese.  That's because everyone loves cheese.

Cheese and other saturated fats were implicated in heart disease for many years, but they were somewhat rehabilitated during the 1990s.  This rehabilitation is controversial, and the fact that most saturated fats have animal origins prompts those wishing to protect animals to influence the debate.  It's been my observation that, over the past two years or so, the consensus of online authoritative sources has shifted from a relatively benign view of saturated fat to a more critical one.  And so some authorities discourage the consumption of saturated fats (for example here and here), while others cite less critical research to permit moderate consumption (for example here and here).  We discussed this in Beating the Dementia Monster, citing the writing of Dr. Mark Hyman, and his book Food; What the heck should I eat.

Regardless of how one might come down on the debate with respect to heart disease, research by the late Dr. Martha Clare Morris sustained the strike against saturated fat with respect to Alzheimer's disease.  (See her book Diet for the Mind.)  Neurologists like to say "what's good for the heart is good for the brain," and there is a strong correlation between heart disease and Alzheimer's disease.  So shouldn't the influence of saturated fat on heart disease (whether strong or weak) have a consistent influence on Alzheimer's disease?  

Well, apparently not.  Dr. Morris's research seems to dissociate the two effects.  (Again, this is all controversial with respect to heart disease, and everyone cites their favorite research.)  

When I was preparing the second edition of Beating the Dementia Monster, I puzzled over this apparent anomaly.  Of course, my underlying assumption was that a negative effect on saturated fat should come to the brain via a negative effect on the cardiovascular system.  But maybe that's not true.  And I've found something to suggest an explanation.

Several times on this blog we have discussed the gut-brain axis.  There is a poorly understood relationship between what goes on in the gut and what goes on in the brain.  Most of it hinges on the activity of many different bacteria (and archaea) in the gut.  So when the life of the "microbiome" in your gut is disrupted by antibiotics or the wrong kind of nutrients, it can adversely influence the brain.  And on this blog, we are very interested in influences on the brain that promote or discouraged the advance of Alzheimer's disease.

I got to thinking about this today when I was at the gym watching this video about diet and the gut microbiome.  This particular channel is big on promoting a vegan or vegetarian lifestyle (and so may be a bit biased), but I found what they were saying compelling.  (Acknowledging that they may be biased is not to discount their authority, only to acknowledge that every source is biased in some way, and we are wise to always consider that in assessing what someone is telling us.)  

What caught my attention was a statement that cheese has a bad effect on the gut microbiome.  If so, that would explain it.  Cheese (and other saturated fats) may be getting something of a pass with respect to cardiovascular disease, but it's still a recognized and important factor in the development and advance of Alzheimer's disease. 

So cheese is bad for brain health, but not because it affects the cardiovascular system.  It affects the gut microbiome.

So what do the recommend that you eat?  After discussing the affect of different nutrients on the gut, the presenter reviewed the best foods to eat for gut health.  Well, guess what ... everything she named as being positive for gut health is right out of the MIND diet.  

Of course, we discuss the MIND diet in Beating the Dementia Monster, and I've been trying to follow it now for several years.  I'm sure it's making a contribution to my success in dealing with Alzheimer's disease.

Why No Cheese?

When we discuss the distinctions between the MIND diet and the Mediterranean diet, the topic of cheese, stick butter, and stick margarine comes up. They are not allowed in the MIND diet. When I speak about this, I might hear a groan from the audience. But what’s wrong with enjoying these common foods? 

The issue was identified by the late Dr. Martha Clare Morris in the longitudinal studies she and her team conducted that led to the development of the MIND diet. She saw a correlation between consumption of these foods and the development of Alzheimer’s disease. And so they were tagged as bad. So that’s correlation. But what does that tell us about causation? 

When asked about causation, dietitians usually point to the saturated fat content of these products. But I’m not sure we know that’s the case. According to some recent research, the story may have more to do with a negative effect that cheese has on the gut microbiome. In fact, while cheese may kill off some beneficial microbes, other dairy products may benefit the microbiome. Quite a paradox. 

In understanding why this might be relevant to our interest in Alzheimer’s disease, we need to recall the mystery of the gut-brain axis. There is some kind of communication between the gut microbiome and the brain, and the brain is in some ways actually controlled by the gut microbiome. The gut is sometimes called “the second brain.” How does that work? If you find out, please let me know! Nevertheless, we associate a healthy gut microbiome with a healthy brain. Eating fermented foods, like sauerkraut and kimchi, are probiotic and are associated with better brain health, because they replenish important bacteria and archaea which may have died at the hands of antibiotics and artificial sweeteners. And, perhaps, cheese. 

The research in question was published in the journal, Nutrients. It studied a relatively small cohort of older men but led to some interesting conclusions. Essentially, dairy, in general, is probiotic and increased the population of beneficial bacteria and archaea in the gut. So dairy is generally good. But cheese, on the other hand, decreased the population of beneficial microbes. Surprisingly, yogurt seemed to be neutral. Yogurt contains some microbes important to a healthy gut, but they may all get destroyed by the digestive juices in the stomach. Or so some believe. On the other hand, older men don’t eat much yogurt, so this may have been the wrong population to use for studying yogurt. (I guess I’m an exception, since I consume plenty of yogurt – mixed with blueberries, walnuts, and monkfruit sweetener.) 

So I’ll speculate. It may well be that saturated fat in butter and cheese is directly detrimental to the brain, promoting the development of Alzheimer’s disease. But also, it may be that the damage to the gut microbiome caused by cheese increased the incidence of Alzheimer’s significantly enough to influence Dr. Morris’s results. 

The research was conducted at Baylor College and involved 34 older men. They basically counted microbes in material taken from their colon mucous and correlated the counts with dairy consumption. Since the study involved such a small population of older men (who didn’t like yogurt) – you guessed it – more research is necessary.

Here's some more, perhaps simpler reading on this.

Guts and Brains ... and More Amazing News

We've written before about the gut-brain axis, that mysterious communications system between the microbes in your gut and your brain.  Somehow, they support each other, and an unhealthy gut can mean an unhealthy brain.  So we do what we can to support a healthy gut.  Which means eating right and avoiding chemicals that kill gut microbes, like artificial sweeteners and animal products that might contain antibiotics.

Neurologists like to say that "what's good for the heart is good for the brain."  We might add to that, "What's good for the gut is good for the brain." 

Therefore, we might want to consume products with probiotic bacteria, like yogurt.  However, these microbes are often destroyed in the digestive process and don't always make it out of your stomach.  So there are supplements that can help with that.  And then there are the benefits of prebiotics, "fermentable soluble food fiber," which help supply the needs of the gut microbes.  A a high fiber diet is good for the gut ... which is good for the brain.

The research on the benefits of probiotics and prebiotics continues, and there's some amazing news.  There was a recent study published in Nature Communications using twins to study the effects of consuming prebiotic supplements on memory and cognition.  The results were pretty remarkable, even over a relatively short period of time.

The supplements were inulin, a dietary fiber in the fructan class, and fructooligosaccharide (FOS), a plant carbohydrate sometimes used as a natural low calorie sweetener.  Looking at a box of Costco nut bars, I see a form of inulin listed as an ingredient.  But asparagus is a great source for both inulin and FOS.  For this study, subjects were given supplements, either with both prebiotics or with a placebo.

The study was conducted by Kings College, London, and it used 36 pairs of twins over the age of 60.  One twin was given a daily prebiotic in a protein powder and the other was given a daily placebo in a protein powder.  After only twelve weeks, there was measurable improvement in cognition.  Using some of the same tests used to diagnose Alzheimer's disease, the prebiotic test subjects showed a significant improvement in a cognitive score compared to subjects who took the placebo.

Moral of the story?  Eat your vegetables, especially the leafy greens in the MIND diet!  And it wouldn't hurt to take inulin and FOS supplements.  They're known to be cheap.

Dietary Salt Causes Cognitive Impairment

For several years, researchers have been studying "the gut-brain axis."  Essentially, there is a form of communication between gut microbes and the brain, and when things go wrong in the gut they can go wrong in the brain.  Also, it's easy to make the case that excess salt intake will have a negative effect on cognition because it raises blood pressure.  High blood pressure is bad for the heart and is a risk factor for Alzheimer's disease.  What's good for the heart is good for the brain.

But a December 2018 article in Scientific American (reproduce here by Pocket) discussed a separate gut-brain axis involving salt but that does not involve blood pressure.  The article's author cited research published in Nature Neuroscience about work with mice.  It found "excess dietary salt suppresses resting cerebral blood flow and endothelial function, leading to cognitive impairment. The effect depends on [certain cells] in the small intestine."  "Endothelial function" refers to the work of endothelial cells lining the blood vessels that control contraction and relaxation of the blood vessels, among other things.  Its failure contributes to a number of bad consequences for both the heart and the brain.

The research with mice points to a pathway between the gut and the brain via the immune system.  Then excessive intake of salt can impact the immune function in the small intestine with a negative effect reflected back to the brain.  A very important consequence is that blood flow may be restricted to the hippocampus and the cortex -- ground zero for Alzheimer's disease.

Prior the research on salt, there was research studying other contributions that issues in the gut can make to Alzheimer's disease.  One idea is that microbes may leak from the gut when the spectrum of gut microbes is disturbed.  The leaked microbes can promote inflammation throughout the body, including in the brain.  Inflammation in the brain plays a role in Alzheimer's disease.

The inflammation can cause impairment of the blood-brain barrier.  The blood-brain barrier protects the brain from pathogens by only allowing small molecules and ions to pass in and out of the blood vessels in the brain.  This is another work of the endothelial cells lining the blood vessels in the brain.  (Special proteins regulate the passage of certain specific molecule that must pass in and out.)  Some studies suggest that impairment of the blood-brain barrier allows beta amyloid molecules to enter the bloodstream and then be more widely distributed in the brain, thus propagating Alzheimer's disease.

Speaking for myself, I have always had fairly low blood pressure.  During periods when it seems too low my cardiologist suggested raising my intake of salt.  Maybe that's good advice, but I'm wondering what it means for neurodegeneration in light of this research.  

Diet, Depression, Alzheimer's Disease, and Your Gut

This week I saw two unrelated articles that involved the connection between the health of your gut and brain health.  One discussed the influence of the gut on depression, and the other discussed research in China with seaweed sugars that affect the gut and may improve cognition for people with Alzheimer's disease.   

The first was an article in The Atlantic Monthly regarding how the DASH diet fights depression.  The article was actually published in 2018 but was recycled by Pocket.  We discuss the DASH diet in Beating the Dementia Monster but not for treating depression.  The DASH diet is a modified Mediterranean diet that is intended to lower blood pressure.  Brain health and cardiovascular health are intertwined, so the neurologists like to say, "What's good for the heart is good for the brain."

The Atlantic article posits an interesting coincidence -- that a leading risk factor for death worldwide is poor diet, and depression is a leading cause of disability worldwide.  It refers to research suggesting that poor diet makes us sick, and resulting depression can make us even sicker.  It then cites research finding that the DASH diet reduces depression by 11%.

How is this supposed to work?  The DASH diet is heavy with plant fiber that ferments in the gut microbiome.  The microbiome is the ecological community of microbes in the gut that participates in the digestion of food.  According to the article, fermentation creates short-chain fatty acids which regulate the immune system and influence gene expression in the brain.  It says this contributes to increased production of proteins called neurotrophins, which act like manure to the brain as they promote the growth of new brain cells in the hippocampus.  (We recall that Alzheimer's disease attacks the hippocampus.)

Anything sound familiar here?  In Beating the Dementia Monster we described how much of my improvement can be attributed to production of the brain-derived neurotrophic factor (BDNF) during exercise.  So it seems that you can get BDNF through both exercise and diet.  (But you need them both!)

Then last week's ALZForum carried the article on Chinese research entitled, "China Approves Seaweed Sugar as First New Alzheimer's Drug in 17 Years."

At least from the standpoint of spending, China is emerging as a world leader in Alzheimer's research.

The article discussed research that found some improvement in people with Alzheimer's disease who were given a drug called GV-971, or oligomannate, which is based on seaweed sugar.  This was a stage 3 (final) drug trial.  The results seemed promising, but it didn't look like a game-changer.  Its mechanism of action is said to be that it alters the gut biome in a beneficial way.  While the drug seems to have an open path to approval by the Chinese government, there are some issues with the data.

The biggest issue seems to be some odd behaviors in the placebo group, where their cognitive test scores seemed to improve at first but then plummet.  Some noted that Chinese people don't see doctors regularly, but all of the test subjects needed medical attention during the trial.  They wonder if unusual (for them) medical attention might have influenced cognition.  I speculate, for example, that doctors may have influenced the placebo population to make lifestyle changes, or they may have given them new drugs for ailments they found.  

Some also identified anomalies in the data that bring the results into question.  One (Chinese) scientist at Rutgers University pointed to research showing that GV-971 in mice had promoted inflammation, not helped brain health.  This brings into question the Chinese explanation for it's mechanism of action. 

An open question whether GV-971 does more than donepezil (sold under the trade name Aricept) and the other acetylcholinesterase inhibitors.  These treat symptoms without changing the course of the disease.  And donepezil made me sick.

China will likely approve the drug for use in China and then promote it in the USA and other countries.  They also plan some worldwide studies.  American researchers seem to be skeptical, but they seem to think that if it's safe, well, why not use it?

I probably would/will.

A new virus linked to Alzheimer's disease - this one in your gut

We've written before about the herpes zoster virus as a potential culprit in the development of Alzheimer's disease -- the virus that causes chickenpox and shingles.  So we quoted some authorities who concluded from their research that the shingles vaccine may provide some protection from Alzheimer's disease originating from that source.  But now there's another virus under the Alzheimer's microscope, another member of the herpes family.  But, while herpes zoster inhabits the nervous system, this one lives in your gut.

The virus is called cytomegalovirus, or HCMV.  You may acquire it as a child and experience an apparently innocuous chronic infection in your gut.  Based on autopsy results, about 80% of us show evidence of having had an HCMV infection by age 80.  So it's pretty common. 

But the trouble starts when the virus either escapes the gut into the blood stream or follows the vagus nerve to the brain.  There it comes into contact with the brain's immune cells -- microglia.  In Beating the Dementia Monster we discussed the role that microglia may play in the development of the disease, notably by way of inflammation.  This somehow triggers the syndrome of amyloid plaques and clumps of microtubules with a defective form of tau protein that we associate with Alzheimer's disease. 

I choose my words carefully here.  It's increasingly clear that what we call Alzheimer's disease comes in different flavors which have different causes.  For example (as we explained in Beating the Dementia Monster), "young onset Alzheimer's disease" or "familial Alzheimer's disease" (which often strikes in someone's 40s or 50s) occurs in a different genetic environment from "sporadic Alzheimer's disease."  The latter is the common version, where symptoms begin to appear after the age of 65.  Are familial and sporadic Alzheimer's diseases exactly the same disease but with different causes, or are they distinct but slightly different diseases?  How many forms of the disease are there?  Or how many different disease are there that we label "Alzheimer's disease?"  Opinions vary.

There was a new study conducted by researchers from Arizona State University and Banner Alzheimer’s Institute on the possible role of HCMV in the development of Alzheimer's disease.  The findings were just published (December 2024) in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, with the title, "Alzheimer's disease-associated CD83(+) microglia are linked with increased immunoglobulin G4 and human cytomegalovirus in the gut, vagal nerve, and brain."  The researchers concluded "[HCMV-microglia biochemistry] is consistent with an active HCMV infection, which may indicate an opportunity for the administration of antiviral therapy in subjects with AD."  Translation: "Stopping or preventing HCMV infections may be a way preventing or treating Alzheimer's disease."  But ... more research is required. 

Click here for more of a deep-dive on this topic.

We said here that there may be different varieties of Alzheimer's disease or even different diseases all labeled "Alzheimer's."  But, from everything I've read, they all respond to the lifestyle tools of the Dementia Toolkit.

M116 RIP, 1907-2024

Maria Branyas Morera, known to the world of science as Subject M116, died on August 19, 2024 at the age of 117.  Not surprisingly, she has been the subject of considerable interest and investigation.  Of course, everyone wants to live to 117 (don't they?), and so we want to know what her secret was.  The most notable evaluation of her story was published in the journal Cell Reports Medicine,  What were the takeaways?  Well, two were that she stayed away from toxic people, and she ate a lot of yogurt.  Apparently, a lot of yogurt.  (Yogurt is, of course, good for the gut microbiome.  And what's good for the gut is good for the brain.)  The researchers said that they "performed a high-throughput multiomics study of the world’s oldest living person, interrogating her genome, transcriptome, metabolome, proteome, microbiome, and epigenome, comparing the results with larger matched cohorts."  (Take that, you skeptics.) 

Maria was actually born in the United States to Spanish parents, but her family returned to Spain when she was 8, where she grew up and lived out her life.  Today, we think of Spain as a peaceful place, but it would have been racked by civil war, two world wars, the Spanish Flu, and then a terribly repressive government during the first half of her life.  (Remember for whom the bell tolls ... it tolls for thee.  (Apologies to Ernest Hemingway and John Donne.))

Not surprisingly, the findings of the Cell Reports study focused on both genetics and lifestyle.  She allowed doctors to collect samples of her blood, saliva, urine, and stool and these were studied.  These provided insights on aspects of her health, notably the health of her gut microbiome.  

The researchers observed that she had genetics that favored a long life.  Her lifestyle was what you would expect -- she was socially active (but not with toxic people), she didn't smoke, she didn't drink, and she got regular exercise.  (Although I'm not sure how many jumping jacks she was doing at 116.)  Regarding her diet, the researchers pointed out that she ate a lot of yogurt.  They thought that the yogurt reduced inflammation, which helped extend her life.  

In Catalonia, where her family originated and where she lived, the life expectancy for women is 86 years.  So she sure beat that.

One thing that surprised researchers was the very short length of her telomeres.  Telomeres are regions on the ends of chromosomes that shorten as you age.  They protect the chromosomes, but they shorten as you age and may be associated with lifespan.  Some research has gone into the hope that by preventing the telomeres from shortening, the folks that want to live to 117 and beyond can extend their lives.  This finding suggests that is a false hope.

I'm not sure what all of this means for the folks that want to live to 117.  In 2016, I was told I could expect to live to 85, although the way I feel today, I might go beyond that.  That's good enough for me.

A New Way to Live to 150?

Many years ago (40 years?), I began seeing articles in popular media about extending your life simply by eating less -- "caloric restriction" they called it.  It was noted that mice, yeast, and monkeys all lived longer if they consumed less calories -- sometimes what seemed like starvation level caloric restriction.  What was attracting attention were people doing extraordinary things to reduce their caloric intake (starving themselves) in the hope that they'd live to (as I read one man say) 150.  This phenomenon has been studied, and there is peer reviewed research (like this) about how that might work.

This suggests that anorexic people should live longer, but I wouldn't call that a good plan.  It may, however, relate to why intermittent fasting has such a positive effect on the chronic diseases (like Alzheimer's) that too often characterize old age.

I very often read about and hear from people wondering if there might not be a pill you can take that would do the same thing that fasting, dieting, and exercise do for the brain.  Well, there's a new candidate for something that might do that.  And not just the brain, perhaps every aspect of aging.  There's a "bile acid" called lithocholic acid (LCA) that might do it.  That's according to a research team at Xiamen University in China.  The acid apparently works by activating the metabolic master regulator AMP-activated protein kinase (AMPK).  Makes sense, right?  (If you figure that out, please let me know.) 

According to the researchers, significant caloric restriction  in people appears to improve metabolic health and markers of aging, even when people are not overweight to start with.  Tests with mice on Alzheimer’s disease suggest caloric restriction suppresses production of amyloid and tau and speeds removal of amyliod from the brain.  In us older folks, caloric restriction benefits working memory and processing speed but perhaps at the expense of our ability to conduct tasks that rely on good hand-eye coordination and cognitive flexibility.  But this means starving all the time and losing muscle mass, so it's not a good idea for most of us. 

According to this research, bacteria produce LCA in the small intestine when they break down primary bile acids.  LCA emulsifies fats to render them digestible.  But LCA can also be absorbed into the blood like other fatty acids produced by the microbiome, some of which improve the health of the brain.  

Remember the gut-brain axis?  Some really weird stuff goes on between the bacteria in your gut and your brain.  So take care of those bacteria.  (Eating beans and fermented foods, like kimchi, can help with this.  Some would add yogurt.  But aspartame and sucralose can be hard on the gut biome.)  

The scientists added LCA to the drinking water of some well-fed mice, and it activated AMPK in their skeletal muscles to the same degree seen in calorie-restricted mice.  While it didn’t extend their lifespans, it did boost their vigor: Old mice that ingested LCA ran farther on a treadmill and gripped a pressure-sensing bar harder. Their insulin sensitivity and glucose tolerance were better, and their muscles recovered faster after damage.  My reaction to this that, despite the promises, feeding people LCA may not actually extend your life.  But it's still improving important markers of Alzheimer's disease, notably insulin sensitivity and glucose tolerance.

So it seems like there's something here.  But all of these breakthroughs we keep seeing are frustratingly far from becoming reliable treatments.

More Stories in the News

Back on August 25, we posted about stories in the news regarding Alzheimer’s and brain science that had caught my attention. Since then, a few more stories have popped up. Several involved early detection of AD. Here’s what I’ve seen: 

1. While “neural plasticity,” the ability of the brain to constantly break and reconnect pathways in the brain, is an important feature of how a healthy brain functions, this process may go to excess in persons developing Alzheimer’s. Higher flexibility in the networks involved with vision may turn out to be a new biomarker for diagnosing the disease. Here’s an article about it. 

2. Another one bites the dust: A phase 1 study of another anti-amyloid beta antibody developed by a company named Prothena found an unacceptably high rate of brain swelling. The treatment candidate was named PRX012. Brain swelling is a significant side effect for all of the monoclonal antibody treatments, like Aduhelm and Leqembi. Here’s an article about PRX012. 

3. If you successfully completed 10th grade biology, you know that adenosine triphosphate, or ATP, facilitates the transfer of energy in the cell. (Of course you do.) In so doing, the ATP molecule loses a phosphate group that must be restored. It’s the job of another molecule called creatinine to take care of that. For some time, creatinine supplements have been sold to help facilitate physical exercise by supporting the transfer of energy in muscles. But, if you read Beating the Dementia Monster and this blog, you know that the brain uses a LOT of energy itself, and creatinine plays a role there too. New research found that creatinine supplementation in older adults (like me) appears to support healthy brain functioning. So my wife and I take 5-gram creatinine gummies once a day. Here’s an article about it. 

4. A recent study found that the lower concentrations of omega-3 fatty acids in women may help explain why women are more likely to develop Alzheimer’s. This might be remedied by women consuming more foods and supplements with omega-3s. (For example, by eating more salmon.) While we know that beta amyloid plaques and tau tangles characteristically appear in the brains of people with Alzheimer’s, Alois Alzheimer also identified the presence of lipid (fat) droplets in the brain. Failure to move the fats out of the cells may be a part of AD pathology, and it may be we haven’t been paying enough attention to this. And it may be that a poor balance between LDL and HDL cholesterol is inhibiting the proper metabolism of these fats, causing them to accumulate. (Cholesterol has an important role in fat metabolism.) This appears to be more the case with women, and some believe it might explain why women are more likely to develop Alzheimer’s. Part of the equation is the omega-3 fatty acids found in, for example, some fish oils. The recommendation would be to ensure you are consuming enough omega-3 fatty acids, especially if you are a woman. Here’s an article about it. 

5. Is Alzheimer's an autoimmune disease?  We knew that changes in sense of smell can suggest the onset of Alzheimer’s. But why? In Beating the Dementia Monster, we discussed the microglia, cells that form part of the unique immune system in the brain and how they may play a role in Alzheimer’s. Recent research suggests that a loss of control of the immune process causes the microglia to incorrectly identify olfactory nerves and attack them. This would occur in the context of the development of the disease. Hence to correlation between loss of smell and the appearance of the disease. Here’s an article about it. 

6. As we’ve discussed before, there is ample evidence associating vitamin D supplementation with brain health. It’s not just about strong bones. But why? Some recent research correlates adequate vitamin D with the preservation of telomeres, the caps on the ends of chromosomes. They get shorter with age, which makes us more vulnerable to the diseases of old age – like cancer and Alzheimer’s. Vitamin D consumption, whether in the MIND diet or with supplements, protects the telomeres that protect us. Here’s an article about it. 

7. New research reinforces our understanding of the role that problems in the gut might play in influencing the development of Alzheimer’s. The answer is, of course, a high-fiber diet – which is the answer to a lot of problems in the gut. Apparently, immune cells in an unhealthy gut can travel to the periphery of the brain and contribute to the development of the disease. At least in mice. While this finding reinforces our existing observation that a high-fiber diet is essential to brain health, it opens to door to more possibilities in how to understand and treat the disease. Here’s an article about it. 

8. There’s a new three-minute brain wave test that, so far, appears to be very good at diagnosing Alzheimer’s. It’s called the Fastball EEG. Apparently, it’s more reliable than the hours of testing I was subject to when I was diagnosed. Basically, the subject learns a set of eight pictures. Then, he or she is shown a blast of pictures at a rate of three per second. One in five of these is one of the eight pictures the subject learned previously. The EEG then registers the reaction the brain has to what it sees. This is pretty interesting, but, for ease of administration, it’ll come in second to the new blood tests we’ve discussed previously, and it may be no more accurate. Here’s an article about it.  My sense is that this test might be good at recognizing hippocampus damage caused by Alzheimer's, but it doesn't probe the other parts of the brain which may be failing due to other diseases and disorders.

This isn't all.  More next time.

The shifting research on vitamin supplements and cognitive decline

Back in 2019 we discussed reports that said not only do vitamins not help with cognitive decline, people who take them have a higher rate of all-cause mortality.  But in 2022 we heard that researchers publishing with the Alzheimer's Association were finding that maybe vitamin supplements help after all.  At least a little.  So that's confusing.

Recently, some of you told me that you'd read about new research supporting the use of multivitamins to fight cognitive decline.  The research was conducted at Massachusetts General Hospital and was published in The American Journal of Clinical Nutrition, January 18, 2024.  In the study, the memory and cognition of 573 individuals were tested at the beginning of the study, although only 492 were still available or willing to be tested at the end of the two-year study period.  The study was placebo controlled, although it wasn't clear to me how many were given the placebo.

The researchers concluded "daily multivitamin supplementation leads to a significantly more favorable two-year change in episodic memory.  [Other research studies] indicate that daily multivitamin use significantly benefits both global cognition and episodic memory.  These findings ... support the benefits of a daily multivitamin in preventing cognitive decline among older adults."  So that's good, although some commentators characterize the effect as "modest."  Some speculate that the multivitamins support the gut microbiome and the gut-brain axis, which we've discussed before.  Other experts believe that the multivitamins are simply making up for vitamin deficiencies that you would not otherwise have if you adhere to the Mediterranean diet.

Of course, the researchers did not believe their findings were sufficiently conclusive; more research needs to be done.

Incidentally, the research did not find a positive effect for executive function or attention, two deficits of brain function associated with Alzheimer's disease.  So I'm inclined to think the context for the benefits of multivitamin supplementation is more associated with slowing the effects of normal aging and less with slowing disease.

Early exposure to a "western diet" impairs memory function. Uh oh.

Yes, it's been more than two weeks since I last posted. I've had plenty to keep me busy; I'm not just running out of gas.  I hear from some of you who worry about me.  But I'm OK.

I came across some recent research with implications for the diets of children and later memory loss.  But there's no real news.  Saturated fats, refined sugar, refined flour, and otherwise processed foods are still bad.  Very bad.  What's new in this research is that the negative effects begin with children when they are on what they referred to as a "western diet."  You know, pizza, red meat, fast food, and other processed foods.  (According to the late Dr. Martha Clare Morris, in her book Diet for the Mind, pizza seems to be the very worst thing for your brain that you can take in...)

The research was published in the journal Brain, Behavior, and Immunity.  The article was "Western diet consumption impairs memory function via dysregulated hippocampus acetylcholine signaling."  The researchers claimed to find causes and effects in several areas we've discussed before, both in Beating the Dementia Monster and in this blog.  For example, the western diet is hard on the gut microbiome that has such an important regulatory function for the brain.  Also, the western diet disrupts processes in the hippocampus that are so vital to memory.

Now, to be fair to McDonald's, the research was conducted with rats, not people.  And we've discussed before how brain research results from rodent models applied to people has sometimes been discredited.  In this case, the researchers wanted to know what would happen if rats ate a western diet during their juvenile stage of development, 26 to 56 days after their birth.  The rats were fed cafeteria-style, giving them the opportunity to choose whatever (junk) food they wanted.

I'm thinking this age may correspond, in people years, to when I began to earn enough money to begin eating fast food on my own.  Fast food became my regular diet at a fairly young age.  So maybe diet in my juvenile years has something to do with why I'm where I'm at today.  But I'm confident that generally following the MIND diet over the past seven or eight years has contributed to my present well-being.