Is Alzheimer's one disease ... or five?

We've said before that there seems to be more than one variation of the disease we call Alzheimer's.  Alzheimer's itself is characterized by the amyloid plaques around brain cells and tangles of collapsed microtubules inside dead cells.  We discussed in Beating the Dementia Monster how amyloid plaques and defective proteins in microtubules apparently kill brain cells.  In the form of the disease we call "young onset" or "familial" Alzheimer's disease, we see certain specific genes in play, and the symptoms appear when someone is in their 40s or 50s.  This differs from the form of the disease we call "old onset" or "sporadic" Alzheimer's, where symptoms don't generally appear before the age of 65.  Sporadic Alzheimer's (like mine) seems to be less influenced by genetic factors and more by lifestyle and environmental factors.  And genetic influence appears to be from different genes than those involved with young onset Alzheimer's, perhaps more than 30 different ones.

By the way, many researchers and doctors try to avoid the term "early onset Alzheimer's," because it confuses the age of the person with the stage of the disease.  Is it early in the persons life (like with young onset disease), or is it an early stage of the sporadic form of the disease but occurring when the person is, say, 80?

So we see here two varieties of Alzheimer's disease.  But can the disease be divided more finely?  Or is it possible that we really have more than one disease that we're dealing with?  In my opinion, we don't understand the disease well enough to say if there is more than one disease, but there is new evidence that we can discern at least five subtypes.  That's important, because it may be that experimental therapies that seemed to fail only failed because they were tried on one or two specific subtypes of the disease -- without realizing the therapy might be more suitable for another subtype.  Also, the varieties may progress differently, confusing expectations and treatments.

Research on different subtypes was published in the journal Nature Aging, "Cerebrospinal fluid proteomics in patients with Alzheimer’s disease reveals five molecular subtypes with distinct genetic risk profiles."  Researchers, primarily from the Alzheimer's disease research center in Amsterdam, studied the cerebrospinal fluid of 609 people, examining the proteins they found.  Some study participants had normal cognition and no evidence of disease (the control group), while others had been diagnosed with varying stages of the disease.  Based on this evidence, the researchers believe they discerned five different subtypes of the disease. 

One thing that struck me right off the bat about these varieties was that subjects with one subtype went from the onset of dementia to death in an average of 5.6 years, while another subtype had an average survival time of 8.9 years.  That's a distinction.  Alzheimer's disease is the third leading cause of death in my state of Washington, and the sixth leading cause of death in the United States.  And, as we said in Beating the Dementia Monster, when I was 66, a researcher told me I was on track to be dead by the time I was 75.  That made sense, because at the time I was still in the mild cognitive impairment stage and so was still a few years out from actual dementia.  He also indicated that if I would just keep up my recent lifestyle changes, I could extend that 85.  And that seems to be what is happening, since I am now 75.  And I'm not dead.

But what are these five subtypes?  Well, if you're not a doctor or physiologist, they can be a bit hard to understand.  Or maybe a lot hard to understand, so we won't try to break them all down here.

But one subtype significantly weakens the blood-brain barrier (BBB), allowing trash to enter the brain from the blood.  As we discussed in Beating the Dementia Monster and in other posts on this blog, the BBB prevents larger molecules (including pathogens) from passing from blood into the brain.  This isolates the brain from the body's general immune system, so the brain must have its own immune system.  This system uses cells we call microglia.  Apparently, with this subtype, the BBB is weakened, and a variety of unwanted proteins enter the brain and begin to cause damage. 

In Beating the Dementia Monster, we said that problems with microglia could play a central role in the development of the disease.  Well, in another of these subtypes, the ability of microglia to protect the brain is impaired.  One thing the microglia are supposed to do is glom onto amyloid plaques and stop them from damaging cells.  But, in the variety here, the microglia are weakened, and their protective function is seriously reduced.

As we always hear, the authors of the study say more research is required.  And it's clear that a better understanding of these subtypes is important.  That will better inform research into treatments, since one treatment might better address subtype A than subtype B.  Also, some trials may have mistakenly found a treatment ineffective simply because it was tested on the wrong subtype.

I have always believed that there were more varieties of Alzheimer's disease than we recognized.  This research confirms my suspicions.

The Top Alzheimer's Discoveries of 2024 and my Cognitive Testing

For our blog, I try to be alert to what's going on in the world of Alzheimer's research, always looking for the next big thing.  When I find something that I think will interest you, I try to post about it here.  Of course, we have an array of readers with an array of interests.  Some say they get a lot out of posts about advances in research, while others tell me they're just interested in what's going on with me and my personal progress.

The twelve days of the Christmas season are in progress as are the eight days of Chanukah.  And so, New Years is only a few days away.  Every year in the media, this period is filled with reviews of the big events of the past year.  And something caught my eye -- an article in the New York Post, "Alzheimer's Discoveries Scientists Made in 2024."  I read it eagerly looking for something new, only to find that we have already covered pretty much all of their finds.  But here they are:

1.  A third new Alzheimer's drug was approved.  That was Kisunla, or, generically, donanemab.  We wrote about that back in July. 

2.  Blood tests could improve speed and accuracy of diagnosis.  We've been writing periodically on the progress of developing blood tests since 2018.  Here's an example.  My concern remains that a bad test result could prevent many from getting long term care insurance.

3.  Wildfire smoke raises risk of dementia.  We wrote about that in July.

4.  Alzheimer's causes physical changes in the brain.  This research "news" focused on the fact that things are going on the brain as much as 20 years before the first symptoms.  We explained that in the original Beating the Dementia Monster book several years ago, but popular media is just picking up on this now.  We wrote about this breaking news a bit cynically back in October.

My cognition hasn't been tested by my doctors for several years, partly because I don't see the point in it for now.  I'm clearly stable, and my memory and cognition are now consistent with normal aging.  That doesn't mean I'm cured; they tell me I've put the disease on hold for maybe 10 years.  Which is OK with me.

That being said, I am in several research studies that do some level of testing.  One of those is a project to validate cognitive testing done over Zoom.  They test me over Zoom, and then have me come to Seattle to test me the same way in person.  They do this annually for a couple of years.  Are the Zoom test results consistent with the in-person tests?  Once they've done enough tests with enough people they'll know.  

I have a number of things I watch in my own behavior as my personal, informal measure of how I'm doing.  Can I remember to lock my car door when I go to the store?  Am I driving well?  Can I speak or read in Spanish consistent with my history (something I do daily)?   My next Zoom test is in a week or two, and I'll have a more "official" read.  They won't tell me the results, but I've taken enough of these tests and seen how I was scored, that I can get a definite intuitive sense for where I'm at.  I don't anticipate anything disappointing.

An audiobook for Beating the Dementia Monster

So Dr. Phatak and I will be signing a contract with Echo Point Books to produce an audiobook of Beating the Dementia Monster.  Publication is still out by a few months, but it will be available on Audible (Amazon), Apple Books, Spotify, and some other platforms.  I had shied away from an audiobook, thinking it would confuse paper book sales, especially with respect to advertising.  But they tell me that people who buy audiobooks don't buy paper books and people who buy paper books don't buy audiobooks.  So this shouldn't cause confusion.

They will be using a professional voice actor to do the reading, so quality should be good.

I'm continuing to make videos for our YouTube channel.  YouTube tells me we've had over 1,000 views, but I'm still thinking of this as an experiment.  Production quality may be improving slowly, but it's still a lot of work to make one short video.  And they are short compared to others.  If you haven't been following a long, you're invited to come over to the channel and take a look.

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.

Finally - MIND Diet Trial Results

In Beating the Dementia Monster, we talked very positively about the MIND diet.  In the book, we noted that a major, hopefully definitive, trial was under way, and we anticipated that we would see results by April 2021.  But then came covid.  I stopped hearing about the trial, and updates to the trial's official web site stopped.  As you can see here, even today, the trial web site stands frozen in time, as though the trial is just getting under way.  (Be sure to click on "Study Progress.")  The FDA's clinical trials web site (which I checked periodically) showed no progress after assembling a study population.  I figured that the covid had major impact on execution of the study, and maybe it had just died.

While I was vigilant (I thought), they did actually complete the study and publish the results.  Yes, covid challenged completion of the study, but also, the results were pretty underwhelming.  So they didn't get much media buzz.  And, of course, they said nothing on their web site. 

The results were published in July 2023 (two years later than expected) in the New England Journal of Medicine.  But I only stumbled on this today.

Long story short, there was very little meaningful difference in outcomes for the two groups studied.  The study population consisted of two cohorts of about 300, cognitively normal, somewhat overweight, older people with family histories of dementia and initially poor dietary habits.  They were not trying to treat Alzheimer's, but simply measure how much decline occurred in populations with normal cognition.  They tried to keep one cohort on the MIND diet, while members of the other group were only supposed to change their eating habits to reduce their intake of calories.  For three years...

The researchers concluded, "Among cognitively unimpaired participants with a family history of dementia, changes in cognition and brain MRI outcomes from baseline to year 3 did not differ significantly between those who followed the MIND diet and those who followed the control diet with mild caloric restriction."

But the study design has its critics.  For one thing, there was some social mingling between the two groups, and some in the control group may have gotten some clues about what their diet should look like from the study group.

Some critics also said the groups were too small for statistically significant results.  Also, covid interfered with conduct of the study, and control by researchers needed to relax to telephone conversations.  And covid caused a significant number of participants to drop out.

So that was the "definitive" study.  Fortunately, there have been other studies with more positive results for the MIND diet.  We've reported on some of them, including this one.  And here's another, more recent one.  An interesting finding is that the MIND diet is more effective for brain health in women than in men.  Why?  Who knows.

So I'm staying with the MIND diet and intermittent fasting.  It's all working for me.  Why rock the boat?

Could the changes between daylight saving time and standard time aggravate Alzheimer's disease?

I hate changing from standard time to daylight saving time.  And I'm not alone.  Going from DST to standard time is OK, but that change in the spring?  Good grief.  So I'm open to any excuse for getting rid of DST, no matter how thin the evidence.  In his book, Why We Sleep, Dr. Matthew Walker points out that each year there is a remarkable spike in deaths due to heart attacks and traffic accidents in the days following the change.  We hate it, but the special interest lobbies have kept the government from taking action to do away with it.  But I want to add one more "justification" for junking it.

As we know, Alzheimer's disease can be understood as an inflammatory disease, and controlling inflammation helps control the disease.  What would it mean if we found that, in addition to heart attacks and car wrecks, the time change was aggravating inflammation, and hence, Alzheimer's disease -- or maybe, increasing the likelihood that someone would develop it?  (If they don't care enough about the heart attacks and car wrecks, would they care about this?)

There's some new research published in the journal of the Federation of American Societies for Experimental Biology.  The research report was entitled "Time-of-day control of mitochondria regulates NLRP3 inflammasome activation in macrophages," and it studied how inflammatory activity in the body (promoted by the cytokines we have discussed before) varies with your circadian rhythm -- based on time of day.  So, for example, arthritis pain from inflammation tends to be worse in the morning than later in the day.

It stands to reason (at least to my reason) that disturbing the circadian rhythm will disturb inflammatory diseases ... like arthritis and Alzheimer's disease.  So we should do away with things that disturb the circadian rhythm.  Now, there's nothing in the research that explicitly supports my thinking, but I want to promote any excuse for getting rid of Daylight Saving Time!

Is consuming olive oil associated with reducing dementia-related death risk? Answer: Yes

We said in Beating the Dementia Monster that olive oil is an important component of the MIND diet -- and, for that matter, the Mediterranean and DASH diets.  Since the MIND diet avoids stick margarine and butter, we use olive oil in their place.  I put olive oil on whole grain bread and enjoy it just as much as butter.  (Your mileage may vary...)  But how good is the evidence that olive oil is really better for you than those other fats?  Well, there's some news.

It turns out that one of the most widely read articles of 2024 in the JAMA Network publication (formerly Journal of the American Medical Association) addressed this.  The article reported on a study of 92,383 adults observed over 28 years that found those who consumed at least 7 grams per day (g/d) of olive oil had a 28% lower risk of dementia-related death compared with never or rarely consuming olive oil.  That's pretty substantial!  This was irrespective of diet quality or genetic predisposition.  Authors of the study concluded, "In US adults, higher olive oil intake was associated with a lower risk of dementia-related mortality, irrespective of diet quality. Beyond heart health, the findings extend the current dietary recommendations of choosing olive oil and other vegetable oils for cognitive-related health."

Some who commented on the research noted that it was a longitudinal study, which is considered a little less reliable than a randomized controlled study.  A longitudinal study looks at a population and draws conclusions about correlations.  But "correlation is not causation," as they like to say.  Randomized controlled studies do a better job of accounting for "confounding variables."  In a randomized controlled study, you actually change something and measure the result.  We look forward to the results of the US POINTER study which is now in progress.  It will hopefully confirm the findings of the FINGER study we discussed in Beating the Dementia Monster.  Both studies address lifestyle factors with respect to the development of Alzheimer's disease, including diet.

I'm thinking that blueberries and olive oil may be the two key ingredients in the MIND diet.  Of course, diet is a key tool in the Dementia Toolkit.

Coffee, Tea, Caffeine? Good for you, bad for you?

When I was a young boy, I wondered why the grownups wouldn't let children drink coffee.  I got the same answer I got for why they wouldn't let us smoke:  "It'll stunt your growth."  Well, I didn't drink coffee, and I didn't smoke.  But my growth was stunted anyway.

Over the years, I've read a lot of articles -- some informed, some not so much -- about whether coffee and caffeine might have bad health effects.  People worried especially that caffeine, a stimulant, could cause cardiovascular problems ... like heart attacks!  There have been a lot of studies about this, and, while caffeine does stimulate the heart, most of the studies found the effect to be benign.  

The next question is whether caffeine might play a role in Alzheimer's disease and other dementias, or if it could actually affect life span.  Back in 2020 and 2021, there were some studies that took a dim or mixed view of caffeine and Alzheimer's disease.  Here's an example of one such study from 2020 in the journal Nature.  The authors concluded, "This review suggests that caffeine consumption, especially moderate quantities consumed through coffee or green tea and in women, may reduce the risk of dementia and cognitive decline, and may ameliorate cognitive decline in cognitively impaired individuals."  On the other hand, this study suggests that coffee can raise the risk of dementia, at least if drank in excess. 

Something I have trouble sorting in these studies is the effect of coffee (which may be decaffeinated) and caffeine itself.  The coffee may be an antioxidant, which would be one effect, while to caffeine is psychoactive, which would have a different effect.

Recently, there were a couple of related research reports.  One, out of Portugal, related coffee consumption of about 3 cups a day to extending life span by 1.84 years.  The study conducted at the University of Coimbra, was an analysis of 85 other studies.  Critics noted the studies reviewed might vary in quality, and much of the data was self-reported.  Also, many of the studies were funded by self-interested commercial organizations.  So, who knows?

Another study published in Nature, September 2024, looked at the influence of coffee and tea on the development of vascular dementia, specifically among people with hypertension -- the people we thought a few years ago were most likely being killed off by caffeine.  (Vascular dementia is not Alzheimer's disease.)  The article was entitled, "Association between coffee and tea consumption and the risk of dementia in individuals with hypertension: a prospective cohort study."  So, did coffee consumption increase or decrease the likelihood that someone with high blood pressure will develop Alzheimer's disease?  

The study authors concluded there was no influence of coffee and tea on any form of dementia for the normal population.  But there was a positive effect with moderate consumption for people with high blood pressure.  This was for people drinking a half to one cup a day of coffee or for someone drinking four to five cups per day of tea.  The coffee drinkers in this range had the lowest risk of all-cause dementia.

In their words, "There was an association between the risk of dementia and coffee and tea consumption in the total population, ... The significant association between the amount of coffee and tea consumed and the risk of all-cause and vascular dementia were more likely to be found in the hypertensive population..."  "The hypertensive patients who drink 0.5–1 cup of coffee or 4–5 cups of tea per day have the lowest risk of dementia."  "...[H]ypertensive individuals consuming 0.5–1 cup daily had the lowest risk of all-cause dementia ..., compared to those having 6 or more cups daily.  No statistically significant connection was observed between coffee consumption and Alzheimer’s disease or vascular dementia risk in this group. Additionally, there was no correlation between coffee consumption and the risk of developing all-cause dementia, Alzheimer’s disease, and vascular dementia in the population without hypertension." 

My takeaway from the last study is that moderate coffee and tea consumption is good for you if you have high blood pressure.  Otherwise, it's a wash.  But going above six cups a day is probably not a good idea.

Nowadays, I'll usually drink one eight-ounce cup a day, but I take in a fair amount of caffeine in other ways.  In my youth, I'm sure I exceeded six cups in a day. 

Please note that I am not a doctor, and I don't give medical advice.  If you have cardiovascular issues, follow the direction of your physician!

Resurecting the Dementia Monster YouTube Channel -- A Good Idea?

You may or may not recall that we initiated a YouTube channel for Beating the Dementia Monster a couple of years ago.  In fact, I haven't posted much since 2022.  Why not?  Well, making one video is a lot of work, and for some of us it can be really frustrating.

I know some people with the "gift of gab" who can just start the camera and speak continuously in ways that keep the audience interested.  Not me.  I stop and start constantly, requiring hours to edit out misstatements and connect jump cuts.  Frustrating.  And to keep your "search engine visibility" up, you must constantly crank out content.  I know why YouTubers have a higher than normal suicide rate.

But I just bought a teleprompter on Amazon, and it's pretty slick.  I can read my prepared text without getting distracted and confused.  I'm hoping to make companion videos for many of my blog posts using the teleprompter.

So far, I've made one video, and you can see it here.  It was definitely a lot less painful to make than earlier videos.  But it's also obviously kind of experimental.  One problem is that you can see my eyes moving as I read, but that can be cured.

We'll see how this project goes.

Belly Fat and Alzheimer's Disease -- the Connection

In Beating the Dementia Monster, we cited research associating obesity in mid-life with the eventual development of Alzheimer's disease.  While I was studying this angle, I encountered researchers who believed, at least based on anecdotal evidence, that this was most notable when the obesity was in the form of visceral fat -- a beer belly.  So, for some time, doctors and others have noticed that people with a beer belly in their 40s and 50s are more likely to develop Alzheimer's disease.  I thought this had been studied, because I saw it discussed seven or eight years ago.  But the definitive study has only been done recently, and it hasn't even been published yet.

Research on this topic was presented this week at the Chicago meeting of the Radiological Society of North America (RSNA). The scientist presenting the research results said belly fat significantly increases accumulation of abnormal amyloid peptides and tau protein, which are precursors to Alzheimer’s symptoms.  They noted the accumulations could begin 20 years before the development of symptom.  The study also highlighted insulin resistance and low HDL ("good cholesterol") as contributing factors.  Of course, insulin resistance leads to type 2 diabetes which is strongly associated with the development of the disease.  (Or, type 2 diabetes is simply a later stage of insulin resistance.)

Why should belly fat contribute to Alzheimer's disease?  One explanation the researchers proposed was that belly fat reduces blood flow to the brain.  Apparently this is a more significant effect with belly fat as opposed to other forms of obesity.

The researchers also noted that addressing belly fat in your 40s and 50s is most effective for reducing the risk of developing Alzheimer's disease.

The researchers studied a total of 80 cognitively normal midlife individuals.  The average age was 49.4 years, with 62.5% being female.  About 57% were obese, with the average body mass index (BMI) of the participants being 32.31.  The participants were subjected to brain positron emission tomography (PET) scans, body magnetic resonance imaging (MRI), and metabolic assessment (glucose and insulin measurements), as well as a lipid (cholesterol) panel.  (My doctors used both PET and MRI scans to assess my brain.)  Researchers also performed MRI scans of the abdomen to measure the volume of the subcutaneous fat (the fat under skin) and visceral fat (deep hidden fat surrounding the organs).

Mahsa Dolatshahi, M.D., M.P.H., a post-doctoral research associate at the Mallinckrodt Institute of Radiology at Washington University School of Medicine and lead author of the study said, “We investigated the association of BMI, visceral fat, subcutaneous fat, liver fat fraction, thigh fat and muscle, as well as insulin resistance and HDL (good cholesterol), with amyloid and tau deposition in Alzheimer’s disease.  Our study showed that higher visceral fat was associated with higher PET levels of the two hallmark pathologic proteins of Alzheimer’s disease—amyloid and tau.  To our knowledge, our study is the only one to demonstrate these findings at midlife where our participants are decades out from developing the earliest symptoms of the dementia that results from Alzheimer’s disease.”  

Some of the same researchers presented their work from another study showing how belly fat reduced blood flow to the brain.  They associated this reduced blood flow with the development of Alzheimer's disease.  (I'll note, however, that I have not seen any other research associating blood flow variation with increased susceptibility to developing the disease.  It makes sense, but I don't think it's been proven.)

If you want to read more on this research, check here.