China. Or How long from the start of Alzheimer's disease to dementia?

We've mentioned before that the Alzheimer's Association is the third leading funder of Alzheimer's disease research in the world.  The United States government is first, but who's in between?  Answer: The government of China.  So we should expect to see some good quality research findings coming from China.

Yesterday, my doorbell rang, and it was my neighbor.  Stu is a retired physician who has helped me a lot in the past with this project.  He came over bringing an article from the February 22 issue of the New England Journal of Medicine (NEJM), "Biomarker Changes during 20 Years Preceding Alzheimer's Disease."  The article published some research from China that was consistent with something we said in Beating the Dementia Monster: Alzheimer's disease begins as much as 15 years before the first symptoms of cognitive impairment and 20 years before actual dementia.  

Since 2011, the medical community has been defining dementia as the point in the advancement of a neurodegenerative disease when someone can no longer completely care for themselves.  (This definition was intended to clear up confusion on how to understand the disease, but some in the medical community have been slow to get on board.)  So someone may have experienced cognitive impairment for five years, but they could still function independently.  Then they reach the point when they can no longer manage their finances.  They have crossed over into dementia.

The Chinese study confirms the existing timeline.  However, it refines it and adds more certainty to our understanding by working with a large population and collecting the results of an array of biomarkers.  Currently, a diagnosis of Alzheimer's disease requires both evidence of cognitive impairment and biomarker evidence.  

The biomarker evidence used to diagnose me in 2015 was my MRI, notably by measuring changes in the volumes of my hippocampus and ventricles.  But that was then.  This is now.  PET scans, spinal tap analyses, and now blood tests provide different ways of understanding what's going on in the brain as the disease begins, and as it advances.

What was helpful about the study was that it took a cohort of about 32,000 people and observed them for 20 years, while testing them every few years using an array of diagnostic tools.  All were initially found to show no evidence of cognitive deficit, but some developed Alzheimer's disease during the 20 year study period.  The number actually used at the end of the study was 1,789, since many had dropped out or were untraceable for various reasons.  At the end, the researchers identified 648 individuals who had developed Alzheimer's disease and matched them up, person by person, with a control population that did not.  Matching was with others in the study with similar sex, age, and education level.

Interesting to me was their ranking of how early different biomarkers would anticipate a medical diagnosis, indicating the sensitivity of the test.  Least sensitive was cognitive testing, which means that all of the biomarkers have some level of predictive power for future cognitive impairment.  But the least sensitive biomarker was hippocampal volume ... how I was diagnosed.  They concluded it would anticipate a straightforward Alzheimer's disease diagnosis by only eight years.  This was how I was diagnosed, but I was already impaired.

Next was "neurofilament light chain" (from spinal tap cerebrospinal fluid (CSF)) that anticipated a diagnosis by an average of nine years, total tau protein in CSF - 10 years, and some specific tau protein measurements that would anticipate a diagnosis by 14 and 18 years.  (Since the disease is detectable at an average of 18 years, we can infer that some would actually be detectable at 20 years -- if you use the right test.)  

Based on my read of the report of my own spinal tap, I believe that I actually received this most sensitive of these analyses.  The conclusion of those who read and interpreted my results was that the results could be Alzheimer's disease, but they were ambiguous.

There were a couple of qualifiers in the report.  One was that the population of subjects was entirely Han Chinese.  We know that studies of diverse populations for Alzheimer's disease have produced diverse results.  Whether due to genetic differences or lifestyle differences, Alzheimer's disease affects different ethnic groups differently.

Another qualifier was that they excluded people with a family history of Alzheimer's disease and those carrying genes associated with developing the disease.  This means they excluded persons with young onset disease, because it is so strongly associated with three specific genes.  It also excluded those carrying the APOe4 gene, which is the one 23andMe and other genetic services test for.  So they excluded certain types of Alzheimer's disease.  

On the other hand, they primarily included only people like me, people for whom no cause other than lifestyle could be correlated as causing the disease.  Presumably, they also excluded people who developed the disease because of lifestyle factors that they shared with others in their families.  (In Beating the Dementia Monster, we discussed how the appearance of multiple cases of Alzheimer's disease in one family may result from shared habits more than shared genetics.)

We define Alzheimer's disease as a neurodegenerative disease characterized by the presence of amyloid plaques and neurofibrillary tangles in the brain.  A big question: when we see plaques and tangles in the brain, is it always the same disease?  Is the disease arising in the presence of a variant of the gene for the amyloid precursor protein the same as the disease that arises in the presence of the APOe4 gene?  Is that the same disease I have (and, presumably, the Chinese subjects) where there is no apparent genetic factor?  We don't really know.  In fact, the more we learn about this disease, the more we find out that we don't know.

Aduhelm/Aducanumab RIP, and Where I'm at

In Beating the Dementia Monster, we told the story of my rejection from the clinical trial for aducanumab. After the trials had their rather ragged ending, Biogen marketed the monoclonal antibody as Aduhelm.   Several members of the FDA's advisory panel quit in disgust with the FDA's decision to approve it, and Biogen marketed it initially at $52K/year.  Then Medicare placed some significant restrictions on when it would be covered.  So it had a rocky start.

Enter lecanemab.  Marketed as Leqembi, this was Biogen's commercial version of the newer monoclonal antibody that had looked better in clinical trials than aducanumab.  So, in January of this year, Biogen discontinued sales of Aduhelm in favor of Leqembi.  

In Beating the Dementia Monster, we referred to lecanemab by its original code name, BAN2401.

If a drug's generic name has "mab" at the end, it's a monoclonal antibody.  For a refresher, some antibodies are taken from the blood of elderly people who do not have Alzheimer's disease.  The antibodies identify and destroy beta amyloid in the brain.  These are peptides that appear in Alzheimer's disease and seem to be one cause of memory loss.  So these mabs are good at cleaning out the brain.  The ability to clean amyloids out of the brain is an amazing feat of science, but that this will improve memory and cognition is based on the "amyloid hypothesis."  And that is very much in question.  As we discussed before, cleaning out the amyloid plaques doesn't always lead to improved memory and cognition.

I wanted to mention here that, by all indicators, I continue to do quite well.  I continue to apply all of the Dementia Toolkit, and my subjective experience with respect to memory and cognition seems to me to be consistent with the complaints of my friends of the same age.  

Researchers at the University of Washington continue to test me weekly, and I am quite happy with my unscientific analysis of my results.  However, they are only testing my short term memory, which I believe only informs us about what is happening in my hippocampus.  But that's ground zero for Alzheimer's disease, and it tells me a lot.

What's frustrating is the continuing deterioration of my balance.  I'm told this is neurodegenerative cerebellar dysfunction ataxia.  Nevertheless, when I wake up each morning, I can't believe how great I feel and how positive things really are.  (I just think back to how things were in 2015, before I began implementing the Dementia Toolkit.)

Some Clarification on my Hippocampus Volumes

Someone posted a comment recently about how remarkable the changes were in my hippocampus volumes measured between 2017 and 2021.  In Beating the Dementia Monster, we cited research showing that brain volume may increase with exercise.  This might include an increase in volume of the hippocampus, ground zero for memory processing.  So, in 2017 and 2018, my normalized hippocampus volume was recorded in two MRIs as <1 percentile for men my age.  In other words, among 100 men my age, I would have the smallest hippocampus.  The conclusion was that my hippocampus had atrophied due to Alzheimer's disease.  But in 2021, a new MRI found that its volume was in the middle of the normal range, at the 52 percentile.

This was certainly good news.  Hippocampus volumes <1 percentile is what is found with people in memory care.  Nevertheless, the numbers here can be deceiving.  This does not mean that my hippocampus got larger.  The raw data says that it did not.  It does mean that the atrophy of my brain had been dramatically slowed. 

While some research found increased brain volume in some people who began exercising, as a rule, all brains atrophy as we age.  Normal brains atrophy at a rate of about 1% per year, while the brains of Alzheimer's disease patients atrophy at a rate of about 4% per year.  So by tracking hippocampus volume as a percentile for men my age, we are actually measuring the rate at which my hippocampus is atrophying with respect to other men.

My neurologist tells me that the normalization processes uses men in 10-year increments.  For example, if I was in my 60s in 2017, my hippocampus would likely be compared to men in an age range of 60 to 69.  I would have been 68, near the older end of the decade.  So (if my understanding is correct) my brain was being compared with men as much as eight years younger than I was.  But when my MRI was conducted in 2021, I was 72, and my volume was now being compared with men in a range of 70 to 79 years of age.  It shouldn't be surprising that my normalized volumes were better on the 2021 MRI than earlier ones, because I was now being compared to men older than I was.

Make no mistake, <1 percentile is a bad number, and it supports the Alzheimer's diagnosis.  Applying the tools of the Dementia Toolkit has significantly altered the course of my cognitive impairment. 

A Good Book on Intermittent Fasting

You may recall that, back at the end of 2019, my wife and I were visiting family in Hawaii.  For New Years, there was a celebration at my wife's sister's home, where we had a discussion with one of my wife's Millennial nephews.  When he approached us, I noticed that he looked remarkably more fit than the last time I had seen him, although he hadn't looked that bad before.  He immediately began talking about intermittent fasting, something I'd never heard of before.  He was on the 5-2 plan, meaning he ate normally five days per week, but had less than 600 calories two days per week.  He mentioned that, in addition to losing weight, he thought he could think more clearly.

We returned home a few days later.  About that time, I received a kind of cryptic email from my sister asking if I'd seen the recent research on fasting.  The answer was no, but I figured I'd better investigate.  The day after we got home, I went to the gym and got on the treadmill.  I immediately began searching YouTube about fasting, encountering a couple of videos referencing an article in the New England Journal of Medicine (NEJM).  I resolved to look for the article on the Internet when I got home.

Well, I was home for about an hour, when the doorbell rang.  It was my next door neighbor, a retired physician who had taken a strong interest in my experience.  He had in his hands the pages he'd torn from his recent copy of the NEJM; the article on intermittent fasting.  "Here. You might be interested in this," he said.

And I was.  And it launched me on my own journey with intermittent fasting.  Regular readers of the blog know that we have posted on it a number of times, and I have been fasting about 20 or so hours a day since then.  I wrote about it in the second edition of Beating the Dementia Monster. 

When I began fasting, the first thing I noticed -- after about two weeks -- was that the chronic arthritis pain in my neck just stopped.  I had deeper pain in my lower back which persisted.  But that, too, disappeared after about six months.  This was not expected, but it reflected the influence of fasting on inflammation.

Has five years of fasting helped my memory and cognition?  I'm applying it alongside all elements of the Dementia Toolkit, and I have no real way of knowing which elements have more or less power than the others.  Nevertheless, I am really, really happy with the state of my memory and cognition at this time.  (I just wished my balance issues would respond as positively.)  I'm sure it's doing something, and I don't want to rock the boat by changing anything.

I recently finished a book by the man who seems to be one of the most highly regarded researchers on the topic of intermittent fasting, Dr. Mark P. Mattson.  The book is The Intermittent Fasting Revolution, and I got it on Amazon.  When I began reading it, I learned that he was actually the author of the NEJM article that started me going back in January, 2020.  For some, the book may be a little hard to follow, since it goes fairly deeply into the science.  But I had a few takeaways worth sharing.

First, it notes that the Western habit of eating three meals per day (topped off with a carbohydrate-rich late-night snack) is not a natural eating regime.  Our ancestors may have feasted on a fresh kill, but likely went hungry until the next hunt. In order to out-smart their game, their brains would have been at peak cognitive performance when they set out.  So the brain functions best when it's in the fasted state.

When fasting, the body exhausts its supply of glucose from carbohydrate metabolism.  It undergoes "metabolic switching" to rely on keto bodies instead as an energy source in the brain.  The keto diet does something similar, although I'm not an advocate for it.  

Mattson describes a variety of metabolic processes that occur in the fasted state that improve brain health.  One of these is the production of the brain-derived neurotrophic factor (BDNF) that is also produced during sustained aerobic exercise.  BDNF from aerobic exercise is likely the single biggest reason that I am not in memory care right now.

He says that exercise in the fasted state gives brain diseases a double-whammy.  Exercise and fasting are powerful, but together, the level of power seems to be greater than the sum of the parts.

For himself, Mattson applies a 6 to 8 hour daily eating window (compared to my 4 or 5 hours).  He started out with a 5-2 plan, but found (as I did) that it was simply easier to adjust to a daily routine.

In addition to getting the body into ketosis through fasting, he emphasized the importance of inducing autophagy.  This is a complex topic, but it's about the removal of dead cell debris from the brain.  The ability to remove debris from the brain is important to its resistance to Alzheimer's disease.

While we won't go into detail here, he also explained my experience where intermittent fasting promotes the same functions in the circulatory system as the drug sildenafil.

Why do I apply an eating window of 4-5 hours when Mattson "only" applies 6-8 hours?  I have seen apparently credible experts on YouTube saying that this is what's required to achieve the level of ketosis and autophagy necessary to address Alzheimer's disease.  Are they right?  Do they know what they're talking about?  Mattson doesn't discuss a 4-5 hour window.  When interviewed on YouTube, he says he's not sure how long it takes to get fully into autophagy.  But he doesn't discuss how to approach Alzheimer's disease with intermittent fasting once (as in my case) the disease has begun to truly assert itself.  He discusses Alzheimer's disease a lot throughout the book, but mostly from the standpoint of prevention.

He does warn that fasting should not be done with children, people with anorexia, or the frail elderly.  (Perhaps I can be described as elderly, but I don't seem to be frail...)

For me, the book was a great read, although he assumed a fair amount of sophistication in the reader.  And it increased my confidence in my fasting routine.

Vitamin D for dementia ... but how much?

Back in September, we wrote about research finding that supplementation with vitamin D was shown to reduce the risk of developing dementia.  My own primary care provider had recommended that I take vitamin D, so I had been taking 50mcg a day of vitamin D-3.

So what are these units?  It turns out that supplements and medications are measured in different ways.  "Mcg" stand for microgram, or one millionth of a gram.  And a gram is 1,000th of a kilogram.  But these are also often measured in "international units," or IU.  Fifty mcg turns out to be 2,000 IU.  

As we noted in the earlier post, vitamin D isn't really a vitamin, it's a hormone.  Hormones only signal different parts of the body to do certain things.  The hormone insulin signals cells to take up glucose from the blood.  It does not actually participate in metabolism of glucose.  Vitamin D signals the initiation of a number of processes throughout the body, including the processes associated with bone development.

Vitamin D is normally produced in the body when the skin is exposed to sunlight.  During winter months, and when people otherwise don't get out in the sun enough, we don't have enough vitamin D to prompt the various processes that it controls.  Including, apparently, some processes that defend against dementia.  The concept here is that the supplements will make up for the missing exposure to sunlight.

So there are different kinds of vitamin D with different numbers associated with them.  Kind of like the B vitamins.  But the B vitamins are not hormones, and it makes a big difference if you have B-12 or vitamin B-6.  However, the research we reviewed in September wasn't able to find a big difference between how different D vitamins function.  So it seems which vitamin D you take doesn't matter.  So I get vitamin D-3 at Costco at a reasonable price.

But what's an appropriate dose?  There are warnings about overdosing, and some recommended supplement doses are quite low.  Fortunately, there is some new research leading to a conclusion that 2,000 IU per day is the sweet spot.  And, as it turns out, that's often the dose of commercially available supplements.  Like the Costco gel cap that I take.

The research was published in the journal Nutrients, with the title "Vitamin D Supplementation: A Review of the Evidence Arguing for a Daily Dose of 2000 International Units (50 µg) of Vitamin D for Adults in the General Population."  (Note µg = mcg.)  It claims to have weighed the dose required to produce positive results in a number of bodily process against doses that might be harmful.

While the September article explicitly discussed influence of vitamin D on dementia, the study in Nutrients did not.  It did, however, discuss influence on the development of diabetes, which is difficult to separate from Alzheimer's disease.  Because lifestyle has so much to do with how both Type 2 diabetes and Alzheimer's disease develop, Alzheimer's disease is sometimes called Type 3 diabetes.

Both vitamin D and vitamin K2 contribute to similar functions in the body and my act synergistically.  According to this study (and a few others), the results with respect to health from supplementation with both together is greater than what would be expected as the sum of both.  So you will see vitamin D and vitamin K2 offered together in the one supplement.  Some say they should still be taken separately.  I take them separately, but I haven't seen research demonstrating that as necessary.

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.