Now We Are Seventy-Six (Apologies to Winnie the Poo.)

Readers of this blog and of Beating the Dementia Monster know that, when I was 66, I was told by an authoritative neuropsychologist and Alzheimer’s researcher that I was on track to be dead by the time I was 75. My subsequent study of the disease found his statement was justified. However, I had also told him that I’d recently done a complete flip of my lifestyle, shifting from one that was quite sedentary to one that was active – joining the gym and paying particular attention to my diet. While I had been working from home without social interaction, I had retired and was now working with other men at the local food bank. This provided more social interaction than I’d had when I was employed. He indicated that, if I kept all of that up, I could expect to live at least to 85. In other words, based on his extensive experience with the disease, I was buying at least 10 years. 

So, about a year ago, I announced here that I had reached that 75, and I wasn’t dead. At least not yet. After all, there are 365 days in a year, and, well, who knows what’ll happen during all those days. I am, however, happy to report that I made it all the way through those 365 days, and I am still not dead. 

But what transpired during those 10 years? Readers will recall that I was in free-fall back in 2015. I had to stop driving and had episodes when I couldn’t recall our zip code or phone numbers of 35 years, even when prompted. After hours of testing at the University of Washington’s Brain Wellness Center I was pronounced “impaired.” In 2017 and 2018, my brain MRIs were for someone in memory care. 

Nevertheless, after about six months of fairly aggressive exercise and work on my diet, I began to see improvement. I may have initially been a bit premature, but I did go back to driving, and I drive quite safely now. Even in Seattle traffic. (But fortunately, we don’t go there very often.) 

I am still followed by the neurologists in Seattle, and I continue to do quite well. My personal assessment is that I continued to improve until 2019, when I seemed hit a plateau. A couple of years ago, I had an essentially normal MRI result, and my memory and cognition are no worse than anyone else I know my age. Within the last hour of preparing this post, I took an online cognitive test for a study at the University of California, San Francisco, and I’m sure that I did just fine. Not perfect, but just fine. About six months ago I took another cognitive test administered for a study at the Brain Wellness Center in Seattle. They weren’t allowed to tell me my exact results, but the results were assessed by the same neuropsychologist who spoke with me back when I was 66. He was at least allowed to tell me that I did just fine. So life is good. 

After we published Beating the Dementia Monster, I met a number of people struggling with memory loss. I usually met them through a spouse who was concerned about them. As I met more and more people who were struggling, I began to appreciate how hard it is for many people to flip their lifestyle the way I did. While I’d lived a very sedentary lifestyle for many years, I wasn’t dealing with any other chronic diseases (yet), and I’d already put considerable effort into getting my weight under control. So I had a head start on getting my physical self in order. I have, however, come to appreciate how hard it can be for many others to replicate my experience, especially if they suffer from chronic diseases. And so, while I do try to encourage people in their 60s and 70s to live well, I’m just as eager to encourage younger people to pay attention to their diet and exercise. 

I do hear from some of you from time to time, and I appreciate that. I’m hoping that there are many who see in me what they can do for themselves and are able to take control of actual or potential memory loss. But it can be hard.

In the News

I haven’t posted much lately, especially with summer travel to the East Coast and North Cascades mountains.  But I have been watching the news on Alzheimer’s disease research.  Here are some things that caught my eye:

1. A study found that having a purpose in life was linked to lower dementia risk.  The study of “over 13,000 adults found that having a strong sense of purpose in life is linked to a reduced risk of dementia. People with a greater purpose were 28% less likely to develop cognitive impairment, even when accounting for genetic risk and other factors.  This was consistent across racial and ethnic groups and modestly delayed the onset of decline by more than a month over eight years. The findings suggest that building purpose through relationships, goals, or meaningful activities may help keep the brain resilient with age.”  Click here.

2. A study found that two supplements can affect levels of gamma-glutamyl transferase (usually referred to as GTP), which is a protein where low levels are seen in Alzheimer’s disease.  (I didn’t know this.)  Some study findings which were published in the journal GeroScience, described how two compounds, nicotinamide (a form of vitamin B3) and epigallocatechin gallate (an antioxidant found in green tea), helped restore guanosine triphosphate, a key molecule that fuels energy production in brain cells. In laboratory experiments on neurons, this treatment not only reversed age-related cellular decline but also enhanced the cells’ ability to clear away amyloid protein clusters, a defining feature of Alzheimer’s.  But these findings seem to have a long way to go before we get to a protocol.  I already take nicotinamide myself, although I don’t drink green tea as often as I should.  Click here.  And here.

3.  We already knew this, but Wendy Suzuki continues to bring attention to the importance of aerobic exercise for brain health.  Click here.

4.  Researchers at St. Jude’s found that a protein, called midkine, blocks amyloid beta from forming harmful clumps linked to Alzheimer’s.  If this checks out, it could lead to breakthrough treatments.  Click here.

5.  Researchers at Harvard found a connection between lithium deficiency in the brain and Alzheimer’s disease.  “The team discovered that loss of lithium in the human brain is among the earliest alterations linked to Alzheimer’s, while in mice, reduced lithium sped up both brain damage and memory decline.”  Click here.

6.  Deficiencies in omega-3 fatty acids may promote Alzheimer’s in women but not in men.  Is this why women are more likely to develop Alzheimer’s than men?  Click here.

7.  Researchers at Rush University (home of the MIND diet) believe they have found out why the MIND diet is effective.  Click here.

8.  In Beating the Dementia Monster, we said that there was a sweet spot for exercise to improve brain health.  But too much is detrimental.  Here’s new research on how it is that too much can be detrimental.  Click here.  Of course, we’re talking a lot of exercise to get over the peak for benefit to get to a downside.

9.  Can AI develop an even better diet for dementia prevention?  The Chinese say they have it.  Click here.  (China is second only to the US government in Alzheimer's research.) 

Now We Have It -- Results of the US Pointer Study

Back in 2020, in Beating the Dementia Monster, we expressed hope that the US POINTER study by the Alzheimer's Association, then in progress, would confirm the results of an important earlier study, the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER).  The FINGER study was to be the "first study to apply a multidomain approach to dementia prevention. The main aim was to prevent cognitive impairment, and secondary aims include decreasing disability, cardiovascular risk factors and related morbidities, depressive symptoms, and to have beneficial effects on the quality of life."  We first discussed the FINGER study in 2018 and have revisited it several times since.  You will also recall that the multidomain approach to battling Alzheimer's disease was an important theme of Beating the Dementia Monster.

The FINGER study applied the multiple domains of: 1) Dietary guidance, 2) Physical activity, 3) Cognitive training and social activities, and 4) Intensive monitoring and management of metabolic and vascular risk factors.

While the FINGER study provided valuable information on the power of lifestyle to offset cognitive decline in the elderly, it had its critics.  The strongest criticism was that the subjects were uniformly white northern Europeans.  We know that dementias manifest differently in diverse populations.  And it's a principle of the scientific method that others should duplicate the results of your findings.  Therefore, several countries around the world set out to confirm the findings, although not necessarily by exactly duplicating the study.  In the United States, it was the US POINTER study.

But then there was Covid.  As with the MIND diet study, the lockdowns seriously disrupted and delayed progress on completing the study and analyzing the results.  So we had hoped to see results by 2022, but we're only seeing them now.

It's important to note that both the FINGER study and the US POINTER studies were randomized controlled trials.  Unlike longitudinal studies, they actually changed peoples' lifestyles and then measured the results.  Results were compared to a control group whose lifestyle was not directly changed.  This is far superior to the much more common longitudinal studies, in which populations are studied for correlations between, say, lifestyle and incidence of dementia.  In longitudinal studies you find correlations, but correlation is not causation.  And confounding factors can fly under the radar and bias your results.  Randomized controlled trials are much harder and more expensive to conduct, but they yield much more reliable results.

Topline results of the US POINTER study were announced at the recent Alzheimer's Association International Conference in Toronto.  The results were very positive, however I was a bit disappointed.  At least so far.  

Here's what they said: "... a structured lifestyle intervention of regular moderate- to high-intensity physical exercise, adherence to the MIND diet, cognitive challenge and social engagement, and cardiovascular health monitoring led to a statistically significant greater improvement in global cognition over 2 years relative to a lower-intensity self-guided intervention."  To which has been added, "Cognitive benefits were consistent across age, sex, ethnicity, heart health status, and APOE4 genotype."

Note the use of the word "improvement."  They didn't find that decline was slowed or even stopped, memory and cognition actually improved. 

Note that, rather than with a traditional control group, they compared test participants on a structured program to participants on a lower intensity, self-guided program.  For the test participants, they aggressively supervised them in changes to their lifestyles, while, for the "control group," they simply advised people on how to live well.  (They thought it would be unethical to discourage anyone from adopting a healthy lifestyle just to help their study.) 

For you nerds, here are the published results, or at least what's available if you don't purchase the whole thing.  There's a little more here.  And more here.

So this is a ringing endorsement of the multidomain approach to brain health.  But these were the "topline" results.  Some things remain to be discerned.  Note that they never mentioned Alzheimer's disease.  I think we can think of "topline" as "preliminary."  They haven't finished evaluating the results, and they haven't gotten to the point of saying anything about Alzheimer's.  They still need to publish information about how many test participants in the structured group developed Alzheimer's (during the two-year period) compared to how many did in the unstructured ("control") group.  That's what I was looking for back in 2020, and I'm still waiting.

Eating Pizza and Dynamic Cerebral Autoregulation. Huh?

We know that the MIND diet encourages us to consume a polyunsaturated fat called "olive oil," but warns us against saturated fats.  Like the cheese in that pizza.  That's not fair.  So why do they tell us that?

Well according to some new research, even one meal high in saturated fat impairs blood flow to the brain.  And we associate brain blood flow problems with the development of Alzheimer's disease.  

"Dynamic cerebral autoregulation (DCA)" is a process likened to a shock absorber in the brain with respect to blood pressure and blood flow.  Blood vessels must remain flexible to accommodate sudden changes in blood pressure such as occur during exercise.  Or even just getting up out of a chair.  DCA ensures blood flow to the brain remains stable despite routine changes in blood pressure, but it depends on flexible blood vessels.  

Levels of fat in the blood rise and peak after around four hours after eating a meal high in saturated fat.  This is thought to cause blood vessels to become stiffer and lose some of their flexibility.  If so, this could disrupt DCA, restricting blood flow around the body, including to the brain.  This concept is not new, but how well is the brain protected when this occurs?  According to some new research, maybe not very well.

The researchers employed about 20 young men and about 20 older men for the study.  They fed them a big milk shake with about the same calorie count and fat content as a fast food meal -- 1,362 calories and 130g of fat.  Using ultrasound, they then measured the effects of the meal on their vascular system over a four-hour period while they exercised periodically. 

What did they find?   The high-fat meal impaired the ability of the blood vessels associated with heart health to open.  This was true in both young and old participants, although it was about 10% worse in the older cohort.  So the impairments reduced the body's ability to buffer changes in blood pressure.  This can easily suggest to us that consuming saturated fat -- even once -- can affect the vascular system in a way that promotes the development of Alzheimer's disease.  Sad news, I'm afraid.

But it gets worse.  The authors published earlier research in which they found saturated fats caused an increase in unstable, cell-damaging molecules, called free radicals, and caused a decrease in the nitric oxide molecules that help blood vessels relax and open.  The relaxed blood vessels are supposed to allow blood to transport oxygen and glucose around the body -- including to the brain.  Less nitric oxide means less flexible blood vessels, which means poorer blood flow to the brain.  This appears to be the link to problems with DCA.  (BTW, the discovery of the effect of nitric oxide on the vascular system was good for a Nobel Prize in 1998.)

Here's an article about the research.  Here's a link to the actual research.

Already approved cancer drugs reverse Alzheimer's? Maybe...

It's not unusual for a drug previously approved for treatment of one condition to be found to also treat something different.  Like many men my age, I take tamsulosin for my prostate, which was originally developed as a treatment for high blood pressure.  Tamsulosin is one of the α1‐blockers, most of which reduce blood pressure.  But that didn't work out in this case.  It was later found to treat benign prostatic hyperplasia (BHP), which makes older men get up a lot during the night.  So, in 1997, it was approved for BHP and not for hypertension.

So what about Alzheimer's?  Are there drugs already approved for some condition that would coincidentally treat Alzheimer's disease?  And treat it effectively?  Suppose we sifted through some massive data base of case histories and look for people who received this or that treatment and then showed improvement in Alzheimer's symptoms?

Well, someone did that, and the results were remarkable.  According to this research, published in the journal Cell, there are two drugs approved for the treatment of cancer that can reverse Alzheimer's symptoms.  The drugs were letrozole and irinotecan.  (Letrozole, like all drugs, has significant side effects, but it looks like irinotecan can be downright nasty.)

The drugs were first identified by analyzing an array of drugs for a "signature" on how they affected the generation of proteins in the brain.  The researchers then looked for correlations with Alzheimer's improvements in a database of case histories.  They then set about testing the drugs on mice.  (Yep, mice again.)  And, well, it checked out.  At least with the mice.

With the mice, the two drugs reversed multiple aspects of Alzheimer’s disease.  They undid the protein signatures in brain cells that are seen as the disease progresses.  They reduced both the formation of amyloid plaques and tau tangles seen with brain degeneration. And -- the most important thing -- they restored memory. 

So that's mice.  But where do we go from here?  Here's an article about the study.  They are, of course, quite excited about results with mice, but there's nothing about carrying this forward with people.  I sure hope something is going on with this.

Women are more prone to Alzheimer's. Why?

It's well understood that women are more prone to develop Alzheimer's disease than men.  But, of course, women live longer than men.  So it stands to reason that by simply living longer, women will be more susceptible to any disease of old age.  But the numbers don't add up.  Women develop Alzheimer's in numbers too much greater than men to be simply accounted for by a longer life.  Women are also more likely to develop MS than men, but men are more likely to develop Parkinson's, brain tumors, and epilepsy.  Why is that?

I recently came across this interesting article that addresses possible explanations.  For Alzheimer's, two dynamics appear to be the differences in male and female chromosomes (XX for women and XY for men) and hormonal changes during menopause.

The X and Y chromosomes contain genes for sex differences.  However, while women have two X chromosomes, one of then is mostly silenced.  Mostly.  Those genes not silenced (on the chromosome that men lack) appear to be related to the immune system, brain function, and Alzheimer's disease.

The article discusses the consequences of hormonal changes during menopause, but sheds little light on how they might influence the development of Alzheimer's disease.  However, we did write about this back in 2018, with a link to a possibly more insightful article.  Or maybe not.  Mostly, they acknowledge that there must be a role for sex hormones in the development of Alzheimer's, but it's really not clear how that works.

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.