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.

Artificial Intelligence to diagnose your Alzheimer's disease?

How Alzheimer's disease is diagnosed has been a moving target for a number of years.  But the gold standard has been and remains -- wait for it -- the autopsy.  But some of us would like to know more before then.

Until 2011 or so, doctors didn't usually pronounce Alzheimer's disease until it was already presenting as actual dementia.  Since then, it's become clearer that the disease may begin as much as 20 years before dementia and 15 years before the first symptoms.  We call that nominal five years between when symptoms first appear until dementia "mild cognitive impairment" (MCI). 

So how is Alzheimer's disease usually diagnosed?  And, if the disease is progressing silently for 15 years, can it be diagnosed prior to MCI?

I'm not a doctor, and I don't even play one here.  But my read of available information is that a doctor will assess cognitive issues mainly through interviews with relatives combined with cognitive testing.  (We discuss this in Beating the Dementia Monster.)  Prior to a formal diagnosis, this evidence must be augmented by biomarker evidence.  Originally, this might be a brain MRI showing typical atrophy of the hippocampus and expansion of the ventricles.  This is how I was assessed.  More recently, biomarkers may be different types of PET scans of the brain, blood tests, and analyses of cerebrospinal fluid.  But even with these in place, our understanding of the disease is so fluid that we may still have difficulty declaring that a case of MCI or dementia is caused by Alzheimer's disease rather than any of the 30 or more other known causes of dementia. 

A goal of some of these diagnostic tools is to identify the disease during that initial 15 years before the first symptoms appear.  Some hope that blood tests will reliably do that.  But it looks to me like the jury is still out.  So there is some subjectivity to the process for the medical professional.  What can be done to refine the process and improve its accuracy and our confidence in the diagnosis?

A company called Darmiyan has just received FDA approval of some artificial intelligence (AI) software to do that.  The software is called BrainSee, and it uses AI to analyze the same information a radiologist will look at.  But it should make a better educated guess.  In their clinical trials, they stacked up diagnoses made by live medical professionals looking at MRIs and cognitive test results with those of their AI robot.  The result?  In summary, the claim is that the clinicians got it right 71% of the time, while BrainSee got it right 83% of the time.

As we said in Beating the Dementia Monster, all brains atrophy with age.  But Alzheimer's disease accelerates the atrophy, and the atrophy may occur in different patterns.   The claim of the developers is that the AI robot can see specific patterns in a way that's better than a human clinician.  Since it's AI, it's up to the robot to decide how to assess the MRI and cognitive testing evidence, so it sounds to me like they really don't understand the details of how the robot gets better results.

Or that's how I read it.  

Darmiyan says, "In a side-by-side comparison between BrainSee and hippocampal volume to predict progression to AD-dementia in 409 [Alzheimer's MCI patients], hippocampal volume performed with 65.0 percent sensitivity, 78.2 percent specificity and 71.6 percent balanced accuracy; BrainSee performed with 84.3 percent sensitivity, 81.6 percent specificity and 83.0 percent balanced accuracy."   

A lot has changed since my initial diagnosis in 2015.  I've changed due to my implementation of the Dementia Toolkit (meaning my brain has changed -- for the better).  But the science and diagnostic tools have also changed.  Considering my robust brain health, a common question I get is, "Are you sure you have Alzheimer's disease?"  I understand the question, but all I know is what the clinicians told me using the evidence they collected in 2015.  I wonder what the BrainSee robot would say, given the same information.

New research on intermittent fasting and brain health

Back in early 2020, I read an article in the New England Journal of Medicine (NEJM) about the benefits of intermittent fasting and brain health.  The article listed many benefits, only one of which was a defense against Alzheimer's disease.  The proposed mechanism with respect to brain health was that fasting encouraged the body to produce the brain-derived neurotrophic factor (BDNF), much as happens in sustained aerobic exercise.  We, of course, discussed BDNF and exercise in Beating the Dementia Monster.  BDNF can repair damaged brain cells and prompt stem cells in the hippocampus to form new neurons.  The NEJM article prompted me to begin a daily fast, which I continue to this day.

When I began, the first thing I noticed after only two weeks was relief from arthritis in my neck.  Six months or so later, I had relief from arthritis in my lower back.  This seems to reflect a reduction in inflammation.  I also lost weight at first, but my body seemed to get used to the fasting, and it was still the same challenge to keep my weight under control.

Since then, the scientific understanding of fasting and brain health has advanced, and I've posted whenever I've seen news.  If fact, I've posted more than 12 times about it.

So now, there's more news, this time from the Buck Institute.  The association of fasting with BDNF is clearly not the whole story.  Some new research was published in Nature which now associates the positive effect with the work of a specific gene, OXR1.  This gene protects cells from oxidative damage, an important factor in Alzheimer's disease.  

The article, "OXR1 Maintains the Retromer to Delay Brain Aging Under Dietary Restriction," is a bit more complex than I want to get into on this forum.  Also, the research is more with fruit flies than human beings.  So I'm not sure how much it really tells us.  But the researchers are all excited about its implications.  Of course, it's not pointing to a new treatment program, it's just trying to explain another way in which intermittent fasting is good for brain health. 

A press release from Buck Institute quoted one researcher:  “When people restrict the amount of food that they eat, they typically think it might affect their digestive tract or fat buildup, but not necessarily about how it affects the brain,” said Kenneth Wilson, PhD, Buck postdoc and first author of the study, published online on January 11, 2024 in Nature Communications. “As it turns out, this is a gene that is important in the brain.”

So do I think three years of intermittent fasting has helped my brain?  I have no idea.  I'm doing everything I can to protect my brain, and I just know that it all really works.  At least for me.  Which tools in the dementia toolkit have the most effect?  There's no way to tell, but I sure will keep doing them all!

Can ultrasound help remove amyloid?

The other day, I was driving home from the gym and saw my neighbor waiting at the bus stop in the cold.  Of course, I stopped to pick him up and take him to the library.  He's a retired physician who has macular degeneration and can no longer drive.  On the way, he mentioned that he'd seen a very interesting article in the New England Journal of Medicine (NEJM) about using ultrasound to speed the movement of Alzheimer's disease medications into the brain.  I had seen the news, although I hadn't looked into it very much.

Before and after this event, I actually heard from a couple of you who had seen the news stories and suggested I look into it.  Which I did.

Long story short, a team of researchers at the West Virginia University Rockefeller Neuroscience Institute used a device that could focus sound waves on different parts of the brain to improve uptake of Alzheimer's medication.  The sound waves briefly weakened the blood-brain barrier, allowing more Alzheimer's disease medication to get to the amyloid plaques than otherwise.  They hoped the medication would then be more successful at removing the plaques.

So how would this work?  We discussed the blood-brain barrier in Beating the Dementia Monster, but you should know that it has to do with the construction of circulatory system capillaries in the brain.  Capillaries throughout the body must run near cells so that oxygen and nutrients can escape the capillaries and get to the cells.  Carbon dioxide and cell waste molecules must also be able to enter the capillaries and be taken up by the blood for removal from the body.  So there are holes in the walls of the capillaries.

The brain has special needs unlike other parts of the body.  It has special needs for protection from microorganisms that cause infection, and so it is isolated from the rest of the body.  In fact, it has its own separate immune system.

The capillaries in the brain have smaller openings in the walls to allow nutrients and waste to pass between the brain and the blood.  This prevents larger molecules and particles, like bacteria and viruses, from entering the brain.  And monoclonal antibodies, like those in Aduhelm and Leqembi must pass through the barrier to get to the brain ... but they're kind of big.  So they need help.  And the ultrasound causes the openings in the capillary walls to open wider.

To do this, the researchers injected tiny micro-bubbles in the blood.  The sound waves cause the bubbles to expand and contract, and this causes the openings in the capillary walls to open wider.  

So how did the research on this work out?  According to this article (no, I didn't purchase the NEJM article), researchers have been working for years on techniques for using ultrasound to briefly weaken the blood-brain barrier.  And this turns out to have been a great opportunity to apply that research.

This was a "proof of concept" trial with only a few participants.  The researchers were pleased with the results, but we have yet to see if this will actually accelerate the removal of amyloid plaques. 

And then there's the other problem that we discussed before.  How effective are these monoclonal antibodies at improving the lives of Alzheimer's patients?  Does removing the plaques improve memory and cognition?  Is the "the amyloid hypothesis" valid?  This is not clear, but it's where most of the research money is going.  It will be interesting to see if future studies with ultrasound find that the technique actually produces improved memory and cognition.

New Research on Young Onset Dementia

You may have seen news articles about a study of young onset dementia published in Nature Neurology.  We discussed younger onset (or familial) Alzheimer's disease (AD) in Beating the Dementia Monster.  We said that, while the cause is much more (perhaps entirely) influenced by genetics than older onset (or sporadic) Alzheimer's, it is often very much affected by lifestyle interventions.  But when I began to read the news articles about it, I got the impression the researchers found most young onset dementias were being caused by lifestyle factors -- smoking, alcohol abuse, sedentary lifestyle, etc.

I went to the journal web site where I could read the abstract without having to purchase the whole article.  After reading the abstract, I figured a couple of things out.  First, as we've noted before, "young" refers to under 65 years of age.  (I didn't always think of that as "young," but I sure do now!)  But also, the article was about all causes of dementia, not just Alzheimer's disease.  So the article addressed dementias that included those from vitamin deficiencies, stroke, etc.  Alzheimer's is conceivably a minority of these dementias in the "young."

I was surprised that the researchers found a correlation with the APOE "risk gene" that we discussed in Beating the Dementia Monster.  This gene is normally associated with old onset Alzheimer's.  And they didn't mention the "deterministic genes" we discussed associated with young onset Alzheimer's.  If you have these genes, you almost certainly will get young onset AD.

The research was conducted by scientists from Maastricht University and the University of Exeter.  They studied 350,000 cases in a European database.  The study found 15 factors associated with the development of young onset dementia, including (with my own comments):

Lower formal education (early learning appears to affect how the brain develops)

Lower socioeconomic status (I believe this correlates with other lifestyle habits, such as smoking, alcohol use, diet, and exercise)

Presence of the fourth variant of the APOE gene (I thought this only went with old onset AD)

Excess alcohol use

No alcohol use (a surprise, but alcohol abstinence may be necessitated by other risk factors)

Social isolation (we have discussed this before)

Hearing loss (this promotes social isolation)

Vitamin D deficiency (they don't mention vitamin B12, which we have discussed before)

High levels of C-reactive protein (a symptom of inflammation in the body which promotes AD)

Reduced hand-grip strength (I'm not sure why this is other than a reflection of physical fitness)

Orthostatic hypotension (a likely heart issue)

Stroke (Obviously)

Diabetes (a well-known correlation with Alzheimer's disease)

Heart disease ("What's good for the heart is good for the brain")

Depression (Possible association with social isolation)

So what is modifiable in this list?  There's not much that's inconsistent with the Dementia Toolkit we provided in Beating the Dementia Monster.  But it surprised me that they did not mention diet or exercise.  Of course, these are highly associated with vitamin deficiencies, heart disease, and diabetes. 

How Many Steps per Day?

When I call my Mom, she's often a bit distracted.  That's because she's "getting in her steps."  One way or another, she's going to get in her recommended 10,000 steps per day as reported by her Apple Watch or Fitbit ... not sure which. 

But who prescribed 10,000 steps per day, and is that a good number for every age and every goal?  Some people are interested in weight loss (or weight control), others want to optimize cardiovascular health, while others just want to live longer, healthier lives.  And the benefits may vary based on how old you are.

Some recent research provides more of a breakdown on all of this.  The research was published in the European Journal of Preventive Cardiology, and it offered a threshold as low as about 4,000 steps per day if your only interest is cardiovascular health.  Of course, if you want other benefits, you will need to do more ... even up to that 10,000 steps per day.  (10,000 steps is about five miles for most people.)

So what did the researchers do?  They performed a "meta-analysis" of other research to synthesize findings suggested by the sum of the data.  They evaluated 17 studies involving 227,000 participants.  They evaluated changes in mortality based on increments of 500 steps per day, mortality due to cardiovascular issues and all-cause deaths.  They evaluated 1,884 deaths due to cardiovascular causes and 7,574 deaths due to all causes.  They went so far as to assess the effect of 20,000 steps per day.

A conclusion was that more steps is always better, but we don't all need to be at the 10,000 steps per day level.

CNN Health quoted Dr. Maciej Banach, deputy editor-in-chief of the European Society of Cardiology, "Adults 60 and older who walked between 6,000 and 10,000 steps a day saw a 42% reduction in risk of early death, while people under 60 who walked between 7,000 and 13,000 steps a day had a 49% reduction in risk."

There was another meta analysis in 2022 with similar results.  Here is a guide someone developed from this analysis. 

I have a FitBit.  Do I track my steps?  No, I use it to track my sleep.  For my regimen, I don't think step-counting would be worth the effort.  I'm on the treadmill six-days per week at 3.5 mph with an incline of 15 degrees for 55 minutes.  As we discussed in Beating the Dementia Monster, I am going for sustained aerobic exercise, and, according to this research, about 5.5 hours a week is optimal for people known to have Alzheimer's disease.  In fact, going more than six hours per week is actually associated with a decline in cognitive ability.  (This decline applies to people with Alzheimer's disease, not the healthy control group--people who do not have Alzheimer's disease.)  If you look at the article and scroll down to their graph, you find that study participants with the amount of exercise I'm getting have nearly the same cognitive health as the control group. 

But one way or another, just keep stepping.