Alzheimer's: Nature or Nurture?

We know that both our genetics and our lifestyle contribute to the development and advance of Alzheimer's disease.  But which is more powerful?  A good question, and new research just published in the journal Brain shows some clues.  At least it shows some clues on how the question may be further pursued.

The research was led by Anouk den Braber and Pieter Jelle Visser at VU Amsterdam.  It studied 39 pairs of identical twins in their 60s and 70s and evaluated their load of abnormal tau protein.  Some also showed the presence of beta amyloid, while others did not.  (Abnormal tau and beta amyloid are markers for Alzheimer's disease.)  Identical twins, of course, have identical genetic makeup, and there was a strong correlation between the appearance and distribution of the tau and the presence of amyloid markers among the twins, but it wasn't complete.  In 86% of cases, researchers could identify twins simply by examining the distribution of tau in their respective brains.

The twins voluntarily submitted to a variety of fMRIs and PET scans the researchers used to identify the amyloid and tau distribution.

The researchers were particularly interested in how lifestyle differences might affect the markers, especially tau.  They were particularly interested in exercise habits, obesity, and social activity.  This is a bit challenging, because, as we noted in Beating the Dementia Monster, family members usually share lifestyle choices, both good and bad.

But a few of the twins did not share all of the lifestyle features of their siblings, and there was some indication that these correlated with differences in Alzheimer's disease markers.  Some twins showed the presence of amyloid plaques, when their siblings did not.  Unfortunately, there were not enough examples of differing lifestyles to be statistically significant.  This was partly due to dropouts from the study.  I'm guessing that covid didn't help that situation. 

In the end they concluded that this was a good way to explore the relative influence of genetics and lifestyle on the development of Alzheimer's disease.  But someone needs to try again with a bigger, more robust cohort of subjects.

More reading on this here.

A novel method of Alzheimer's disease drug absorption

In the Age of Covid, news on research has been really, really slow.  When I see something interesting I try to write about it, but it's been slow.  According to ALZForum, the most important thing about last year was the Aduhelm controversy.  But maybe things are perking up.

The company IntelGenx has just resumed the Phase 2a clinical trial of the repurposed asthma drug montelukast for mild to moderate Alzheimer’s disease, although it has some challenging side effects.  The trial was interrupted by covid.  It was approved in 1998 to treat asthma, but it appears to have anti-inflammatory characteristics and can help in the formation of new neurons.  

And the drug has been re-tooled with some new technology.  When it is inhaled or ingested it goes straight from the intestines to the liver and can get lost.  IntelGenx has a new film technology that promotes absorption in the mouth directly into the blood stream.  This bypasses the liver and allows it to travel unimpeded to the brain.

"Montelukast VersaFilm" may have advantages over ingested medication, including an easier method of administration. It's an oral film that allows for increased concentration at the affected site because it bypasses the body’s initial treatment of swallowed medications in the liver.

The phase 1 trial found that VersaFilm administration was safe and tolerated by healthy subjects.  It had 52% higher bioavailability than other forms of administration (pills or inhaled), and it easily crosses the blood-brain barrier.  (We discussed the blood-brain barrier in Beating the Dementia Monster.)  But did it work?  That remains to be seen.  If it worked really well in the phase 1 trial I believe that we'd have heard more about it.

For the current trial, patients will receive the drug once or twice daily for 26 weeks.  After 26 weeks, they will receive a battery of neuropsychological tests.  I'd guess the tests will be similar to the tests I've been getting almost annually since 2015.

It will be a while before we know anything, but if the re-tooled montelukast does anything at all to improve memory and cognition, it can rival Aduhelm.  Semiannual MRIs won't be required, and it will be a lot cheaper.  Montelukast is already generic, although we will need to spend more on the VersaFilm technology.  But I doubt it will be the $28,000 per year that Biogen wants for Aduhelm. All factors considered, it may not need to do much to challenge Aduhelm.

You can read more here.

Meditation and Insomnia ... and Alzheiemer's disease

I have not slept all night for about two years. I can often (not always) get to sleep reasonably quickly, but I will invariably awaken at about 2 a.m.  If I just lay in bed after that, I will not get back to sleep. I apply all of the rules of sleep hygiene -- consistent bed time, dark room, no screens before bed, room temperature around 68F, exercise during the day (not near bed time), little or no caffeine throughout the day (and none in the 6 hours or so before bed time), and no eating for 3 hours before bed time.  I also use a white noise (or Brown noise) machine.  I'm sure that if I backed off on any of these, things would get much worse, but I'm still up every night at around 2.

I remember the good old days when I would eagerly go to bed at 11 p.m., fall right to sleep, and wake up refreshed at 6 a.m. -- seven hours later.  Those days are long gone.

I have tried some meds.  My neurologist recommended trazadone, but that wrecks my already struggling sense of balance.  Belsomra and Ramelteon help some, but the insurance company won't cover more than one prescription per year.  I can afford some Ramelteon at the cash price, but Belsomra is $1,400 for a 3 month supply.  (No thank you.)  And I'll still wake up.  I will, however, feel like I slept more soundly when I did sleep and feel better during the day.  Neither of these drugs disturbs my balance, and I have not experienced any rebound when stopping them.  If fact, after taking these for a couple of days, my sleep after discontinuing them seems better than before I started.  Most importantly, I feel rested all day and not wanting to take a nap.

For the last year, I've been a little satisfied by simply accepting that I won't sleep, and getting out of bed soon after I awaken.  I'll be up for about an hour and a half, and it's likely (not guaranteed) I can get back to sleep after that.  If I get to bed at 9:15, I would often finally get up at 7 or sometimes 8.  So I would need to dedicate 10 or 11 hours of my day to sleep.  But sometimes I would be completely unable to get back to sleep.  This would lead to a pretty nasty day.

But it's not quite as bad as it would seem.  Before things started to go badly on my sleep (perhaps a little more than two years ago, maybe more), I would normally begin my day with an hour and a half or so of Bible reading and prayer.  So now I do this during the time when I am up in the middle of the night.  

Over the past year of so, I've been reading and hearing from friends and family that meditation can help with sleep.  My wife's long time friend, now in her 80s, tells Amy that she had had a lot of success with meditation in improving her sleep.  My mother and some of my siblings have similar stories.  A lot of people have stories about how melatonin helps with their sleep, but the best research says that it's primarily a placebo.  Dr. Matthew Walker allows that it's a particularly powerful placebo.  I've taken a lot of melatonin, but it's never done a thing for me.  (We discussed melatonin back in March 2021.)  So is meditation another placebo that works for some but wouldn't work for a skeptic like me?

When we think of meditation, we often think of Eastern religions.  There is someone sitting in the lotus position, singing "Ouuuuuuuummmm...."  The person focuses on a secret word, and tries to empty their mind.  Is that what people are talking about when considering meditation that will help with sleep?  Maybe not.

My mother sent me this research report on meditation and sleep from the journal Frontiers in Neurology.  I also found this report from the Journal of Alzheimer's Disease which explicitly addresses a beneficial effect for Alzheimer's disease.  

Why would meditation help with Alzheimer's disease?  Especially in diet, much of what we do to fight the disease is to reduce inflammation in the brain, and apparently meditation can help with that.  At least according to these studies.

While Yoga and meditation are related as artifacts of Eastern religion, they are not the same thing.  In the HABIT study we discussed in Beating the Dementia Monster, the only domain they evaluated that produced positive results was Yoga.  My guess is that Yoga may also influence inflammation.

So is the meditation in these studies the same as the meditation of Eastern religions?  Does this practice of meditation also involve trying to empty the mind?

According to the Bible, Jews and Christians are to meditate on the Bible day and night.  Some of us interpret that to mean to select brief passages for repetitive reading or memorization.  Gregorian chants recall this.  

And according to the study my mother sent me, the goal is not to empty the mind.  There is no secret word, but the practice does involve finding something to focus on repetitively: a word, a thought, breathing, a sound, or a short prayer.  Their full prescription goes like this:

1. Comfort: Sit easily in a chair or on the floor. 

2. Quiet: Be alone in a spot where you will not be disturbed, i.e., no texts, emails, cell phones, etc., while eliciting the relaxation response. 

3. Tool: Focus on a word, thought, breathing, sound, or short prayer. 

4. Attitude: When other thoughts enter your mind, re-focus on your tool to the exclusion of everything else for 10 to 20 minutes twice a day. 

Amy's friend has focused on her breathing, and she says that it has really helped her.  She also said that it didn't help right away; it took some time.

So what about me?  For months before I read this, I had been making a point of counting my breaths as I tried to go to sleep.  This seemed to be the same sort of thing, but maybe not.  But after reading the research report, I began to try to meditate more deliberately and in keeping with their formula.

So what "tool" do I use?  Sometimes in our liturgy at church we use this chant based on Psalm 102.  The chant was originated by the Taizé Community, a French religious order, and this rendition of the chant is performed by a Catholic church in Canada.  To me, it's stunningly beautiful.

I was discussing with my wife the distinctions that I see between this kind of meditation and the meditation of Eastern religion ... at least as understood by American popular culture.  The report states explicitly that the goal is not to empty the mind.  For me, I am emptying my mind of a lot of clutter and replacing it with something beautiful.  Especially when I use good quality headphones. 

So how is this working out for me?  I've been at it for several weeks, and I can't say that it has produced overnight results.  Amy's friend said that it took a while before she had results, and I've been having trouble making sure that I do it consistently twice a day.  

But subjectively, at least, I am doing better.  I still wake up at 2 or 3 (or 12), but I feel that I have slept more soundly than before, and I don't get sleepy during the day.  Where I would sometimes need until 8 a.m. to get a full night sleep, I'm consistently up around 6:30, feeling well rested throughout the day.  And I've still had my devotional time during the night.

The Aduhelm controversy is not dying down ... at all

Aduhelm continues to be in the news, even with its dramatically lowered price -- $56,000 per year now reduced to $28,200 per year.  These prices do not include the cost of regular MRIs to check for brain hemorrhages.  Patients would still have an annual copay of $5,640.  Since it's not clear that the treatment actually works, should insurance companies be covering it?  Should Medicare cover it?  It depends on who you ask.

My high school classmate, Mike, sent me this article from the WaPo that sums up the situation pretty well, as does this later article from Alzheimer's News Today.  For 2022, Medicare is raising the standard monthly premium from $148.50 to $170.10.  Half of that increase is intended to provide a cushion to pay for anticipated Aduhelm treatments, although, so far, not many people seem interested.

So will Medicare cover it?  To begin with, it's important to understand that we're actually in a phase 4 trial.  Because of the nature of the FDA's provisional approval the treatment got, Biogen is still on the hook to produce real-world data that shows people actually improving when they get it.  That data remains to be collected.  "Improving" doesn't mean they get better or that the progress of the disease is reversed, only that the rate of decline slows.  Biogen wants to do this in a population of paying customers.  

So what does Medicare say about that?  In a recent press release, the Centers for Medicare and Medicaid proposed a system in which they would cover it in a "coverage with evidence development" protocol.  In other words, they will cover people only in the context of participation in a controlled drug trial.  This has ignited a fire storm.

Dr. Matthew S. Schrag, a vascular neurologist at Vanderbilt University Medical Center said, “This drug is an empty promise.  It’s very unlikely to provide beneficial effects.”  Vanderbilt will not offer Aduhelm, nor will Cleveland Clinic, Johns Hopkins, the University of California at Los Angeles or the University of Michigan, all due to lack of evidence of efficacy.

But the Alzheimer's Association is all in on Aduhelm, and they screamed bloody murder. They hyperbolically decried the “shocking discrimination against everyone with Alzheimer’s disease, especially those who are already disproportionately impacted by this fatal disease, including women, Blacks, and Hispanics.”

It seems to me that the Alzheimer's Association is wrong to place so much confidence in Aduhelm at this stage of the game, and I think they are seriously overplaying their hand here.

It will be interesting to see how this all plays out.

Another nose spray for Alzheimer's disease? It's worth a try.

My friend Paul, high school classmate from many, many years ago, sent me an article about use of the antibiotic rifampicin to prevent or treat Alzheimer's disease.  The article talked about administering the antibiotic to the brain using a nasal spray.  Apparently, rifampicin is protective of the brain in ways other than by being an antibiotic.  This has actually been known for several years, as explained in this article from 2018.  But the trick is to get it past the blood-brain barrier (BBB).  Another trick is to prevent the liver damage that rifampicin is famous for.

Why a nasal spray?  To get around the BBB I presume.  If you read Beating the Dementia Monster, you know that I participated in a trial of the use of nasal insulin.  Twice a day for 18 months I squirted insulin into my nose so that it could be transported directly into the brain without going through the blood stream.  The insulin followed the path of the olfactory nerve into my brain.  The BBB was not an issue with insulin, since it must get into the brain anyway.  They simply wanted a higher level of insulin in the brain than in the blood flow servicing the rest of the body.  

But it's a little harder for rifampicin, and it won't pass easily into the brain from the blood stream.  So going through the nose bypasses the BBB.  (I wrote previously about the higher levels of dementia among people who live near freeways or in areas of high air pollution.  It's believed that pollutants are entering the brain via the pathway of the olfactory nerve.)

The article that Paul sent me is here.  It is about starting drug trials to find out if this will work.  The plan is to combine rifampicin with resveratrol and have people squirt that in their noses.  If you read Beating the Dementia Monster, you know that we find resveratrol in red wine, and it's thought to support brain health when taken in wine.  (As a supplement it seems to be ineffective.)  But, at least from what I read, the function of the resveratrol with the rifampicin is to prevent liver damage.  How that will happen, I don't know.

But, so far, it all seems to work great in mice. 

I don't know if they will be drawing on anything from the insulin study, but that study was bedeviled by problems with the design of the applicator.  They redesigned it several times, but after they told me the trial had failed to produce improved cognition, I read that there was still doubt about how well the applicator delivered the insulin.  Hopefully, they won't have similar problems with a rifampicin trial.

So what is this antibiotic going to do in the brain?  Apparently in mice it has mitigated the rise of amyloid plaques and defective tau proteins.  It has also prompted the production of the brain-derived neurotrophic factor (BDNF).  In Beating the Dementia Monster, we explained that BDNF is generated in aerobic exercise and in intermittent fasting, and it can both repair damaged neurons and prompt stem cells form new neurons.  

The 2018 research found that rifampicin conducts "inhibitory activity on free oxygen radicals, tau and beta amyloid protein accumulation, microglial activation, apoptotic cascades, and its most recently defined stimulating effect on brain Aß clearance." In other words, in addition to generating BDNF, it reduces oxidation and inflammation, while booting out beta amyloid and bad tau.  Who could ask for more?

The trials haven't started yet.  We'll see what happens.

Video of my Talk to Asia Is now Posted on YouTube

In my previous post, I said that I had spoken by Zoom to about 100 people in the Philippines, and maybe one or two in Singapore.  I have now posted the video on YouTube.  Click here. 

There is nothing in this presentation that wasn't in my talk at Miramar Beach back in May.  Click here for that one.  When it comes to making presentations, I'm more comfortable speaking in person than by Zoom, so I may have done a little better back then.  But this recent event was still interesting.

I spoke to the Philippines last night (and Singapore)

At the behest of my friend, Dr. Jimmy Chua, I spoke to a couple of churches in Manila last night, and maybe to some others who tuned in from Singapore.  Via Zoom, of course.  At the peak, there were about 100 participants.  I was joined by Dr. Dan Washington, a neurologist who reviewed the second edition of Beating the Dementia Monster before it went to publication.

It seemed to go OK, but I have an easier time speaking with people in person.  We did record the session, and I'm hoping to get the recording to post on my YouTube channel with my other talks.

Dr. Chua also has contacts in Latin America, and he wants me to talk about my experience with English-speaking people there as well.  He had me record something in Spanish a few months ago that he used (< 5 minutes), but I'll want to speak in English on a Zoom call.  I am in the late stages of producing an edition of Beating the Dementia Monster in Spanish, and I'd want to have that ready before going ahead with a Zoom call to Latin America.

Updated national action plan to address Alzheimer's disease goes after lifestyle risks

Ten years ago today, President Obama signed into law the National Alzheimer's Project Act (NAPA) (Public Law 111-375).  As the law required, Health and Human Services (HHS) developed the National Plan to Address Alzheimer's Disease.  The plan addressed many aspects of the challenge presented by the disease -- such as data tracking, public awareness, research funding, caregiving -- and including prevention.  But it's not clear that we're preventing much of it yet.

So on December 27, 2021, HHS released an update to the plan that, among other things, strengthens its posture on prevention.  I was encouraged by this because it places a lot more emphasis on the preventability of Alzheimer's disease through lifestyle changes.  That includes lifestyle changes targeting dementia precursors such as diabetes and cardiovascular disease.

Recall that as many as 40% of all cases of Alzheimer's disease are preventable through appropriate lifestyle changes.  If you read Beating the Dementia Monster you know what needs to be addressed: physical activity, sleep, social engagement, diet, head injury, mental activity, etc.  

We briefly discussed the correlation between hearing loss and the advent of Alzheimer's disease in January 2020 and again in December 2020.  The hypothesis is that hearing loss interferes with social engagement, and lack of social engagement is a risk factor for Alzheimer's disease.  I wish I had devoted more space to this in the second edition of Beating the Dementia Monster, and perhaps I will in a future update.  (I am currently working on a Spanish language edition.)  So I was gratified to see that they are now addressing hearing loss in the updated action plan.

The lifestyle updates in the form of new actions in the plan are in Goal 6, and they are as follows:

• Action 6.A.1: Enhance the focus on risk reduction in existing research summits
• Action 6.A.3: Expand and diversify clinical research studies on promising interventions to reduce individual and community-level risk
• Action 6.A.4: Enhance research to better understand the varying levels of or types of dementia risk across demographic groups 
• Action 6.A.6: Expand research on the impact of emerging potential risk factors such as COVID-19
• Action 6.A.7: Continue clinical trials on the most promising health promotion interventions
• Action 6.B.1: Educate the health care workforce about risk reduction
• Action 6.B.2: Increase access to hearing aids for individuals with hearing loss
• Action 6.C.1: Convene summit to establish public health priorities for reducing Alzheimer’s disease and related dementias risk factors
• Action 6.C.4: Improve nutrition by lowering sodium in the food supply
• Action 6.C.5: Promote physical activity among older adults
• Action 6.E.3: Reduce financial barriers to hearing aids for individuals with hearing loss
• Action 6.F.1: Target and coordinate public health campaigns aimed at reducing risk factors
• Action 6.F.3: Enhance the reach and effectiveness of public health messaging on blood pressure control

These are the new and updated actions.  There are existing actions that more passively address lifestyle and Alzheimer's disease, but this is a significant upgrade.  I've highlighted in red a couple of items that more strongly underscore what we said in Beating the Dementia Monster about lifestyle.  

The number 1 goal of the NAPA action plan is to "prevent and effectively treat Alzheimer's disease and related dementias by 2025."  But being overweight is a risk factor for Alzheimer's disease.  I read about a recent survey saying that most Americans believe their weight is "about right," but 74% of us are overweight and 43% of us are actually obese according to the CDC.  If the NAPA plan goal is to be realized, we will need to make some pretty big changes in lifestyle very soon!