"Blind Spots" by Dr. Marty Makary

Dr. Marty Makary's book, Blind Spots, was available September 17 of this year and now shows up as #14 on the NY Times non-fiction best sellers list.  The subtitle is, "When Medicine Gets It Wrong, and What It Means for Our Health."  I have skimmed it and am now reading it.  The book takes a rather critical view of the approach medicine has taken to a number of health issues, pointing out that incorrect ideas propagate in the medical community and are not challenged until many people have been hurt.

The book attracted my attention because I hoped it would address how medicine has focused on a pharmaceutical approach to Alzheimer's disease as opposed to taking lifestyle head on.  That's not outside of the scope of the book, but he doesn't really spend time there.  

In Beating the Dementia Monster, we mentioned that Dr. Dale Bredesen had encouraged post-menopausal women who had stopped taking hormone replacement therapy to resume it.  Makary has the same assertion.  Women were discouraged from taking it, after a study connected the therapy with an increased risk of breast cancer.

Makary cites this as a major fail of medical science.  He cites studies that failed to support the connection with cancer, and he says the benefits of the therapy far outweigh the risks.  He specifically cites some significant statistical evidence that women taking hormone replacement therapy have a very much reduced probability of developing Alzheimer's disease.

Makary cites other conditions he believes represent failures on modern medicine, including:

-- Promotion of nut allergies in children by preventing their early exposure to nuts

-- Abuse of antibiotics

-- Demonization of dietary cholesterol and red meat

-- Origins of the opioid crisis

and more.

Makary focuses on the phenomenon of "group think."  A chunk of my engineering career was taken up with accident investigation.  I investigated serious industrial accidents as well as nuclear facility events and accidents.  The goal was always to find the root cause, a cause that could be corrected to prevent recurrence.  And quite often, we identified group think as a cause.  In group think, a consensus on a process or solution to a problem arises in the group.  Being consensus grants a proposed process or solution special authority, and so bad ideas are not easily challenged.  When the idea arises in the medical community and propagates in the culture that peanut allergies can be prevented by keeping peanuts away from young children, we get an epidemic of peanut allergies.  Even though evidence arises to contradict this belief, it remains embedded in the thinking society in general and doctors in particular. 

When I bought the book, I was hoping for more focus on chronic diseases (like Alzheimer's disease).  He seems to have some thoughts there, but they don't come out so much in this book other than in hormone replacement therapy.

Robert F. Kennedy, Jr. has some serious thoughts on chronic diseases.  While I definitely don't want to get into any political discussion on this blog, I was impressed to hear the focus he wants to bring to chronic disease.  I heard him speak on the subject.  He wants to make changes to the food supply and otherwise discourage the lifestyle habits that lead to many chronic diseases.  Alzheimer's disease would, of course, be a prime target for such an effort.

My New Speculation on the Sundowning Phenomenon

In Beating the Dementia Monster, I commented on mild depressions I was experiencing in 2015, 2016, 2017, and perhaps later.  They would begin in late afternoon, but disappear in the later evening.  During my diagnosis, my doctors asked me a number of questions suggesting they were investigating my reports as sundowning.  They never concluded anything, but I'm convinced this was sundowning.

Originally, the depressive episodes occurred four or five times per week, but became less frequent when I began changing my exercise, diet, and other habits.  To my recollection, they did not decrease in intensity, but they became less frequent as I proceeded with implementing the Dementia Toolkit.  After six months, they occurred something like twice per week; and after a year, once every two or three weeks.  Or so I recall.  It seems that during 2017 they might occur once every couple of months.  At this point, it's been several years since I had an episode.

In Beating the Dementia Monster, we discussed the conventional medical hypothesis that changing shadows late in the day cause confusion among the elderly with dementia.  But I haven't seen this explained as proven fact, and, quite frankly, I reject it.  I said that during one of the worst periods of my experience, we traveled to Alaska during summer.  At 9 p.m., the sun was still high in the sky, and I didn't experience an obvious period of "changing shadows."  Nevertheless, I experienced the depressive episodes according to the same timing as back at home.  As near as I could tell, the experience in Alaska was identical to what I experienced at home.  I speculatively concluded that the timing of the episodes was more associated with my circadian rhythm than environmental factors. 

What may (or may not) support my speculative take on this is this article referred to me by my friend, Teale.  We've written several times about new methods for diagnosing Alzheimer's disease, including blood tests.  The article refers to some new research from the University of Surrey in the UK exploring some of these blood tests.  The tests, of course, look for proteins and other chemical biomarkers for Alzheimer's disease in the blood.  What the researchers were surprised to discover is that the biomarker concentrations varied with the circadian rhythm and were highest in the evening ... right when sundowning occurs.  So ... something we don't understand about Alzheimer's disease varies according to the circadian rhythm.  For some reason -- without a clear cause and effect relationship -- both chemical activity and depressive episodes vary together.

Now I am making this connection all by myself.  From what I can see, no one has tried to connect this phenomenon in blood tests with sundowning.  But for me, it makes a lot more sense than the changing shadows hypothesis. 

BTW, here's a picture I took on our trip to Alaska.  I kind of like it.

What's up with Alzheimer's research?

So I haven't posted for a while.  One of our children was married over in Seattle, and, as an elder in our church, I've had a lot to do there.  And then I sometimes have slow periods finding content I think you'd find interesting.

For those interested, I've given up on acupuncture for insomnia.  At least according to my Fitbit, I had some minor, transitory improvement in sleep quality, but I can't really say it did anything for my insomnia.  So I just continue to adapt to life the way it is.

But what’s been going on in the world of Alzheimer’s research?  Are there new drugs coming?  Any breakthroughs in understanding the disease?  Well, here are a few items of interest that I’ve noticed.  It’s certainly not complete, and the items are in no particular order.  Spoiler alert: there are no breakthroughs.  But these were interesting to me. 

Fosgonimeton, a drug with a history of safety, was expected to improve cognitive and daily functioning in adults with mild to moderate Alzheimer’s disease.  But it failed to meet its goals in a recent second phase of a three-phase clinical trial.  The drug was being developed by Athira Pharma.  It is not designed to remove amyloid plaques.  After all, removing amyloid plaques may not be the best approach to treating the disease anyway.  There were some positive improvements in some of the test subjects, so this drug may not be dead yet.

Alzamend Neuro and Massachusetts General Hospital are preparing to conduct a Phase 2 clinical trial of a candidate treatment code named AL001.  This is an oral therapy being developed for dementia related to Alzheimer’s disease.  It will use a new system for delivering lithium to the brain.  So far, pre-clinical studies and the Phase 1 trial have demonstrated its safety with a small group of test subjects … the main purpose of Phase 1 trials.  But I don’t see any claim that the earlier trials found any improvement in memory and cognition.

Amylyx Pharmaceuticals is testing an oral therapy code named AMX0035.  In a recent trial, the study drug reduced the levels of several biomarkers associated with Alzheimer’s disease.  A company press release stated, “The results from this exploratory analysis suggest that AMX0035 engages important pathways implicated in the [development] of Alzheimer’s disease and other neurodegenerative diseases.”  Despite these results, data from a Phase 2 trial showed that six months of oral treatment failed to slow cognitive decline compared with a placebo.

In a proof-of-concept clinical trial, treatment with a prospective pharmaceutical, CT1812, previously called Elayta, slowed the decline of cognitive function among adults with mild to moderate Alzheimer’s disease.  That’s according to results after about six months of treatment at trial sites in the U.S., Europe, and Australia.  In a company press release, Lisa Ricciardi, president and CEO of CT1812’s developer Cognition Therapeutics said, “The trial showed that after 182 days of treatment, [CT1812] demonstrated evidence of clinical improvements on cognition coupled with a favorable safety and tolerability profile.”  Ricciardi added that the findings “will inform dose selection and provide a foundation for advancing [the therapy] to the next stage of clinical development.”  Of course, a “proof of concept trial” comes even before a Phase 1 trial.  So this one has a long way to go.

As I found out when I was first diagnosed, donepezil (Aricept) can cause significant gastro-intestinal issues.  That’s why I stopped taking it.  This is a problem with this whole class of drugs, the acetylcholinesterase inhibitors.  Now, the FDA has approved the oral therapy Zunveyl (benzgalantamine), previously known as ALPHA-1062.  Zunveyl carries the acetylcholinesterase inhibitor galantamine through the digestive track and then into the blood stream before releasing it.  This bypasses the stomach issues.  According to Dr. Elaine Peskind, (with whom I am acquainted), an Alzheimer’s expert at the University of Washington School of Medicine in Seattle, approval of the drug “marks a meaningful step forward in improving the quality of life for those living with Alzheimer’s and their families.”

Administration of Montelukast oral film, an existing therapy being repurposed by Intelgenx to treat mild to moderate Alzheimer’s disease, led to significant improvements in patients’ cognition versus a placebo.  This was according to a report of a Phase 2 clinical trial.  The drug was approved years ago as a treatment for asthma, but it may have value in treating Alzheimer’s and Parkinson’s diseases.  But there was a confusion factor in the report summary: “[W]hen considered across all doses of [Montelukast], no benefit to general cognition was observed when compared to change under placebo.”  Go figure.

A New Drug on the Horizon?

Troriluzole.  I've never heard of it before.  But it just popped up on my radar as a new treatment candidate for Alzheimer's disease.  It's currently being investigated as a treatment for some forms of cerebellar ataxia (like mine?), obsessive-compulsive disorder, and some other neurological disorders.  It's a formulation of the existing drug riluzole that is used to treat ALS -- Lou Gehrig's disease.  The re-formulation is to increase its bioavailability.  

But suddenly, a study from Auburn University in Alabama, published in the Journal of Neurochemistry, indicates that it may treat underlying mechanisms in Alzheimer's disease ... in mice.  Mice again, but you have to start somewhere.  At least we already have a lot of experience with the riluzole from a safety standpoint.  And administration of the drug to genetically modified mice -- modified to produce a disease like Alzheimer's -- improved their memory and cognition.

It's probably a long way from the work with mice to an approved treatment.  But what's interesting about this investigation is that it may lead to better insight on how Alzheimer's actually works.  It's increasingly evident that removing amyloid plaques simply addresses symptoms, not the underlying disease.  But most of the drug strategies getting attention are about removing plaques.  And sometimes removing plaques doesn't even help.  So it may be that, not only do we get a new drug that will deal more directly with the underlying disease, but we will learn more about what the disease even is.  (Because we don't really know!)

Here's an article about the research.  But beyond what I've said here, the discussion gets pretty deep.

Whither the Acupuncture?

Back on August 10, we wrote that I had begun getting acupuncture treatments for my insomnia.  At the time, I had completed one treatment, and believed I had gotten some improvement.  Not that I didn't wake up in the middle of the night as in the past, but that first night my Fitbit recorded significant improvement in sleep quality.  So I thought it was worth continuing to see what would happen.  (Some of you suggested this was a placebo effect, and -- I don't know -- maybe you're right.)  The research I cited in my August 10 post used six treatments as a benchmark for evaluation.  I thought that was a good goal for me.

Except that I need to be good at counting to make sure I get all six...

As of last Friday, I thought I had completed the six treatment goal.  Aside from the initial boost in sleep quality, I didn't feel that my sleep had improved.  I still woke up in the middle of the night, and my sleep scores were back to being pretty bad.  So I said that last Friday's treatment would be my last.  Except that was only five treatments, not six.  (I don't count good.)

My pattern is to get to sleep relatively easily, but then wake up at 1 or 2 a.m.  When I wake up, I REALLY wake up, and in an unpleasant way.  It's painful even just to lie there.  So, I would get up and take care of a few things, but I had always been able to go back to bed and get back to seep after being up for one and a half hours.  This might yield six and a half hours of sleep.  Not ideal, but I can live on that.  But for the past few months, getting back to sleep has been nearly impossible.  I would feel unwell during the day, and I thought I could just nap after noon.  Aside from a schedule that didn't accommodate naps well, I usually couldn't even get to sleep for the nap.  If I could get to sleep, it would be only for 15 minutes or so -- not making up for what I lost the night before.

After cancelling my subsequent appointments, it occurred to me that, after starting the acupuncture, I have recently actually been getting back to sleep at about 4 a.m. and been sleeping OK after that.  Waking up last night was quite unpleasant, but I went back to bed after an hour and a half, and my Fitbit says I actually got seven hours with a (for me) good sleep quality score.  This is a more sustained improvement -- it's been a long time since I've seen that.  So maybe I was premature on cancelling my appointments, and I should reschedule.  Stay tuned.

Ultraprocessed Foods Redux

We wrote previously about ultraprocessed foods, referring to them as the "highway to Alzheimer's disease."  Some estimate that 73% of the American food supply is composed of ultraprocessed foods.  I'm thinking that, putting together my many-year history of living off of ultraprocessed foods and my history of shingles infections, perhaps there is an explanation for my disease.  But who knows.

In any event, I came across this article about some research on the effects of living on ultraprocessed foods.  The article references research published in the journal Cell Metabolism in 2019.  The researchers worked with one cohort of subjects living on ultraprocessed foods and another living for the same period on unprocessed foods.  The upshot of their finding was that, over the period of a month of living under controlled conditions, the people consuming ultraprocessed foods gained an average of two pounds, while those living on unprocessed foods lost an average of two pounds.

Those results don't say much about the influence on brain health, but in her book Diet for the Mind, the late Dr. Martha Clare Morris rounds up other research making the connections.  Ultraprocessed foods are bad for your brain.  But they taste so good...

Some commentators provide guidance that the unprocessed foods are on the outer perimeter of what's in you're supermarket, and the processed and ultraprocessed foods are on the interior.  That's consistent with my observation.  

We've listed examples of ultraprocessed foods before, but here's the list we've used in the past:

Carbonated soft drinks 

Sweet, fatty, or salty packaged snacks 

Candies (confectionery) 

Mass-produced packaged breads and buns 

Cookies (biscuits) 

Pastries 

Cakes and cake mixes 

Margarine and other spreads 

Sweetened breakfast cereals 

Sweetened fruit yogurt and energy drinks 

Powdered and packaged instant soups, noodles, and desserts 

Pre-prepared meat, cheese, pasta, and pizza dishes 

Poultry and fish nuggets and sticks 

Sausages, hamburgers, hot dogs, and other reconstituted meat products

Shingles Is Still Causing Dementia

We've written before in this blog ... and in Beating the Dementia Monster ... that there is a correlation between episodes of shingles with the development of dementia.  Shingles is caused by the herpes zoster virus which also causes chicken pox.  In fact, shingles is probably caused by the herpes zoster virus living in the body after a childhood chicken pox infection.

This topic is interesting to me because I don't have many risk factors for Alzheimer's disease.  But I did have shingles several times over the years; at least three times.  So maybe that explains my disease.

There was a new study published in August in the journal Alzheimer's Research and Therapy.  It reported on research with almost 150,000 subjects in three large cohorts of medical professionals.  Researchers followed them over decades, beginning as long ago as 1976.  Consistent with other research, they found a correlation between shingles events and the onset of dementia.  Surprisingly (to me, at least) they found that, in the context of shingles infections, carrying the APOE ε4 gene variant affected men much more than women.  (The ε4 variant of the APOE gene is what 23andMe tests for when predicting your risk of developing Alzheimer's disease.  It's the strongest genetic risk factor for Alzheimer's disease, although there are many others.)

But how much did shingles infection affect risk of dementia?  With such a large sample size and such a long period of time, we should see some reliable answers to this question.  So what did they find?

The researchers found that a history of shingles infection raised the risk of dementia by about 20%.  That's actually kind of a lot when you think about it.  

They further wrote, "Findings from these three large independent cohorts of women and men suggest herpes zoster was associated with a higher long-term risk of subjective cognitive decline. The risk may be greater for the APOE ε4 allele carriers among men, but not among women. The relation did not differ among those with potentially immunocompromising conditions. The magnitude of the elevated long-term risk of [subjective cognitive decline] may potentially be reduced by [shingles] vaccination, but further study is needed."

Note that, loosely defined, "subjective cognitive decline" is cognitive decline concerning enough to the patient to cause him or her to seek medical advice.  Statistically, these people are more likely to be diagnosed with actual Alzheimer's disease.