What do I do now?

In Beating the Dementia Monster, I described eight domains in which I proactively work to maintain my cognitive health.  I established habits in most of these when I was about 66 years old.  But I'm five years older now, and my habits have evolved some to accommodate my aging body.  For example, my aerobic exercise was ambitious, and I can't keep up that pace anymore.  Nevertheless, it seems my recent cognitive test scores show that it's all still working for me.

So what am I doing now?

1. I'm on the treadmill six days a week with very few missed days.  But I now go 3.5 mph with an incline of 12 degrees.  I monitor my heart rate, and when it exceeds 65% of my maximum heart rate, I start bringing the incline down to regulate it.  I ensure it doesn't approach my maximum heart rate.  I may end up at 8 or even 6 degrees.  To calculate my maximum heart rate, I subtract my age from 220.  That gets me to 149 BPM.  65% of that is 97 BPM.  So I vary the incline to regulate my heart rate between 97 and 149 BPM, but well below the 149.
2. I continue to work at the food bank, conduct activities with the Alzheimer's Association, serve in my church, participate with my photography club, and do other things that maintain social engagement.
3. I continue to eat the MIND diet.
4. I have now been fasting intermittently for more than 18 months.  I fast daily for 20 hours, confining all eating to a four-hour window.  I have had very few deviations from the regimen.
5. I take Theracurmin and another turmeric supplement twice per day.
   
6. I continue to struggle with sleep.  This is my toughest area.  The sleep meds that have seemed to work have either caused an allergic reaction (rash), caused me serious problems with balance, or both.  I follow the recommended strategy for sleep hygiene, and I use a white noise machine.
7. I have been trying to maintain intellectual activity.  I read and converse in Spanish every day, and I read both fiction and non-fiction books.
8. I've tried to maintain my stress-level on the low side.  Only problem is, whenever I back away from a commitment, another one seems to take it's place.  My wife is tired of me complaining about that...

I know these sound hard, especially the diet and exercise items.  But I think of what's at stake.  I remember how desperate I was in 2015 and 2016, and it gets a lot easier.

Six new gene variants that increase Alzheimer's disease risk

In Beating the Dementia Monster, we noted that variants of three genes can nearly guarantee that someone with one of the variants will develop young-onset (or early-onset) Alzheimer's disease.  These are for the amyloid precursor protein (APP) on chromosome 21, presenilin 1 (PSEN1) on chromosome 14, and presenilin 2 (PSEN2) on chromosome 1.  When these genes work properly, the APP protein is chopped up into water soluble fragments.  When their variants don't work correctly, the fragments are different, and they don't dissolve.  Instead, they accumulate on neurons as plaques and apparently kill the neurons.  People with these variants may develop the disease when they are in their thirties, forties, or fifties.  

But few people have these gene variants.  Some estimate that they exist in as few as 300 families around the world.

Then there is the APOE4 variant of the apolipoprotein E (APOE) gene on chromosome 19.  The APOE gene describes a protein that assists in the transport of cholesterol in the blood.  This variant, APOE4, does not guarantee you will get Alzheimer's disease, but it significantly increases your risk -- especially if your genome carries more than one copy.  Consumer genetic testing services, like 23andMe, look specifically for the APOE4 variant to describe your genetic risk for Alzheimer's disease.

However, as we noted in Beating the Dementia Monster, researchers have identified as many as 30 other genes that also increase your risk of Alzheimer's disease.  In most cases, they predispose the brain for inflammation, an important mechanism in the advance of the disease.  Researchers have been scouring the human genome to find them all, but perhaps 40% of our DNA remains to be evaluated.  So there are almost certainly more to be found. 

Six more turned up recently.  In research published in Alzheimer's and Dementia, the Journal of the Alzheimer's Association, researchers from the University of Kentucky claimed to have identified the six new genes, in addition to confirming five previously identified.  

Apparently, these genes are relatively rare.  Researchers found them by studying the genomes of members of several families in Utah, identified using the Utah Population Database.  In the database, researchers have been able to identify families with various disease occurrences, including both cancers and Alzheimer's disease.  In the case of this research, they identified families predisposed to Alzheimer's disease, and they were then able to compare the genomes of various family members, looking for similarities and differences.  This way, they found correlations of specific genes with the appearance of Alzheimer's disease. 

If you learn that you have genes in your DNA that predispose you to Alzheimer's disease, what should you do?  Read Beating the Dementia Monster!  There are things you can do.  You can fight inflammation, you can fight oxidation, and you can rebuild brain tissue.  So just do it.

A question being asked: Will we ever know if Aduhelm is effective?

Recently, my friend Mike from back in high school sent me a link to an editorial in the Washington Post, "Why we may never know whether the $56,000 Alzheimer's drug actually works."  It was written by Elizabeth Rosenthal, author of An American Sickness.  She makes the case that, because of the nature of the FDA's provisional approval system and the chronic nature of Alzheimer's disease, Biogen may simply never be able to complete a credible testing process for Aduhelm.

Biogen is committed to years of further testing as a condition of the approval.  So here's one question: How do you recruit people for the new drug trials required by the FDA's process?  People interested in the drug can already get it -- if they can get their insurance to pay for it.  So why should anyone volunteer for the drug trial knowing they could draw the short straw and spend years on the placebo?  If another, better treatment is approved, opting for that treatment means you will be removed from the Aduhelm trial.

Rosenthal notes that the accelerated approval process the FDA used for aducanumab has been applied to some cancer treatments in the past, and the FDA considers these efforts to have been wisely chosen.  This accelerated process is only used in situations where the disease in question is grave, and there is no alternative treatment.  In the case of the cancers in question, the diseases progress relatively rapidly, and you get a decisive answer to the question of efficacy quickly enough.  But for Alzheimer's disease?  The time frame for a convincing trial stretches out over a time period when the patient's health is likely deteriorating from multiple causes. 

Anger toward Biogen and the FDA has been growing ever since the approval of Aduhelm was announced.  Two House committees have already announced their intentions to investigate both Biogen and the FDA.  My sense is that the situation will become increasingly unpleasant for all involved.

Video of my talk in Florida

You likely know that, back on May 14, I spoke at a conference in Miramar Beach, Florida.  We tried to make a video of it to share here, but I kind of blew it.  I brought a new camera, and managed to really mess up the settings.  The product was unusable.  Amy did a great job as camera person, but her tech support was lacking.

However, the people running the conference also made a video, and they were willing to share it with me.  It runs about 46 minutes, and you can see it here.  You can see all three of my presentation videos by clicking here.

This just in: My cognitive test results

As I said earlier, the results of my annual cognitive tests of July 6 are to be formally presented to me by my neurologist on July 20.  However, the neuropsychologist has completed the evaluation, and the report has been posted to my patient portal.  I am quite happy with the results.

There were 51 individual tests, a few of which I'd never seen before.  A few tests I'd received in the past were not repeated.  

What follows is a terrible way to assess the results.  But I counted one of the 51 tests scored as "very superior," five as "superior," nine as "high average," 27 as "average," two as "low average," and seven "within normal limits."  

Regarding changes from last year, 14 tests were higher, and four were lower.  The rest were unchanged.

Regarding changes from 2018, four were higher and 14 were lower.  The rest were unchanged.

This bean counting doesn't reflect how much better or worse I was between tests with any rigor, nor does it provide a professional assessment of actual change.  Also, it's not clear to me how much these tests would change with simple normal aging.  It would be normal for the scores to decline over a two year period in a completely normal person, but I don't know by how much. 

The neuropsychologist's interpretation in the report is that there has been no indication of progressive decline since 2018.  (Yay.)  The report acknowledged that I did less well last year, but that could be attributed to sleep issues.  In fact, as with 2019, we should probably skip testing next year, delaying 18 to 24 months.  I'm OK with that.

Is my brain growing?

If you read Beating the Dementia Monster, or if you've heard me speak, you know that I had five MRIs of my brain between 2012 and 2018.  The MRIs of 2017 and 2018 found that my brain had atrophied to the point that, among 100 men my age, I would have had the most tissue loss.  Under normal circumstances, all brains atrophy, but brains with neurodegenerative diseases atrophy much faster.  And mine was going pretty fast.  (My first MRI was in April 2012, and it explicitly found no atrophy.)

You will also know from my book that some researchers have found an increase in brain volume among elderly people who began to get more exercise.  This could include just exercise from working in the garden -- which can be hard work.  This appears to occur when the body generates the brain-derived neurotrophic factor which prompts stem cells to form new brain cells.

What about me?  I've gotten a lot of new exercise since my last MRI.  Has my brain volume increased?

It would take another MRI to compare to the past, and that's not likely to happen.  The insurance company wouldn't pay for it because it wouldn't alter my course of treatment -- it would be for the sake of curiosity.  It would be a different story if I were to begin taking Aduhelm, because brain swelling and micro-hemorrhaging are a problem with it, and you get an MRI monthly during the course of treatment.  But I'm not doing that.  So, unless I'm involved in another drug trial that uses MRIs to assess what's happening in the brain, I won't be getting one.

Unless, of course, an unanticipated medical condition emerges that demands one.

About two weeks ago, I was sitting at the computer when I felt as if a fist or something hit me in the back of my head, kind of hard.  I was alone, so it wasn't a fist but rather some event inside my head.  It was quite jarring.  For the next minute or so, I couldn't coordinate my eyes; they just looked in whatever direction each eye wanted to look.  It passed, and things seemed to return to normal.  I had a minor headache the next day.

This actually happened once a few years before, and my neurologist and primary care provider scolded me for not going to the ER.  So I went this time.  The ER people wanted an image of my brain to look for abnormalities, so they gave me a CT scan.  The results surprised me.

First, they found no new abnormalities, and they have no explanation for either of the two events.  So now, life just seems to be going on as before.  A few days later, I had almost four hours of cognitive testing for my annual evaluation, and, as I reported before, I think I may have done better than last year.  (I'll find out for sure on Tuesday, July 20.)  So, whatever it was that happened, it doesn't seem to have had a lasting effect.

A CT scan is not an MRI, and when I discussed this with the neuropsychologist before my tests, she pointed out that the CT scan has less resolution.  Nevertheless, as with all of my MRIs from 2015 and later, the analysis of the CT scan image noted there has been tissue loss.  However, on the standard rubric of "mild," "moderate," and "severe," the report classified my tissue loss as "mild."  My previous MRIs from 2015 and later noted "moderate diffuse cerebral and cerebellar volume loss."  So I've gone from moderate to mild ... maybe. 

A question that comes to mind is, if my brain had atrophied enough to put me in that < 1 percentile category, why isn't my volume loss "severe?"  I don't know.  I'd just guess that, for men my age, the number of men with severe volume loss may be considerably less than 1% of the population of interest -- men my age.  There would then be room for men with moderate volume loss who were still in the <1 %.

That this CT scan shows that my brain volume might be increasing is pure conjecture on my part.  And my neurologist warns that changes in brain volume don't always correlate with changes in cognition.  But it has me wondering what another MRI would show.

A New Treatment Candidate from Japan

Most of the love in Alzheimer's research has been going toward getting rid of beta amyloid plaques, but there are plenty of other ideas out there.  Especially since it's not clear how effective that strategy will turn out to be in improving cognition.  Recently, my friend Jim sent me an article from Tohoku University in Japan regarding a new treatment candidate that will begin human trials soon.  So far, it has produced promising results in mice, but we know how that goes.  The Japanese medical authorities have judged it to be safe for humans.

So here's the standard disclaimer on mouse models:  Mice are not people.  In the past, research with mice has generated a great deal of excitement until it was learned that a phenomenon with mice could not be replicated in humans.  Also, mice don't get Alzheimer's disease.  Instead, their genome (their DNA) can be modified to produce a disorder similar to Alzheimer's disease in humans, but it's not the same.  Often, mice are not very good models.

But you never know.

In this case, researchers administered a new molecule called SAK3 daily to some mice.  The mice had their genes edited to produce a disorder that mimics Alzheimer's disease.  With this disorder, amyloid plaques build up in the brains of the mice, and they experience cognitive decline in the same way that humans do.  This disorder can be used to model how different treatments will affect Alzheimer's disease in humans.  As we explained in Beating the Dementia Monster, mice with this disorder experience improved cognition when they get aerobic exercise.  So what happens when they take SAK3?

Obviously, the results so far have been promising, or I wouldn't have written this.

SAK3 appears to have a positive effect on a number of neurodegenerative diseases, not just Alzheimer's.  These include Parkinson's disease, Lewy body dementia, and Huntington's disease.  What these diseases have in common is that they all involve, in one way or another, misfolded proteins.  (Jim's son has done medical research on protein misfolding.) 

So what's the deal with misfolded proteins?  As you are certainly aware, proteins accomplish a LOT of tasks inside the brain as well as in the rest of the body.  They are constructed by taking specifically ordered chains of amino acids and folding them into a precises shape.  Two of the most important features of proteins that allow them to do their jobs is their shape and the arrangement of electrical charges on their surface.  Their shape is dictated by the sequence of charges in the amino acid chain, some of which attract and some of which repel other charges.  When the chain is jostled enough, attracting charges find each other, and the chain should fold up into a precisely formed protein molecule.

Except sometimes it doesn't. 

In the case of these diseases involving misfolded proteins in the brain, the defective proteins can't do their jobs, but they can cause trouble.  The biggest problem is that they can accumulate in places where they interfere with proper function of various brain cells and can even kill them.  In the case of Lewy body dementia, there is a presence of misfolded alpha-synuclein proteins.  Being misfolded, they can't perform their necessary function, which is to regulate certain neurotransmitters.

What can SAK3 do for us?  The researchers believe that it enhances the brain's natural ability to find and destroy misfolded proteins.  It the case of Alzheimer's disease, this should include, among other things, getting rid of amyloid plaques.

But even Aduhelm can do that.  What else can it do?  It appears to promote neuronal activity by increasing releases of acetylcholine and dopamine, two neurotransmitters found to reduce in activity in neurodegenerative disease.  This, of course, should improve cognition and perhaps even impede the advance of the disease.

Researchers are only now beginning to prepare for phase one studies, and so we are a long way from knowing more.  But, who knows?  Maybe SAK3 will turn out to produce dramatic results someday, overshadowing other drug treatments.

My Annual Cognitive Tests and My Insomnia

We returned last night from a trip to Seattle where we saw our new granddaughter in person for the first time and saw another son's new (to them) house.  I also went through almost four hours of intense cognitive tests to update us on what's been going on in my brain.  To cut through the anticipation, let me say that I feel well about the results.  When they deliver the results (perhaps in 2 weeks) I expect to see actual improvement over last year.  The young man who administered the test was looking at last year's results as he administered the tests.  He couldn't say much, but he seemed very positive about how I was doing as we went along.

Before we went over to Seattle, I wrote to both my neurologist and neuropsychologist that I was not optimistic about how I would do.  I've mentioned before that I have several informal tests that I apply to track changes in my cognition, and they hadn't been pointing in the right direction recently.  I track sometime innocuous seeming absent mindedness and how well I can speak Spanish (which I do several times a week).

But the big variable is sleep.  As we discussed in Beating the Dementia Monster, the first thing about sleep is that failure to spend time in deep sleep can apparently cause or exacerbate Alzheimer's disease.  On top of that, memory and cognition on a given day are influenced by how well you slept the night before.  This is why Matthew Walker cites studies showing that students who pulled all-nighters did poorly on their exams.  

Last year, I was struggling with terrible insomnia.  I had four hours of sleep the night before the test, and I'd had four hours of sleep the night before that.  Needless to say, all of my doctors (and I) were disappointed in my performance.  Insomnia continues to plague me, but I've made progress with some medications.

Mathew Walker and most other doctors caution against resorting to drugs to solve insomnia.  Certainly some of the hypnotics, like Ambien, have been shown to make you feel well in the morning, but apparently prevented you from going into that all-important deep sleep during the night.  I applied the sleep hygiene techniques that have been recommended, and it wasn't helping.  (I intend to investigate meditation further, but I haven't seriously looked into that yet.)  My neurologist and my sleep doctor concluded that it was time to try some sleep aids.

The first was a low dose of trazadone, whose day job is as an antidepressant, but it works as a sleep aid in low doses.  It's been the go-to sleep aid for the elderly, especially for those with Alzheimer's disease.  Unlike "nonbenzodiazepine receptor agonists," like Ambien and Lunesta, trazadone is not a controlled substance, and I've found that it does not cause dependence.  I was able to quit cold turkey with no rebound effect.  In fact, I slept well when I quit, perhaps because it was training my brain to sleep at certain times.

Why did I quit trazadone?  It had not been working well to keep me asleep all night, at least at the dose my sleep doctor prescribed.  Also, it was seriously aggravating my balance problem.  I was now shuffling along, and I had some close calls with serious falls.  My sleep doctor prescribed Belsomra, which was approved by the FDA for insomnia in the elderly, notably for those with Alzheimer's disease.  

Belsomra is not generic, and so it's pricey.  But even a low dose seems to work OK for me.  On the other hand, it also seemed to cause me memory problems, so I went off of it a few days before my cognitive tests.  I did not have a problem with rebound, and it also seemed to have trained my brain on when to sleep.  I believe that having been taking the Belsomra, but then getting off of it a few days before my tests, contributed to how I did -- for better or worse, because I have yet to get my results back.  Stay tuned.

BAN2401 in the News -- and Donanemab

In Beating the Dementia Monster we mentioned that the prospective Alzheimer's treatment, BAN2401, had shown promise in clinical trials.  We also discussed its prospects on this blog as early as July 2018 and a few times subsequently.  BAN2401 is another monoclonal antibody treatment, which you can tell by the "MAB" ending of its generic name: lecanemab.   Like aducanumab, lecanemab is being developed by Biogen and its Japanese partner, Esai.   

So there is good news for BAN2401 in that the FDA has granted it "breakthrough status."  What is "breakthrough status?"  According to the FDA, its "a process designed to expedite the development and review of drugs that are intended to treat a serious condition and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over available therapy on a clinically significant endpoint(s)."  In other words, the FDA thinks the drug is important enough and promising enough that they want to grease the skids in the approval process.  This could begin as early as the phase 1 trial, although BAN2401 has just completed a phase 2b study.  

This is entirely different from the method used by the FDA to actually grant provisional approval to Aduhelm.  

The FDA's decision was based on the recently published results of a Phase 2b clinical trial of 856 patients with mild cognitive impairment due to Alzheimer's disease and mild Alzheimer's disease with confirmed presence of amyloid pathology.   In this study, an analysis showed consistent reduction of clinical decline across several clinical and biomarker endpoints at the highest doses.

But is Biogen the only show in town with monoclonal antibodies for Alzheimer's disease?  Back in April, we discussed Eli Lilly's entry, donanemab.  It too has shown enough promise to win it breakthrough therapy status.  This was announced was just days before the FDA acted on BAN2401.  It's evident that there is momentum in the world of monoclonal antibody treatments for Alzheimer's disease. 

Bear in mind that none of these treatments is a cure.  They appear to slow the progress of the disease, including the slowing of cognitive decline and memory loss.  They also support the idea that further research based on the amyloid hypothesis will bear fruit.