Alzheimer's Disease Research on the Final Frontier

We learned this week that, at 90 years of age, William Shatner will be flying into space aboard a SpaceX rocket.  Good for him.  As for me ...  I thought about it.  No thanks.

There's also some other interesting news about outer space in the realm of Alzheimer's research.  We kind of understand how beta amyloid forms in the brain, but not completely.  And perhaps a better understanding of this process can help us find a way to stop beta amyloid from forming and damaging, even killing brain cells. 

Dr. Amir Hirsha of Rensselaer Polytechnic Institute has come up with the novel idea of studying formation of the renegade peptides we find in Alzheimer's and Parkinson's diseases in a weightless environment -- or rather in "microgravity."  Since early August, they have been conducting experiments with insulin on the International Space Station (ISS) to study the formation of amyloid fibrils under special conditions.  Initial studies have been with insulin to model the process, and later studies will actually use alpha-synuclein (Parkinson’s) and beta-amyloid (Alzheimer’s) peptides. 

Peptides are strings of amino acids that are not long enough to qualify as proteins.  Before becoming a peptide, beta amyloid was a protein known as the "amyloid precursor protein," but it was cut into pieces by a couple of enzymes.  You will, of course, already know this if you read Beating the Dementia Monster.

The problem with doing the research under normal gravity is that you must conduct it in a container, maybe a test tube, and the containers don't simulate conditions of the brain very well.  A part of the process of amyloid fibril formation involves movement of fluids.  The forces that exist between layers in moving fluids influence the reactions, and friction with container walls will interfere with the fluid motion.

So what Dr. Hirsha and his grad students are doing is analyzing reactions inside drops of fluid suspended weightlessly inside the ISS.   They are able to generate circulation within the drops, clockwise on one end and counterclockwise on the other.  This produces the forces between the layers of fluid that more closely resemble what happens inside the brain when the fibrils are formed.

(Fluid mechanics was my worst class in college...)

Where will this lead?  I have no idea.  But it illustrates both how little we know about how Alzheimer's disease progresses and the ingenuity we are applying to learn what we need to know.

I Saw my Neurologist Again...

This past weekend we traveled to Seattle, and I saw my neurologist yesterday.  I was specifically concerned that my balance has gotten very bad, and I've begun to shuffle like men I know that are 10 years and more older than I am.  It's keeping me from some things I enjoy that require physical agility, such as going places for photography.  I haven't fallen yet, but it seems like a matter of time.  But something very unexpected (to me) came out of the visit. 

In the past year I have flown twice to the East Coast, once with my wife, and once (in August) by myself.  On this past trip I was shocked by the number of people offering me their seats or helping me with my bags on buses, on the airplane, in the airports, etc.  It didn't happen on our trip in the spring.  I guess I have begun to look really, really old and frail to people, although I feel plenty strong at the gym, working out on the treadmill and with weights.  The problem is that my balance issues cause me to shuffle and appear a lot more feeble than I am.  And I look increasingly awkward getting up and down stairs.

If you read Beating the Dementia Monster, you know that the very first sign of trouble for me back in 2013 was problems with balance.  They sent me for physical therapy, where I learned very effective habituation exercises that gave me great relief.  Following 10 minutes of exercises, the relief would last three or four days.  But that stopped working just about a year ago.  I have been able to systematically evaluate my meds, and I know they aren't the problem.  Or rather, I've been able to stop taking the ones that have clearly contributed.

During my visit I met a new colleague of my neurologist who specializes in movement problems, such as with Parkinson's disease.  She did most of the examination, and then the two neurologists collaborated on trying to find a resolution. 

One very good outcome is that I will get another MRI.  My last one was in 2018, and I am personally interested in physiological changes in my brain that research shows may have come as a consequence of my lifestyle changes.  I'm specifically hopeful that my hippocampus may have grown.

However, they are interested in a possible connection between my balance problem, a chronic cough that I'm trying to resolve, and visual migraines (more properly called "scintillating scotoma") that I experience daily.  I had always called these "ocular migraines" (more properly called "retinal migraines"), but they are not the same.  Ocular migraines originate in the eye, while visual migraines occur in the occipital lobe of the brain; in the back, where the optic nerves plug in.  Ocular migraines affect only one eye, while visual migraines affect both eyes simultaneously.  

I will look into this further, but I'm thinking there may be a connection between visual migraines and Alzheimer's disease.  A quick Google search suggests there are.  As we noted in Beating the Dementia Monster, one of my early challenges was being unable to drive, likely due to Benson's Syndrome, also called posterior cortical atrophy.  My occipital lobe was under attack, and my brain was having trouble forming images in my mind using information from my eyes.   

Both of these phenomena are associated with migraine headaches, but I'm very fortunate to be in the minority that does not get the headache part of the experience.  So it ends up being kind of like what I imagine an LSD trip might be like, with brightly colored shimmering shapes all through my field of view.  Here are some artists' reasonably accurate renditions of what we see when we're having one.  (Some of these incorrectly confuse visual migraines with retinal migraines, calling them ocular migraines.)  Most of my episodes last about 20 minutes.

Yesterday I had one while we were on the freeway returning from Seattle.  (Speed limit 70 mph.)  A rest area came up quickly, so I pulled into it until the episode has passed. 

But I've also been trying to resolve a chronic cough.  The cough comes as a result of excess mucous production in the nasal cavity.  The first ENT specialist I saw about it a few years ago said that the solution was some significant surgery, but that it hadn't helped some of his previous patients.  So he wouldn't do it.  Later, I was told that the surgery involved removing a nerve connecting the nasal cavity to the brain.  My new ENT suspects a neurological component to the problem, and he is pursuing that angle.  The neurologists are also picking up on this theme.  It's why they think a new MRI is called for.

The neurologists are both of the opinion that my intermittent fasting routine may be contributing to the problem, at least to the visual migraines.  I don't know if the fasting didn't have a significant influence on my improved test scores last July, so I'm reluctant to back off on that.

So now I'm trying to get a new MRI, but they also want me to see two more specialists at Harborview.  Hopefully, these can be done online.  And hopefully they can find me some new answers, especially that might help with my balance. 

A New Study on Omega-3 Fatty Acid Supplements and Alzheimer's Disease

It has been known for some time that eating fish provides a level of protection from Alzheimer's disease, especially if red meat is eliminated from the diet.  The assumption was that omega-3 fatty acids in the oil in the fish was the protective agent.  Therefore, using fish oil supplements was deemed to be a good protective strategy.  (Omega-3 fatty acids are also found in olive oil and tree nuts, and these too convey a protective effect.)  But innumerable placebo controlled studies failed to support the notion that fish oil itself, separated from the fish, provides protection.  As with some other food-borne agents (like resveratrol), once the agent is separated from the food, the agent loses its protective or healing power.

However, a new study out of Sweden has found some preventative effect from certain omega-3 fatty acid supplements, including limited restoration of cognition in persons with mild symptoms of Alzheimer's disease.  

The study was small, involving only 33 patients, 15 of whom were on the placebo.  Eighteen were given omega-3 fatty acid supplements twice per day for six months.  The researchers looked for changes in mini mental status exam (MMSE) results and changes in biomarkers in cerebrospinal fluid (CSF).  (We discuss the MMSE in Beating the Dementia Monster.)

In a press release, Dr. Yvonne Freund-Levi noted, “We can see that the memory function of the patients in the group that had taken omega-3 is stable, whereas the patients in the control group have deteriorated. That’s what the memory tests show. But we can’t see any differences between the groups when we look at the various biomarkers in the spinal fluid samples.”  So this is kind of a disconnect.  If you see improvement in cognitive test scores, you should also see changes in the CSF.  But they didn't.

Also, the patients that did show improved MMSE scores began from relatively high levels -- maybe higher than mine when I was first diagnosed.  Subjects with lower scores at the beginning did not improve.

They concluded that this points to the need for a larger study, maybe one with 200 subjects.  In the meantime, this study does not provide a basis for changing health recommendations.  According to Dr. Freund-Levi, the existing recommendations are to be physically active and include omega-3 in your diet – in the form of oily fish or as supplement.  Do you remember the Dementia Tool Kit in Beating the Dementia Monster?  If you apply the exercise and diet tools, you're there.

First Day of the "Collaborating for a Demenitia-Friendly Washington" Conference

Today was the first day of the conference, and it did not disappoint.  We have been working hard on planning this for nearly a year, and our efforts are paying off.  Tomorrow is the second and last day.  Thanks to covid, we are again this year entirely on Zoom.

The keynote speaker, LueRachelle Brim-Atkins, told a moving story about her mother's decline.  There wasn't a dry eye in the house.  

Lue-Rachelle's presentation was followed by a panel discussion, that included a participant whom I had recruited from our local parks and rec department.  She spoke about how, as the city Recreation Manager for Parks and Public Facilities, she ensured that people working at the rec center desk would know how to recognize and respond to someone showing evidence of dementia.

I then attended a breakout session led by a woman from Prince George's County, MD who spoke on programs they have implemented in churches to care for those among them with dementia.  This included "purple services," periodic shortened worship services structured for people with dementia.  Prince George's County is near where I grew up.

After this was a talk by someone from the American Library Association in the mid-West (a Seattle ex-pat) who spoke about programs that libraries implement to serve those in the community with dementia.

If you read Beating the Dementia Monster, you know that the ability to read is one of the very late casualties of Alzheimer's disease.  People preserve their ability to read until very late in the progress of the disease.  As a result, libraries are in a unique position to serve victims of Alzheimer's disease throughout much of it's course.  

And it's the same thing with music.  In even the later stages of dementia, people respond very positively to music that they recall from their youth.  Back in 2019 we posted about a documentary called Alive Inside.  It attracted attention at the 2014 Sundance Film Festival and was all about the impact of music on people with dementia.

I expect that tomorrow will be just as interesting.

Please Support Me

Behind the governments of the United States and China, the third biggest funder of Alzheimer's research in the world is the Alzheimer's Association.  And their biggest single source of funds is the annual Walk to End Alzheimer's.  This year's walk in my city will be on October 10, and, like last year, my wife and I will be participating.  

Last year, many of you were very generous in supporting us, and I was in one of the higher percentiles of donations brought in by walkers.  I'm very grateful for that, as are the many people who need the services and support of the Alzheimer's Association -- to say nothing of the researchers who depend on their funding.  

I would again very much appreciate your support.  If you want to support me, you should visit my personal walker page by clicking here.

Thank you so very, very much for considering a contribution!

The heat is on ... the FDA

We noted previously that two congressional committees have begun investigations into how the FDA came to approve Aduhelm.  Last week, both the House committees on Oversight and Reform as well as Energy and Commerce issued this letter to the FDA stating they are "concerned by apparent anomalies in FDA’s processes surrounding its review of Aduhelm.”  And they "are also concerned by reports of unusual coordination between FDA and Biogen throughout the drug’s approval process.”  The letter is 13 pages long, and it contains 15 very detailed questions regarding the process by which they approved the treatment and how they dealt with staff dissent.  There are several probing questions concerning the FDA's relationship with Biogen.  The committees are demanding the FDA's response by September 16 -- one week from today, which 15 days after the letter was issued.

For me, this is a sort of deja vu all over again.  More than once, I've been in the middle of the maelstrom when a government agency was scrambling to provide answers to tough questions from a Senate committee on highly controversial issues.  I once even carried the answers to Capitol Hill myself.  So I don't envy them at the FDA.

The case for porphyromonas gingivalis as the cause of Alzheimer's disease gets stronger ... a lot stronger

In Beating the Dementia Monster we wrote about a connection between gum disease and Alzheimer's disease.  We noted that some believe gum disease is the cause of Alzheimer's disease, and defeating gum disease should defeat Alzheimer's disease.  This is hard to believe, considering all of the dynamics around how the disease develops and progresses.  But there's some new research findings that at least reinforce our understanding of some kind of strong connection between the bacterium p. gingivalis and the disease.  In fact, there is growing evidence that beta amyloid, considered a culprit in development of Alzheimer's disease is, in fact, part of the body's mechanism for keeping p. gingivalis from damaging brain cells.

In January 2021, we wrote about a new treatment candidate, atuzaginstat, that we hoped would be an effective antibiotic treatment against p. gingivalis.   We wrote that it had begun a phase 2/3 trial and had then passed an important milestone.  We looked forward to final results in December 2021.

While December isn't here yet, good news continues to come from the ongoing trial, sponsored by the pharmaceutical company, Cortexyme.  The news is that, among the 230 Alzheimer's patients selected as current phase test subjects, 100% showed evidence of p. gingivalis infection in their cerebrospinal fluid (CSF).  I don't know what other surveys have been done to associate antibodies and other biomarkers for p. gingivalis in CSF, but this certainly shows that the association is really, really common.  

Does that mean that killing off all of the p. gingivalis will reverse Alzheimer's disease?  That remains to be seen.  However, other research finds that the greater the p. gingivalis infection, the faster the cognitive decline.  This suggests that controlling the infection may control the rate of decline.

In late August, the pharmaceutical industry held it's annual Biomarkers for Alzheimer’s Disease Summit (online).  During the summit, Leslie Holsinger, Executive Vice President, Research and Development at Cortexyme, Inc. presented the status of the trial and discussed the significance of what's been learned so far.  Her presentation slides are here.  To me, the most interesting information was the graph on page 7 relating the speed of cognitive decline to the severity of gum infection. 

Also fascinating is the graphic on page 8 showing Cortexyme's understanding of disease progression from initial gum infection, to infiltration of the brain by the bacterium, the secretion of gingipains by the p. gingivalis, the mischief the gingipains cause, fragmentation of tau proteins (as we discussed in Beating the Dementia Monster), the involvement of ApoE proteins (from the famous "Alzheimer's gene"), and finally the body's response via beta amyloid production and inflammation.

Page 19 had some interesting test results for a female Alzheimer's disease patient from the now-complete phase 1 study.  It was a test I am familiar with in which the test subject must explain what they see in a picture.  After 28 days of treatment, the improvement is obvious.  Of course, that's just one person, but who knows what more we'll learn from the current trial?

So ... moral of the story?  Floss your teeth!

If inadequate sleep is bad for Alzheimer's, what about too much sleep?

Too much sleep is probably bad too.  So says a study just published in JAMA Neurology, "Association of Short and Long Sleep Duration With Amyloid-β Burden and Cognition in Aging."

We know that a history of inadequate sleep may promote the development of Alzheimer's disease, so the Alzheimer's Association and other authorities tell us to ensure we get enough.  But the older we get, the harder it is to sleep.  We discussed "the glymphatic system" in Beating the Dementia Monster, explaining how deep sleep enables the brain to clear cell waste and debris -- waste and debris that promote Alzheimer's disease if left in the brain.  The waste and debris include beta amyloid, which is ever present in Alzheimer's disease.  In his book Why We Sleep, Dr. Matthew Walker discusses what we have learned about the fascinating phenomenon of the glymphatic system.  Some say that ensuring you get adequate sleep is second only to exercise among the tools available to you for supporting brain health.

Dr. Walker also noted that the difficulties older people have in sleeping has led to the misconception that older people don't need as much sleep.  The reality is that older people need just as much sleep as younger people.  We just have a harder time getting it.

I continue to be quite the insomniac, so getting above a minimum number of hours of sleep is something I am always working at.  But for a long time I have been often asked, is there harm in too much sleep?  This study proposes some answers.

The study drew from data accumulated for the clinical trial of the monoclonal antibody treatment, solanezumab.  (Say that three times fast.)  Solanezumab didn't fare well in it's clinical trial as an Alzheimer's disease treatment, but it nevertheless left us with a pile of useful data to help with other investigations.  It this case, we can correlate loading of beta amyloid in the brains of thousands of normal people with their performance on cognitive tests as well as with how much they slept each night.  ("Normal people," means that none of the subjects had Alzheimer's disease.)

The researchers reviewed data for about 4,500 participants from the US, Canada, Australia, and Japan.  The participants had a mean age of 71.3 years, with a 59/41% split between women and men.  All were cognitively normal at the beginning of the trial as measured by cognitive tests, and all had their beta amyloid loading measured by PET scans.  All self-reported their experience with sleep.  Subjects were then grouped by those who got six hours or less sleep per night, those who got seven to eight hours, and those who got nine hours or more.

So what did they find?

One:  Short sleep duration was associated with higher beta amyloid loading.
Two:  Short sleep duration was associated with reduced cognition that was mostly in memory domains.
Three:  Beta amyloid loading was similar between normal and long duration sleep.
Four:  Long sleep duration was associated with worse test performance across multiple cognitive domains.
Five:  Both short and long sleep durations were associated with higher body mass index, depressive symptoms, and daytime napping.

The moral of the story?  Do everything you can to get between seven and eight hours of sleep every night.  But don't overdo it.