Participating in another study -- and the state of the game

The Alzheimer's Disease Research Center (ADRC) at the University of Washington's Harborview Hospital recruited me for a new study.  The people who give me my care at Harborview work in the ADRC, so I was a natural for this.  The name of the study is Clinical Core, and it's been going on for a long time -- several decades.  It's main purpose is to create an extensive database of health histories of people who have some form of neurodegenerative disease as a resource for a range of specific studies.  It also includes tracking of people with normal function who can serve as controls.

The study assesses physical condition of test subjects, testing blood, spinal fluid, and other physiological characteristics known to change with (or characterize) Alzheimer's disease.  It includes annual cognitive testing but not imaging.  

I began this past week.  Due to covid-19 restrictions, there was no in-person activity, and thus no physical testing.  They did conduct an initial, limited cognitive test via Zoom.

So how did that go?  Not as well as I'd hoped, but consistent with my tests from last June.  

I've said before that I have a range of ways in which I self-evaluate, and I'm thinking to make a graph of my experience.  Essentially, it would show a steep decline into early 2016, steady improvement into early 2019, and a bumpy road after that.  The bumpy road would show a drop-off in early 2019 and into the summer, a gradual improvement into early 2020, and a gradual decline to the present.  I believe that where I am now is certainly below where I was at the end of 2018, but perhaps a little better than the spring of 2019.  But my measures tend to be very subjective.  Certainly I am not unable to do any normal tasks requiring full cognition.  I can manage my meds by myself (they are few), and I don't have any trouble with managing finances.  The main things limiting activities I want to do are due to covid risk.

I have now been doing a pretty strict 20 hour fast for a year.  I had hoped this would make a difference, but I have no indication that it has.  But it did do a lot to relive my arthritis, so it's been worth it.  And it hasn't been as hard as I thought it would be.  Once it was a habit, it was easy to maintain.  Now it would seem strange to be eating anything in the morning.  Elderly people (a strange sounding phrase) tend to lose weight, so fasting is not recommended for them.  In my case, I've lost a little weight from fasting, but it's stabilized at a very appropriate level for someone my age.  

My stamina on the treadmill has gone down, perhaps because of the years going by.  I'm still at it for 50-55 minutes per day, but I'm slower now.  I track my heart rate, and I cut back when it gets to my target from the formula we discussed in Beating the Dementia Monster.  I begin at 3.3 mph with an incline of 10 degrees.  That gets me to my target heart rate after 20 minutes.  Then I slow down to 3.0 mph.

In early 2016, a researcher indicated to us that what I've been doing could stall the progress of the disease and add perhaps a decade to my life.  At this point, half of that decade is gone.  And so I'm not surprised by some erosion of my progress -- or perhaps a plateauing.  But I have a long way to go get back to where I was in 2015-2016.  That was when I had trouble remembering my phone number and zip code.

Sleep continues to be a problem, and I've pretty much given up on prescription sleep aids -- doxepin and trazadone.  These leave me too dizzy the following day.  I'll need to get up at perhaps 3:00 a.m. each night and do some things for about 2 hours.  Then I go back to bed and can usually sleep well after that.  I feel well when I finally get out of bed, but the research I've read associates this pattern with a higher level of beta amyloid in blood and spinal fluid.  This suggests that interrupted sleep is bad for Alzheimer's disease.  But Alzheimer's disease also causes insomnia.  So it's a viscous cycle.

Unsteadiness and dizziness continue to be a problem, and I recently went back for physical therapy.  The therapists seem to understand the problems in the brain causing the dizziness.

I don't know what the coming years hold, but I want to be clear that these past five years have been some of the most wonderful years of my life.  It has been quite a journey of exploration and learning -- even when my brain seemed to be trying not to learn.  I wouldn't have missed these years for anything, and I look forward to what's to come.          

Herpes causes Alzheimer's ... or does it?

It was almost exactly one year ago we posted on the unfolding story of the relationship between Alzheimer's disease and the herpes simplex virus.  What we said then was that the research results have been conflicting.  A year later, more research has been done, but little has changed.  Research results have still been conflicting.

According to an article this week in ALZForum, some new research in European health databases found correlations between herpes infection and Alzheimer's disease in some countries, but much less so in others.  There were also conflicting results regarding anti-viral treatments and their influence on Alzheimer's disease.  In some cases it looked like treating with certain drugs actually helped, but in other places it did not.  And then, is it herpes, or any virus -- like, for example, covid-19?

The manifestation of a herpes infection most easily followed is herpes zoster, or shingles.  Shingles is usually considered to be a late appearance of the virus following its first appearance as a childhood chicken pox infection.  But there was evidence in the research of elevated incidence of Alzheimer's disease from most any virus, not just herpes.  And then, what about bacterial infection?  They found evidence that hospitalization for any infection increased the probability of Alzheimer's disease by a factor of 1.6.  (Correlation is not causation...)

Have there been previous studies of national health databases looking for correlations?  A few years ago, three studies of the Taiwanese national healthcare database found that a severe herpes infection raised the risk of Alzheimer's disease by a factor of 2.5 to 3 times.  Consistent -- and inconsistent -- with the results of the European study, treatment with the drugs acyclovir and valacyclovir dramatically diminished the odds of getting dementia in these situations.

Of course, some to the inconsistencies may be consequences of inconsistencies in research methodologies.

This seems to be a topic of heated discussion.  To resolve the matter, several incentives have been offered.  Most notably, anyone “who provides persuasive evidence that an infectious agent is the root cause of Alzheimer's disease,” will be awarded a $1 million prize by Leslie Norins at ALZgerm.org.   

Over 1,000 sold!

I remember from my youth when McDonald's displayed a sign, "Over 1 million sold."  It took a while, but later, it said, "Over 2 million sold."  It's a little higher number today.

So we shall emulate McDonald's.  As of this week we have sold over 1,000 copies of Beating the Dementia Monster, second edition.  That's since July 16, or six months ago.  That's a lot faster clip than we ever moved the first edition.  We'll see how long it takes to get to 2,000 copies.

And then there's donanemab

Say that three times fast.  And where do they get these names from, anyway?  

Actually there is a system.  For example, the "mab" at the end of aducanumab and donanemab stands for monoclonal antibody.  And so another "mAb" or "moAb" is in the news with some new promise.

The news (and it's good news) is that Eli Lilly is finding favorable results in their phase 2 trials of donanemab.  We recall that phase 2 still uses a relatively small number of subjects and so is not considered confirmatory.  Nevertheless, these trials can give us hope.  

The hope is based on Lilly's finding that test subjects experienced a reduction in beta amyloid plaques to levels associated with normal people and improved their cognition.  These improvements are among people with early stage Alzheimer's disease.  Lilly said, "Donanemab met the primary endpoint of change from baseline to 76 weeks in the Integrated Alzheimer's Disease Rating Scale, slowing decline by 32 percent relative to placebo, which was statistically significant."  In other words, a slowing of cognitive decline by a third after 18 months of treatment.  

Lilly began another 18 month phase 2 trial of donanemab in June 2020, although they have not completed the recruitment of test subjects.  This will be a larger study with less restrictive criteria.  For example, the first study excluded people with certain tau pathologies, but the second trial will not.  The hope is that both trials taken together will preclude the requirement for an extended phase 3 trial before the FDA approves the treatment.

Similar to aducanumab, the treatment does not "cure" Alzheimer's disease, but it does significantly slow it's progress.  Also, similar to aducanumab, it causes some level of edema in the brain, which is troubling.  But, so far, it's meeting its safety criteria.

Perhaps what's especially important about these test results is the evidence that removing amyloid plaques can play a role in interrupting and, perhaps someday, reversing progress of the disease.  It also associates removal of the plaques with improved cognition, an association we haven't seen in some of the new treatments.    You can read more about the trial here.

Washington State Advocacy Day, 2021

I participated in Advocacy Day 2021 for Alzheimer's disease here on January 14.  In the past we traveled to Olympia to meet our legislators face-to-face, but you know how that goes nowadays.  So the Alzheimer's Association organized opportunities for advocates of help for families and sufferers with Alzheimer's disease to meet our legislators via Zoom to discuss Alzheimer's Association priorities with them.  I was initially scheduled to meet as a team member with each of our two representatives and our senator, but there were complications.  Some last minute schedule changes meant that I would only meet with one representative, Brad Klippert.  But things went well with him as well as with our senator, Sharon Brown. 

Each of us spoke briefly about our personal stories, and then about our two priorities.  The priorities are to restore 1.3M in funding for the Dementia Action Collaborative and to provide 1.9M in funding for two Dementia Resource Catalyst programs.

We were graciously received by all, and each legislator pledged to support our priorities.

Here are some Zoom pictures. 

Representative Klippert in the upper left.

Senator Brown in the upper left.

  #EndALZ, #AdvocacyWA

Making it past 90 ... in style

My Mom is an extremely active 92 with signs only of normal aging.  She recently had me watch an episode of 60 Minutes from 2014 about a study of the "oldest of the old," those over 90.  I watched it and found it had a lot to say.  There wasn't much new for me, and some of it seemed to conflict a little with some newer studies.  But it had a number of good takeaways.

The study was conducted at UC Irvine, with Dr. Claudia Kawas as principal investigator.  Most of the story was based on an interview with her.  Her study was called the 90+ Study.  (Their page did not display well in Firefox, but did in Safari.  I don't know about Windows browsers.)

The study keyed off of a 1981 study of residents of a retirement community in California called Leisure World, now called Laguna Woods.  The earlier study compiled questionnaire responses from 14,000 people in their mid-late 50s.  At the time of the 90+ Study, those still living were in their 90s.  The researchers attempted to track down all of the 14,000 to learn what had become of them and learn about those still living.  About 1,600 of these were enrolled in the new study.  The researchers studied their lives, gave them cognitive tests, and studied their brains with fMRIs and in autopsy.  (We discussed fMRIs, functional magnetic resonance imaging, here.) 

The 60 Minutes story was an engaging look into the lives of some study participants with insights on how well and how poorly some of them were doing.  

I couldn't find a copy of the study outside of the paywall, but here are the main conclusions Dr. Kawas stated in the video:

• Taking vitamins had no effect on longevity or preservation of cognition.  (This is consistent with other research we've discussed.)
• People who drank alcohol moderately lived longer than those who drank immoderately or who did not drink alcohol at all.  It didn't matter what you drank, so, in their study, there was no special advantage in red wine.
• People who drank 1-3 cups of coffee per day lived longer than those who drank more or less.
• It's never good to be obese, but people who lived longer tended to be normal or somewhat overweight in their later years.  However, people who were overweight when they were younger did not do well. 
  
• Making it to 90 without dementia does not mean you won't still develop it.  After age 65, the probability you will develop dementia doubles every five years, and that continues in your 90s.
• The fMRIs found that 40% of those found to have dementia did not have the plaques and tangles we associate with Alzheimer's disease.  However, they found a strong presence of evidence for vascular dementia.
• As in the Nun Study which we discussed in the second edition of Beating the Dementia Monster, the brains of some test subjects showed evidence of Alzheimer's disease (plaques and tangles in both autopsy and fMRI) but did not show evidence of cognitive decline.  Essentially half of the people who died without evidence of dementia still had plaques and tangles in their brains at autopsy.  The big question is "why not?"
• Low blood pressure, at least later in life, correlated with a shorter life span.  Most current research correlates low blood pressure with less risk of dementia and lower risk of early death from cardiovascular disease.  But, perhaps, if you get to an older age with higher blood pressure, it's somehow protective?  I haven't seen an explanation for that one, but who knows.

This study was focused on what prolongs life, not so much on Alzheimer's disease or other dementias.  However, at the end, Dr. Kawas discussed Alzheimer's disease, saying that we may be misguided in seeking a simple answer.  We want one thing to explain Alzheimer's disease, but it may be too complex for that.  In the six years since they made this video, research has continued to confirm the confounding complexity of the disease.  

A couple of things I saw

I try to scan various neurology and Alzheimer's disease journals looking for interesting news to share.  Most of them cost several hundred dollars for a subscription, but all have synopses of their content.  Most will occasionally offer interesting material for free, but not often enough.  The going rate to purchase a single article is $30.  Unfortunately, the synopses usually include just enough information to pique your interest, but without a punch line.  And, as I've mentioned before, the volume of research news has been throttled by covid-19.  Nevertheless, here are a couple of interesting tidbits I came across, although I didn't always have enough access to fill in all the blanks:

• JAMA Neurology (JAMA used to be Journal of the American Medical Association) included an editorial on blood tests for Alzheimer's disease.  Apparently there is anticipation that consumer kits will be available for these tests.  So far, the tests aren't yet available to medical professionals, but they seem to be candidates for something you can do in your home.  The opening lines of the editorial expressed ethical concerns about this, possibly due to concerns that people may have trouble understanding the implications of they resulsts they are getting from the test.
• An article in Neurology, the Journal of the American Academy of Neurology, examined the relationship between sleep, major depressive disorders in older people, and a diagnosis of Alzheimer's disease.  They found that Alzheimer's disease may influence sleep patterns.  (I'm not sure what the news is there.)  However, they did not find evidence supporting a causal role of disturbed sleep patterns for AD or evidence for a causal relationship between major depressive disorders and Alzheimer's disease.  Both of the latter conflict with other things I've read, although the distinction may be dissociating cause from correlation.  But they also associated genetically-based "being a morning person" with a higher risk of Alzheimer's disease and found an inverse correlation between risk of insomnia and risk of developing Alzheimer's disease.  These findings appears to conflict with other research of read on these topics.  For example, there seems to be evidence elsewhere for a correlation between depression and Alzheimer's disease.  They did not seem to reconcile their novel results with other research.  However, they may be more focused on looking for causal relationships rather than than the simple correlations identified by others.
  
• An article in ALZForum discussed the discovery of many new genes that both: 
• Promote development of Alzheimer's disease in people carrying the APOE2 gene variant (a gene normally not associated with Alzheimer's disease)
• Discourage development of Alzheimer's disease in people carrying the APOE4 gene (a gene strongly associated with Alzheimer's disease, at least in people of European ancestry).

So the genetic picture is more complicated than we previously thought.  We did say in Beating the Dementia Monster that having the APOE4 gene variant in your genome (in your personal DNA) is a risk factor for developing Alzheimer's disease, but it does not guarantee that you will get it.  We also said that there are other genes that can promote Alzheimer's disease, usually by promoting inflammation.  We have also noted that the "normal" form of the APOE gene is #2, which we will often write as APOE2, or ApoE2.  The purpose of the gene is to describe a protein used to transport cholesterol in the blood stream.

 

According to 23&Me, I do not carry the APOE4 gene variant, but I still developed Alzheimer's disease.  So, if you follow the genetic model for understanding how the disease develops, these other new genes might explain why I have it anyway. 

 

The old biology teacher in me wants to call the variants "alleles," which is the correct term.  That wouldn't be hard for you regular readers to follow, but I don't want to confuse the casual visitor with unfamiliar terminology. 

If not BAN2401, what about Atuzaginstat? (Say that 3 times fast.)

Back in February 2019, we wrote about the bacterium p. gingivalis, reporting the growing evidence that it may play a role in Alzheimer's disease.  We discussed this further in the second edition of Beating the Dementia Monster.  The microbe causes gum disease, and some believe it may be the sole cause of Alzheimer's disease.  Whether it's the sole cause or not, interest in the role of p. gingivalis has been growing, and one drug is showing particular promise as a treatment.  That drug is COR388 or Atuzaginstat.  A stage 2/3 clinical trial just passed an important milestone that's worth talking about.

The drug was developed by the biopharmaceutical company Cortexyme.  The trial involves about 640 test subjects and is intended to run for a year.  In December, the trial reached the 6-month point, and an independent committee reviewed the results so far in what's called a futility study.  This was intended to determine if there is enough evidence of the drug's efficacy and safety to justify continuing the trial.  You may recall that some trials of aducanumab were terminated by a futility study, when they failed to meet some interim goals.  

So the big news is that the independent Data Monitoring Committee reviewed the 6-month data for 300 of the test subjects and found sufficient evidence of safety and efficacy to recommend continuing the trial to the end.  That's good news, because this system is intended to protect people from unnecessary exposure to experimental drugs that may be dangerous and/or ineffective.  Presumably, the committee found good evidence that the drug is both safe and effective.

Cortexyme expects to complete the trial, process the data, and present the final results by December 2021.

P. gingivalis is known to generate an enzyme called gingipain which causes inflammation.  This occurs first in gum disease, but p. gingivalis and gingipain can almost always be found in the brains of people deceased with Alzheimer's disease.  Atuzaginstat targets the generation of gingipain.

In the past month or so we have reviewed the status of an array of promising treatments for Alzheimer's disease.  Alzheimer's disease is very complex, and these treatments target different mechanisms influencing how the disease develops.  Many believe that we will eventually be treating Alzheimer's disease simultaneously with several different drugs.  Perhaps Atuzaginstat will be one of them.