A Zoom presentation, but no new drug breakthroughs at AAIC ... so far

Yesterday a presented my story to my brother Hollis's church men's group in Virginia via (what else?) Zoom.  I was very well received, and the questions suggested that they heard my message.  I had bought plane tickets to present in person during February, but you can guess what happened to that.

As I mentioned earlier, the schedule for the week at the AAIC2020 "Amsterdam" conference has some presentations embargoed with the idea they will contain important news.  So we have drama.  There's only one day left, so I wonder if the big news isn't out already:

1. Flu/pneumonia shots reduce Alzheimer's disease risk
2. We're making progress on a blood test. 

Regarding blood tests, I heard people say that, when the blood tests come out, they should only be used to screen drug trial subjects.  There should not be general testing.  I'm guessing that's because they realize that a positive test means that you will never be able to get long-term care insurance, at least not the way the industry is currently structured.

There is another item that can probably be added to my list above, and that is what's been learned about the influence of bad health habits during youth on Alzheimer's disease risk.  It's huge.  Poor habits of diet and exercise in your teen years can double the risk of Alzheimer's disease in women and multiply it by 2.5 in men.  That's significant.  But what's the practical value?  Who's going to convince their kids to stop eating at McDonald's?

Now that I think about it, as soon as I had a job and could pay to eat out, that's all I did.  A hamburger was $0.15, fries were $0.11, and a milk shake was $0.20.  Who could ask for more?  Maybe this explains my current condition.

An underlying theme of most presentations was lifestyle.  Exercise, diet, social connection, etc.  You've heard it all before.  Sometimes this was explicit and sometimes tangential, but it was very often present.  This was in the absence of any drugs or other magic bullets to talk about.

This morning there was in interesting presentation about the measurement of Alzheimer's disease prevalence and measurement in the African American community.  The vast majority of the work done in Alzheimer's disease research has been with Europeans and Americans of European ancestry.  (And some Australians.)  This has led to overlooking some important things.  For example, the single most common genetic risk factor for Alzheimer's disease is the presence of the ApoE4 gene in your genome.  Turns out, that's only true if you're of European ancestry.  For African American's, many have that gene, but the level of influence is noise.  And she presented credible research on problems with how cognition is assessed among African Americans.

We'll see what tomorrow brings.

Are we going back to "hardening of the arteries?"

According to Google's analytics, people aren't much interested in my reporting on the AAIC conference.  So I'm wondering if I shouldn't go light on that before it hurts my SEO.  In any event, I heard several things this morning that have changed my understanding of Alzheimer's disease.

Yesterday's meetings made news on NPR, the NY Times, the Wall Street Journal, etc.  It was about how close we are to a blood test for Alzheimer's disease, but we're just not quite there yet.  The lectures on how the various candidate tests work were fascinating, but a bit geeky.  So I'll spare you.

But my question remains: What''s taking so long??

The answer seems to be that a set of criteria was established early on for what would constitute a reliable test, and no one has quite met all the end points.  So it continues as a work in progress.

This morning (while on the treadmill) I heard fascinating talks on the role of the vascular system in Alzheiemer's disease and on younger-onset Alzheimer's disease (YOAD).  Both had news in them for me.

Until about 1990, we associated dementia with "hardening of the arteries," the idea being that cholesterol was clogging arteries, and restricted blood flow caused Alzheimer's disease.  This would have to be separate from vascular dementia, although the distinction was emerging slowly.  So they call this understanding a "global" view of the disease because it tries to look at what is happening in the whole brain.

But in the early 1990s, the focus moved to the cellular level, to the amyloid plaques and microtubule tangles that Alois Alzheimer first noted in 1906.  These are associated with individual cell death.  Since then, it's been all about peptides and proteins -- amyloid and tau.  But some research is bringing the global view back into focus.

In this morning's lecture, the researcher discussed a new (to me) idea that the amyloid plaques interact with the vascular system in a way that damages blood vessels and impedes blood flow.  This starves cells for blood-borne nutrients, contributing to their deaths.  This occurs in an environment where oxidative damage is occurring -- so eat your blueberries!  (He also discussed a role for dietary salt in this process, similar to what we discussed here before.)

The second talk I heard was on YOAD, and it offered new information on the role of genetics.

They defined YOAD as any Alzheimer's disease manifesting symptoms before age 65.  I had always thought of it as a variant of older-onset ("sporadic") Alzheimer's disease, and that it was a slightly different disease driven entirely by a specific set of genes.  Well, maybe not.  (This is not entirely resolved, and there are differing opinions.)

It may be that those specific genes will inevitably cause YOAD, but not all YOAD is caused by those genes.  I may need to go back and tweak the text in my book, because this may conflict with what I wrote.

A couple of things he noted about YOAD were that it advances more rapidly than sporadic Alzheimer's disease, and, not coincidentally, leads to earlier death.  Essentially, YOAD cuts about 18 years from someone's life.  However, people with YOAD are a rich population for study, because they have fewer other health complications to confuse a study, and they are easier to identify in the general population.  Being younger, they tend to be more eager to help with research. 

"Amsterdam" Confence, First Day

The virtual Alzheimer's Association International Conference began this morning at 6 a.m. our time, but I was still in bed.  And then I went to the food bank to work.  But when I got home I watched a number of recorded sessions and then watched the recap.  It was mostly over my head, but I did pick up a number of interesting things.

One research finding is that there is a correlation between people who have a history of getting their flu shot every year and a reduced risk of Alzheimer's disease.  If they also got the pneumonia vaccine, their risk is even less.  And the risk reduction is substantial.

But correlation is not causation, and everyone is speculating on what's going on there.  Perhaps the vaccine perturbs the immune system in such a way that it provides a protective function for Alzheimer's disease.  Or maybe people who get their vaccinations are more likely to get exercise and live a more healthful lifestyle.

I haven't seen anything indicating someone wants to present research on a breakthrough drug intervention, but there are some secret presentations coming up.  So we'll see.

But we are looking for a breakthrough in early detection, and there were a number of presentations on that.  The main promise at the moment is for a blood test, and I thought we would have one by now.  That's how it looked two years ago.  What I saw today was people being very methodical about how they can correlate blood test results with actual inception of the disease, perhaps 15 years before the first symptoms.

I also saw a series of related papers on what is happening with neural activity as the disease progresses.  The different parts of the brain talk to each other, and brain waves are a part of that.  These connections seem to be perturbed during Alzheimer's disease, but not always in the way you'd believe intuitively.

You would think that neural activity would go down as Alzheimer's disease advances, and you'd believe that "neuronal hyperactivity" would indicate improving cognition.  But you'd be wrong.  Apparently, neural activity in the hippocampus rises dramatically when cognition begins to erode, but then falls often even more dramatically as the dementia advances. 

I haven't seen this elsewhere, but the researchers associated increased delta wave activity with the hippocampus.  (Neural activity generates brain waves.)  Delta waves have a frequency of 0.5 to 4 Hz, so they are very slow and are associated with deep sleep.  We know that the hippocampus is busy during deep sleep, consolidating short term memories to long term memories. 

I'm looking forward to whatever they have to share tomorrow.

Your brain on covid-19

Covid-19 is an acute respiratory illness, but it often affects many organs in the body.  If you read the newspaper or watch TV you know this.  But is one of those organs the brain?  And does this mean anything for cognitive function?  The answer seems to be yes.

The first organ damaged by the virus is the lungs.  According to several articles I've read, this occurs in part due to an unusually powerful inflammatory response.  Inflammation in the lungs can cause extensive damage to lung tissue.

We have discussed the role of inflammation in various diseases before.  Inflammation begins as the body's response to infection or injury, but it has a way of doing its own damage -- maybe lots of it.  Neuroinflammation, inflammation in the brain, plays a major role in Alzheimer's disease.  Can inflammation spread from the infection site in the lungs to the brain and thereby aggravate Alzheimer's disease?  Or can it simply attack the brain in the way that causes cognitive impairment in the absence of Alzheimer's disease?

When the body mounts an inflammatory response, immune cells release proteins called cytokines.  Cytokines coordinate the body's immune response and promote inflammation.  In the case of a massive inflammatory response, the cells release a "cytokine storm."  The cytokines may leave the infection site and circulate to other parts of the body to encourage inflammation elsewhere.

Does the blood-brain barrier protect the brain from cytokines?  You will recall that we explained how the blood-brain barrier protects the brain from many pathogens.  Pathogens in the blood can't pass through the walls of capillaries in the brain because the walls of these blood vessels limit the size of particles able to enter or leave.  Pathogens (and antibodies) are usually too big, so they're screened out.  But cytokines are at about the size limit, and some can get in.  It's also believed that they can enter the brain by way of the olfactory nerve.

Another problem is that impairment of lung function can deprive the brain of oxygen.  And the first casualty of oxygen deprivation is the hippocampus -- which is often the first casualty of Alzheimer's disease.  So people whose brains have been damaged by oxygen deprivation sometimes display symptoms similar to Alzheimer's disease.  It's also easy to see how covid-19 might aggravate a case of Alzheimer's disease in multiple ways.

This article, written by a South African neuropsychologist and her husband provide a more detailed discussion of how this all works.

Going to Amsterdam ... sort of

Every year there are many conferences of Alzheimer's disease researchers where they present the results of research and compare notes.  From what I can tell, the two biggest international conferences are in Barcelona and Amsterdam.  Important research with dramatic results is usually kept under wraps until it is presented at one of these conferences. 

This year's Barcelona conference was held early this year, and, of course, it went virtual.  No one was going to fly to Spain to participate.  Well, the Amsterdam conference is to be held next week, and it too will be virtual.  Which means, I get to go!  And so I am registered. 

The conference runs all week with, fortunately, a recap at the end of each day.  As I understand it, more than 1,800 research studies will be presented in one way or another.  Time zones are a problem, but each day starts at 8:00 a.m. Pacific time.  Presenters and participants will be distributed around the world, but the timing seems to favor North America.

If I learn anything I find interesting you can be sure that I will share it with you here.   

On to the Fountain of Youth

As we've discussed before, variant #4 of the gene that specifies the design of the the apolipoprotein E protein -- APOE4 -- is a significant risk factor for Alzheimer's disease.  If you carry one copy of the gene, your risk of developing Alzheimer's disease is higher than normal, and if you carry two copies it's quite a bit higher.  It's thought that the form of the protein produced using this gene causes or aggravates inflammation which is a key factor in Alzheimer's disease.

Companies that test your DNA will tell you whether or not you carry this gene.  Not carrying this gene does not mean that you won't get the disease, and carrying it doesn't mean that you will.  Nevertheless, we keep our eyes on it.

One question is, why do some people who carry the gene variant not get Alzheimer's disease?  Is it just dumb luck?  Yes, but maybe the luck relates to what other genes may be in your genetic makeup.

In the 1990's researchers discovered the gene klotho, named for the Greek goddess Clotho, a Fate who spins the thread of life.  Like APOE, it has several variants, and the presence of one variant in your genome is associated with longevity.  And so, it's called the longevity gene.  The protein it describes is an enzyme that can influence sensitivity to insulin and also participates in the aging process.  Insulin sensitivity relates to type 2 diabetes, which is another risk factor in Alzheimer's disease.

Some believe that studying klotho can lead to the discovery of ways to control the aging process and significantly extend human life.  Unless Alzheimer's disease gets in the way.

There have been several recent studies trying to understand how klotho might influence the advent and advance of Alzheimer's disease, and its role may be significant.  It might do this by significantly suppressing both oxidation and inflammation in the brain.  These are two major processes in Alzheimer's disease.  

I found this article in Scientific American that addresses how the proteins from APOE4 and klotho might influence Alzheimer's disease.  In fact, I saw another article suggesting that the right combination of klotho variants and APOE4 might have someone with a risk of Alzheimer's disease less than if they did not have APOE4.

It's kind of early to tell if studying klotho will lead us to the Fountain of Youth.  But near-term it can be a real benefit to Alzheimer's researchers.  In studying new drugs, we want to identify test subjects developing the disease long before symptoms begin to present.  So researchers look for people carrying the APOE4 gene variant -- who may or may not develop it.  Weeding people out who carry the helpful klotho variant will significantly increase the probability that your test subjects actually will develop Alzheimer's disease, and you will have more confidence in the test results.

#1 in Amazon "Hot New Releases"

After one day, Amazon is showing the new edition of Beating the Dementia Monster as the #1 "hot new releases" in the Neurology browse category.  Hopefully, this portends well for its future.

The second edition is now out!

The second edition of Beating the Dementia Monster is now out!  It's been almost two and a half years since I started on it, and it's been a lot of work.  You can see it here.

If you read the first edition, I can tell you this is a major update and upgrade.  I have also taken on a co-author, Dr. Vaishali Phatak.  She is associate professor of neuropsychology at the University of Nebraska Medical School, and she brings a lot to the table.  She was my attending neuropsychologist at Harborview in Seattle in 2015 and 2016.

For two weeks, I have set an introductory price of $0.99 for the Kindle edition and $5.50 for the paperback.  After two weeks, both prices will rise to their consumer level.  If you read it, you are invited to review it on Amazon and/or Goodreads.  

Will Baby Einstein avoid Alzheimer's disease when she gets old?

Is a higher level of early-life cognitive enrichment (ELCE) associated with lower levels of late-life Alzheimer disease and other common dementia-related pathological changes?  This was a question addressed by research published in the journal JAMA Neurology on June 29, 2020.

Their conclusion: "Early life cognitive enrichment was associated with better late-life cognitive health, in part through an association with fewer AD pathological changes."

So what did they do to get to this conclusion?

The research involved a longitudinal study of 813 elderly participants for seven years through to their deaths.  Their cognition was measured throughout the seven years, and their autopsies looked for evidence of neurodegenerative disease -- notably amyloid plaques and tangles.

At the outset of the research, participants completed an extensive questionnaire to establish an index representing an individual's ELCE.  The index was composed of four indicators of ELCE (early-life socioeconomic status, availability of cognitive resources at 12 years of age, frequency of participation in cognitively stimulating activities, and early-life foreign language instruction). These were established by evaluating education levels of the parents and the number of children in the family; availability of cognitive resources, such as a newspaper subscription, encyclopedias, or a globe, at 12 years of age; frequency of participation in cognitively stimulating activities such as reading; and years of foreign-language instruction by 18 years of age.

The researchers attempted to control for "recall bias" which might result from selective memories of the participants' childhoods.  Most were in their 70s at enrollment.

The findings identified a clear correlation between greater ELCE and fewer plaques and tangles in the autopsy as well as better cognitive performance during the preceding seven years.  In fact, an index one unit higher for a participant correlated with Alzheimer's pathology of someone eight years younger.  It also correlated with a 25% slower rate of cognitive decline.

The researchers evaluated the effect of greater ELCE on eight other brain pathologies.  Only Alzheimer's disease was found to be affected.

Some commentators noted that the cohort was more female, white, and highly educated than the general U.S. population. This creates some questions about how the the results should be interpreted, since we know that Alzheimer's disease unfolds differently in diverse populations.  Are there confounding factors that should have been further considered?

I don't know how much providing children with cognitive stimulation makes them smarter, but I do know that it's a lot of fun!

Exercise stimulates the genesis of new brain cells ... via the liver?

As we discussed in Beating the Dementia Monster, exercise stimulates production of the the BDNF protein, the brain derived neurotrophic factor.  BDNF plays a role in neurogenesis, prompting stem cells in the hippocampus to form new neurons.  It may also have a healing function for cells damaged by Alzheimer's disease.  How this works remains kind of mysterious.  But according the this week's ALZForum, some researchers at UC San Francisco found that, during exercise, the liver produces an enzyme that plays a role in the production of BDNF and may have other positive effects.  At least in mice.  They were able to link this with improved cognition in older mice.

Some suggest this points to a "liver-brain axis."

What's also interesting is that serum taken from exercising, older mice and delivered to sedentary mice appears to convey a positive effect to the sedentary mice, perhaps by carrying over the enzyme.

The enzyme is glycosylphosphatidylinositol-specific phospholipase D1. We’ll just call it Gpld1.

Gpld1 removes certain proteins from the surfaces of cells, but also suppresses the complement system, which is part of the body's immune response.  Isn't that bad?  But part of the immune response is inflammation, and, as we have discussed before, too much inflammation is bad.  Therefore, much of our effort to treat Alzheimer's disease is through reducing inflammation.  Diet, exercise, intermittent fasting, and getting good sleep can all contribute to reducing inflammation.  Apparently the production of Gpld1 is part of the story regarding how exercise can be associated with reducing inflammation in the brain, even though injury to the body during exercise has its own inflammatory response.

According to the article, there is a connection between neuroinflammation (inflammation in the brain) and peripheral inflammation (inflammation in the rest of the body).  But it's not well understood.  Gpld1 is a large molecule, and so it is blocked from involvement with brain chemistry by the blood-brain barrier.  The blood-brain barrier blocks pathogens from getting into the brain, but it also blocks antibodies and other large proteins.  So it's not clear how this Gpld1 is able to act on the brain, but it does appear to stimulate the production of BDNF, which is the main factor in my success in battling my disease.  In mice, at least, overproduction of Gpld1 in exercising mice increased production of BDNF by 40% and tripled the generation of new neurons.

There two things worthy of further consideration.  The first is the open question of whether what has been observed in mice reflects what occurs in the human body.  The second is whether the increased expression of Gpld1 from the liver can be stimulated pharmacologically in people too frail to exercise.  If so, that would be great.

The aducanumab drama continues to continue

As we discussed back in December 2019, Biogen has now filed with the FDA their application for approval of aducanumab.  You will recall that the monoclonal antibody treatment initially failed its phase three trial, but Biogen reevaluated the test data and concluded the drug was effective.  You will also recall from Beating the Dementia Monster that I had auditioned for the phase three trial but was screened out.

Out of fear of adverse effects on test subjects (brain micro-hemorrhages), Biogen reduced the dose part way through the trial.  After first concluding that the drug had failed the trial, they later re-evaluated the data with a focus on only results unaffected by the dose change.  They claim that these results confirm that the drug is actually effective.  Will the FDA agree?  We shall see. 

The biggest obstacle for Biogen will be to convince everyone that they don't need to start over with the phase three trial.  The argument for a do-over is that they didn't complete the trial, and the evidence for the drug's effectiveness is weak.  My perception is that the argument for going straight to market is that the safety risks are reasonably well understood, and that the need for something ... anything ... that will actually address the disease mechanisms is more significant than any call for caution.

Aducanumab is one of several drugs that have been shown to actually remove amyloid plaques from the brain.  These plaques are a consequence of the progression of Alzheimer's disease.  They appear to inhibit the flow of information in the brain which affects memory and cognition.  They also appear to kill brain cells.  But it's not clear that removing the plaques improves cognition or slows progress of the disease.

Biogen claims that their data shows aducanumab slows progress of the disease and improves cognition.  (They don't claim that it "cures" Alzheimer's disease.)  We'll see if the FDA agrees. 

More Etcetera

Consistent with my last post, I did get the written results of my tests of June 15.  They were, of course, what my neurologist said they would be.  They compared my 2020 results with 2018, and I could see the areas where I had weakened.  However, I then compared the 2020 results to my results of 2015, and I am still doing a lot better!

And so far, declining test results have not been reflected in declining abilities.  I'm still able to do everything I set out to do, although I'm being more cautious about what I choose to do.  Managing the complexity of getting the new book out is an example of what I'm fully able to do.  A role I'd begun to take on with the Alzheimer's Association (point man with our congressional representative) is an example of a source of stress I needed to shed.

Getting the new edition to Beating the Dementia Monster continues to be an important focus right now.  I got an author proof copy the other day, and I found several things that needed correction.  I found one badly misspelled word, and a number of formatting oversights.  Also, there's a graphic with poor contrast.  So I've corrected these, but I really need to see anther author's proof copy to make sure that I fixed everything well.  Too often, it looks great on the computer, but in real life ... not so much.

If all goes according to plan, I'll find the book ready to go by, say, next Tuesday.  At that point I can submit it for final publication.  Up to now, Amazon's robot has been ensuring that the book conforms to all of their requirements.  But prior to actual publication, a human must look at it.  This usually takes a couple of days.  So, who knows, maybe we can go to press over the weekend of June 18?  Readers of this blog will be the first to know.

I anticipate that the introductory price will be $0.99 for the eBook and $5.50 for the paperback.  After two weeks, this will rise to the regular consumer price.

Test Results, etc.

I "saw" my neurologist yesterday for my annual assessment.  (I "saw" her by Zoom conference.)  The neuropsychologist had tested me two weeks before, and yesterday I received the results.  They weren't great -- which wasn't a surprise.

As I said before, I've been on kind of a cognitive roller coaster since April 2019, and I had two terrible nights of insomnia before the test.  So I was expecting disappointing results.  They didn't quantify the results, but they said they were concerned.  I should receive the report in the mail with all of the numbers in a few days.  She said they would compare the results over the past few years.

One thing the neurologist noted is that I have been steadily taking on more responsibilities which raises stress levels.  The stress hormone, cortisol, has been known to be hard on the hippocampus of people with Alzheimer's disease.  She also suggested that I speak with my primary care provider about the possibility of a vitamin D3 deficiency.  So I sent him an email asking about the blood test she suggested.

We also talked a little bit about the SNIFF study with insulin.  She said that it may not be dead yet.  As noted here, there may have been a problem with the delivery system, and so the research may not have been valid.

After meeting with her, I attended an on-line webinar about progress with Alzheimer's research in the Pacific Northwest.  Most research is at a standstill, and some research has been abandoned due to the pandemic.  Most of the research they discussed was promising work showing how much can be gained through exercise and other lifestyle improvements.

We have finalized the new book (Beating the Dementia Monster, 2nd edition) and the cover -- I hope.  My co-author and I should receive proof copies on Tuesday.  If they're good, we go to press next week!  There will be a two-week window with a low introductory price, and you will be told when that starts.