Some new ideas about sleep in Alzheimer's disease

In his book, Why We Sleep, Dr. Matthew Walker notes that sleep is controlled by a center in the brain above the level of the nose.  Or maybe several centers.  As we said in Beating the Dementia Monster, all brains atrophy as we age, and Walker notes that the sleep control center is not an exception.  So all of us experience problems with sleep as we age, and the control center atrophies.  However, in neurodegenerative diseases, the atrophy accelerates, and people with Alzheimer's disease have more serious problems with insomnia.  I am not an exception.

But is that the whole story?  In my love-hate relationship with sleep meds, I was surprised to read about the mode of action of the drug Belsomra.  It actually acts on the centers that control wakefulness, not that control sleep.  I didn't know there was such a center (or centers) that control wakefulness, and, as it turns out, these can atrophy as well.  A possible pattern is that insomnia gets worse as Alzheimer's advances, but it later subsides as the "wakefulness" neurons die.  An exception to this pattern may be another disease called "progressive supranuclear palsy (PSP)."  In PSP, affected people do not lose wakefuness neurons, only the ones involved in getting to sleep.  The wakefulness ones stay strong.  So their experience with insomnia is much worse.

So where are these "wakefulness neurons?"  They are located in three tiny areas of the brain, the locus coeruleus, lateral hypothalamic area, and tuberomammillary nucleus.  These produce the neuropeptides (chemical messengers) noradrenaline, orexin, and histamine, respectively that encourage wakefulness.  (These will be in Friday's quiz.)

As I understand it, there are three factors that can affect sleep disturbance: loss of neurons promoting sleep, loss of neurons promoting wakefulness, and changes in the activity of these neurons.  So how do these play together?  There is some interesting recent research.

The journal JAMA Neurology (formerly Journal of the American Medical Association) published some interesting research here.  This research is further discussed here.  The study involved 33 patients with Alzheimer's disease, 20 with PSP, and 32 in a control group.  The study’s findings suggest that loss of wakefulness-promoting neurons at the early stages of neurodegenerative disease may be sufficient to reduce regulation of sleep-wake stability in patients with both Alzheimer's disease and PSP.  The degree of degeneration was measured, in part, by counting neurons in the different parts of the brain on autopsy.  (The mean age of death was 70.  I'm 72.)

There's an apparent inconsistency here.  Dr. Walker is concerned with how Alzheimer's disease shortens sleep, while the more recently published research is about Alzheimer's disease promoting longer sleep.  I Googled for "how does Alzheimer's disease affect sleep."  There was information like this about how Alzheimer's disease creates sleep disturbances that cause people to sleep more, and others like this one that associates it with less sleep.  

How do we reconcile these?  This article is helpful and focuses on the quality of sleep.  But no matter how you cut it, sleeping well is so very important.  Overall, your best bet is good sleep hygiene.

500 Varients of the genes for younger-onset Alzheimer's disease?

In Beating the Dementia Monster, we said that there were three variants of the gene most commonly associated with "sporadic" or late-onset Alzheimer's disease.  This is the most common type of Alzheimer's, but it arises in different ways.  It's only partially genetic.  The three variants of the gene are ApoE2, ApoE3, and ApoE4.  These are the genes 23&Me tests for to tell you your risk of developing the disease.  If you carry the E2 variant, you have some extra resistance to the disease, E3 seems to be neutral, but E4 is associated with a higher risk.  But this is a shallow analysis, since you can develop Alzheimer's disease even if you carry the E1, and you can miss it even if you carry the E4.  And, as we wrote earlier, researchers have now discovered as many as 72 genes that can contribute to you developing it.  

(The ApoE gene provides for a protein that is responsible for packaging cholesterol and other fats and carrying them through the bloodstream.)

But then there are the three genes associated with "familial," or younger-onset Alzheimer's disease.  There is a much stronger correlation between people who are gene carriers and those who develop the disease in their 50s, 40s, or even 30s.  Variants of the gene that produces the amyloid precursor protein (APP) as well as variants of the presenilin 1 (PSEN1), and presenilin 2 (PSEN 2) genes are strongly associated with familial disease.  

(We don't know what APP is good for, but the PSEN 1 and 2 proteins are associated with the function of calcium ions in neurotransmitters.  You can read up on this in the link above, but good luck...)

So if there are three primary variants of the ApoE gene, how many variants are there of the three genes associated with familial disease?  Between the three of them -- 500!

That's a lot of variants, but they do not all have the same level of influence over probability of developing the disease.  Since familial Alzheimer's disease is more strongly driven by genetics than the sporadic form, knowing how significant each variant is can help assess someone risk for developing the familial form.  So, thirty years ago researchers developed a database of the variants that assesses the strength of each, making such assessments possible.  

It's called the Alzforum Mutations database.  Alzforum is an organization that brings together many researchers and research organizations in a quest to find a cure for Alzheimer's disease.  (I'm an avid reader of their weekly newsletter.)  This week, Alzforum's newsletter described efforts to overhaul and improve the way they catalog and estimate the toxicity of each variant associated with familial Alzheimer's disease.  This was necessitated by the explosive growth in the number of variants of these three genes that have been found.

So how am I doing?

How am I doing?  From the standpoint of memory and cognition, great.  But in some other areas...

My memory and cognition are my #1 interest, since there's nothing more important to how I'm able to navigate this world.  After my initial diagnosis of MCI in 2015, I joined the gym and began a course of steady improvement.  I probably hit bottom in early 2016, and my improvement probably peaked in April 2019.  Since then, they've been generally stable, although kind of an up and down.

Whenever I meet with one of my neurologists, they ask me how I'm doing.  I remark that people in memory care have good days and bad days.  I have good months and not-so-good months.  As a rule of thumb, I have one not-so-good month for three good months.  I can't call them "bad" months, but they're scary.  But whenever I seem to be going downhill again, I suddenly just sort of pull out of it.  Over the past couple of weeks I've felt unusually well following a scary period.

So what constitutes a not-so-good month?  In April 2019, the fist time I thought I might be losing ground, I stopped remembering to lock the car door when I parked.  (Bad idea in Seattle.)  I might be reminding myself while pulling into a parking space, but I'd find out later I had never locked the door.  And this could happen a few days in a row.

Probably my most sensitive measure is how well I can converse in Spanish.  I have been speaking with a couple of people in Latin America in Spanish four times per week for more than 10 years.  During some periods I have command of an extensive Spanish vocabulary, but during other times I can barely recall any words.  (Oddly, when I can't recall a word in Spanish, I'm also unable to recall the English equivalent.)

In Beating the Dementia Monster we discussed the logopenic syndrome which is associated with both aphasia and Alzheimer's disease.  (Bruce Willis and aphasia have been in the news lately.)  And the relationship between aphasia and Alzheimer's disease is not clear.  Aphasia involves a significant deterioration in language skills, and I've never been there.  Nevertheless, I've had periods that appear to me to be incipient aphasia or the logopenic syndrome.  This involves problems with word finding or understanding what's being said by another person.  But everyone over the age of 55 or so begins to have trouble with word finding, and it's not caused by disease.

During a not-so-good period I have trouble putting a sentence together in English.  This is not obvious to people I talk to, but I'll say less when I know I'm having trouble.  It's not just word finding, but also ordering the words into a coherent sentence.  During a difficult period, whether in English or Spanish, I feel victorious when I know I just said something meaningful and grammatically correct.

And then there are things like managing my meds and finding my car in a parking lot.  These go up and down, but lately it has all been well.  In fact, very well.  So I continue to get to the gym every day, eat right, maintain social connections, and do the rest of the strategy of the Dementia Toolkit.

What has not been going well is my balance.  It's gotten really bad, and I shuffle to get around.  I get a little bit of relief from the habituation exercises we discussed in Beating the Dementia Monster, but not nearly as much relief as I got just a year or two ago.  And bad balance affects almost everything I do.  Last year, I traveled twice to the East Coast, once with Amy and once alone.  Traveling alone now seems a bit dicey, as I worry about falling in the shower in a motel.  Fortunately, it has no influence on me when sitting, and I have no sense of it when driving a car.  At least for now.  So that's good.

My neurologists in Seattle are on it, and I had a set of three MRIs of my back about a month ago.  The idea is that this problem may be arising in my back and not my brain.  I have the radiologists report, but I have yet to get a readout from my neurologists.  That will happen on May 3.

The upshot of this is that, since April 2019, my memory and cognition have been relatively stable, albeit up and down.  But it's been mostly up, and I'm incredibly grateful for that.  Balance problems are significantly affecting my quality of life, but I'm waiting to see if the neurologists can do something about that.

PBS Video on Alzheimer's Disease

The other day I watched a remarkable 53-minute video about three women confronting the possibility that they were developing Alzheimer's disease  -- Determined: Fighting Alzheimer's.  All were enrolled in a research project, the Wisconsin Registry for Alzheimer's Prevention.  In each case, the fact that others in their families had previously been found to have dementia due to Alzheimer's had advanced their concerns.  The video follows each of them through a search to determine their future, including their tests and the impact of their anxiety on their families.  In one case, the story follows through to the very difficult death of the mother on one of the women.

You can see the video here.  

Several things resonated with me.  The video was copyrighted in 2021 and 2022, but much of it was shot in 2014 and 2015.  (I suspect some production delays due to covid.)  You will recall that I received my diagnosis of "MCI, likely due to Alzheimer's disease" in 2015.  One of the women auditions for a drug trial that I am sure was aducanumab (now marketed as Aduhelm), and she is rejected.  I, of course, had the same experience at about the same time.  

In the case of the woman who lost her mother, the video depicts in very stark terms the mother's struggle to live, fighting for each breath.  Her mother dies at the age of 74, having wasted away to 88 pounds.  If you read Beating the Dementia Monster, you know that in 2017 (when I was 67), a neuropsychologist indicated that I was on track to be dead when I am 75.  (I'll turn 73 in a couple of months.)  But the neuropsychologist also indicated that, if I stuck to my physical exercise and other lifestyle changes, I could extend that to age 85.  And this certainly seems to be what has been happening to me.  I infer from some of the dialog that the mother followed the course that I was taking before I began my lifestyle changes.

The video ends in a sort of crescendo of emphasis on how each of these women embarks on fighting the possibility of disease by getting to the gym and making other lifestyle changes.

I say the "possibility of disease," because at the end it wasn't clear that any of them actually had Alzheimer's disease.  One woman was pretty much cleared through a PET scan, but the others were still candidates.  While all had evidence of memory loss, none had advanced to dementia at the time the video was released.  It may be that the two who weren't cleared did have Alzheimer's disease but sustained their brain health through the lifestyle changes they made.  Their changes were depicted in the video. 

Every morning when I wake up and I recall how things were going for me in 2015, I am simply astounded -- and grateful.

Genes, genes, and more genes...

In Beating the Dementia Monster, we said that about 30 genes had been identified that caused or contributed to the development and/or advance of Alzheimer's disease.  These genes, of course, vary in how strongly they influence the disease.  The gene for the amyloid precursor protein and the two presenilin genes are almost certain to cause the rare but devastating young onset form of the disease.  But 23&Me will test you for the ApoE4 gene which is correlated with many cases of the more common old-onset form of the disease.

In addition to that 30, we noted back in July that six more had been identified.  But is that all?  My sister recently pointed me to a story in CNN about research reported in Nature Genetics regarding the identification of 42 more.  The researchers also developed a scorecard to predict someone's probability of developing Alzheimer's disease or for advancing from mild cognitive impairment to dementia based on which variants of these genes you may carry.

As we noted in our July posting, the genes we discussed don't explicitly cause Alzheimer's disease, but rather they create a favorable environment in the brain for the disease to start and/or advance.  Most often, this is an environment favorable to inflammation.  Lifestyle changes then don't fight the proteins originating with the genes but rather attempt to modify the environment they create.

This new research is interesting in that it finds a broader influence of genetics and the development of Alzheimer's disease.  In Beating the Dementia Monster, we discussed the possible role of microglia in the advance of the disease.  Microglia are the specialized immune cells peculiar to the brain and spine that operate independently from the immune system in the rest of the body.  The microglia help clean up the trash in the brain, such as the amyloid plaques and tau tangles that are central to the disease process.  We said it may be that as we age, the microglia become less effective.  This new research correlated some genes associated with microglia with Alzheimer's disease.  The thinking is that some genes may affect how well the microglia cells function.

Genes specify the design of the proteins in the cell, and over time, mutations result in variations in the design.  This creates variations in how the proteins do their jobs.

The more deeply the researchers got into the role that these many genes play in the advance of the disease, the more impressed they were with the incredible complexity of how the genes influence the disease.  This led them to develop a scorecard for evaluating someone's risk of developing Alzheimer's disease based on which variant of all these genes they carry.  They wrote, "Based on this evidence, we developed a systematic gene prioritization strategy that yielded a total weighted score of between 0 and 100 for each gene."  Their analysis identified 31 tier 1 (higher influence) genes and 24 tier 2 (lower influence) genes for weighting purposes.

As we said in Beating the Dementia Monster, carrying the ApoE4 gene does not guarantee that you will develop Alzheimer's disease.  The scorecard goes on to quantify the risk for someone carrying this famous gene when the person's genome includes a mix of the other genes.

So to me, this scorecard is a remarkable development.  I wonder if 23&Me will adopt it.  I'm sure that, before 23andMe adopts it, the long-term care insurance companies will jump on it to set premiums and screen out those they won't want to insure.

The number of people dying with a diagnosis of dementia has risen to almost 50%

So says a recent study conducted by researchers at the University of Michigan.  In fact, almost half of older people now die with a diagnosis of dementia.  The study results were published April 1 in JAMA Health Forum.  

While Alzheimer's disease is the sixth leading cause of death in the United States, we also wrote in Beating the Dementia Monster that the incidence of Alzheimer's disease has been declining in Western countries over the past 25 years.  This is likely a consequence of the success we've had in fighting heart disease, such as by cutting tobacco use and controlling blood pressure.  Remember, what's good for the heart is good for the brain.

But what's going on here?  Bear in mind that the study looked for people dying with a diagnosis of dementia, which is different than looking for Alzheimer's disease case rates.  All study data was drawn from Medicare records.  In the study, people could have died from cancer, heart attack, or a car accident.  But if they had a diagnosis of dementia at the time of death they would be counted as dying with that diagnosis.  That's different from dying from Alzheimer's disease or another dementia.

So what did they find?   

In a sample of Medicare fee-for-service subjects from 2004 to 2017, when adjusted for age and sex, the percentage of people who died with a diagnosis of dementia increased from 34.7% in 2004 to 47.2% in 2017.  This equates to a 36.0% increase over the 14 years.

The hypothesis of the study (what they wanted to prove or disprove) was that the frequency of an Alzheimer's disease diagnosis would increase over time through changes in diagnostic billing behavior during the time frame of the study.  This is a bit different from the headlines the study has received in the media.

So bear in mind that the study was to measure how diagnosis of dementia has varied with changes in diagnosis standards and regulations, as well as increasing awareness of Alzheimer's disease.  The coding and billing system has changed, and there is also a lot more awareness about dementia, likely as a consequence of the National Alzheimer Project Act.  They noted that in 2000, Alzheimer's disease was considered the eighth leading cause of death, while it was considered the sixth leading cause in 2018.  No one believes that reflects a change in the prevalence of the disease, only that it has been diagnosed more frequently.

The study did a couple of things to refine their results.  First, by relying on Medicare claims, their method did not consider more advanced diagnosis techniques which could more frequently identify Alzheimer's and other forms of dementia in their early stages.  This would add a lot of people like me who may have Alzheimer's disease but are not actually in dementia.  They also separately considered subjects with a single diagnosis and those with two or more diagnoses.  The data set with a single claim was intended to avoid missing cases that were under-diagnosed.  Studies often look for two diagnoses to add confidence that the patient actually had the disease in question.  And so the data set with two diagnoses (at least seven days apart) was intended to weed out spurious diagnoses.

So what's our takeaway?  As we wrote back in March, getting a handle on good Alzheimer's disease statistics is getting better, but there's still plenty of uncertainty.  Also, as awareness among physicians and the public increases, the disease is more readily recognized and our statistics improve.  Increased awareness allows families and services a greater understanding of the challenges they face as more people develop the disease.