Sleep Fragmentation and Alzheimer's Risk

I can no longer get a good night's sleep.  My sleep doctor tells me that 7 hours is a good night for me, but getting to 7 hours has proven nearly impossible.  I normally go to bed at 10, but awaken most nights at about 3.  After laying in bed for a while I'll get up and do something for an hour or two, and then go back to bed.  I can usually get enough total sleep time to get to that 7 hour threshold, but, from the standpoint of brain health, is that just as good as sleeping straight through?  I wonder about that a lot.

In July 2018 we posted about why sleep is important in Alzheimer's disease prevention and treatment.  One of the things we noted was that, in deep sleep, the brain cells shrink, causing circulation of cerebrospinal fluid (CSF).  This allows the CSF to deliver the beta amyloid waste to the lymphatic system for removal from the brain.  Accumulation of amyloid plaques in the brain is part of the Alzheimer's disease process, so removal is important.  Varying levels of beta amyloid in the CSF are reflected in varying levels of beta amyloid in the blood.

The sleep cycle is generally about 90 minutes, and the cycle repeats throughout the night.  Deep sleep is only one phase of the cycle, and it begins well into a new cycle.  It is during deep sleep that researchers can measure falling concentrations of beta amyloid in mice and in humans.  And so getting a good night's sleep, with plenty of deep sleep, is important to brain health.

The question that's been on my mind is, if I wake up repeatedly during the night but still get seven hours, is that as good as sleeping seven hours straight?

Probably not.  There was some interesting research reported in the May 2020 issue of the journal Alzheimer's and Dementia that addressed this.  The article was titled "The overnight reduction of amyloid β 1‐42 plasma levels is diminished by the extent of sleep fragmentation, sAPP‐β, and APOE ε4 in psychiatrists on call."  Conclusion: sleep fragmentation diminishes the reduction of beta amyloid levels overnight, so fragmented sleep is probably not as good as uninterrupted sleep.

The research was interesting.  The researchers studied psychiatrists in a hospital in Germany that were on call and thus experienced fairly frequent interruptions in their sleep.  Blood samples were taken from subjects at the beginning and end of their shifts so that change in amyloid levels could be determined.  This was then correlated with sleep interruptions.  There were 17 participants, and they were studied over a total of 90 nights.   Participants kept a log of sleep interruptions, but they also wore instruments to detect motion and corroborate their record.  The subjects were sleeping at the hospital and not at home, and so researchers made an effort to control for varying sources of stress that could confound their results.

So what does this mean for me?  One more thing to worry about.  My neurologist believes that sleep is likely my biggest challenge in dealing with my disease.  Sleep needs vary between individuals, but all of the research I read suggests that I'm not getting enough.  And I wonder if I can even get to an ideal amount of sleep regardless of what I do.

My cognition is to be tested at Harborview in about three weeks.  I was not tested last year, but my subjective sense is that I experienced some unexpected decline then from which I rebounded.  I further sense that I was doing better in the early part of 2020, but I have been declining again.  This goes along with increased trouble with sleep.

But have I really been declining again?  The upcoming testing should provide some clarity.  

A Covid-Related Death?

In September 2019, we posted regarding two friends living in elder care facilities.  For reasons of privacy, I called them "Bill" and "Mike."  In January 2020, I wrote that Bill had died.  He was a WWII veteran who was usually quite lucid but occasionally hallucinated.  He was almost 100.

Mike, on the other hand, was in a memory care facility where he lived largely in isolation.  I visited him daily in the afternoon, and he was always happy to see me.  But I know he didn't get out of his room much, and I believe he thought I was a different person each visit.  His wife also visited him often, usually late in the morning.  When I spoke with him, he could always tell me his first name but often could not recall his last name.

In January of this year we posted some observations (well, speculation) about people with neurodegenerative diseases living there in isolation.  In the time that I had been visiting Mike he had not seemed to decline, although others around him did -- at least to my eye.  I wondered if this wasn't a result of frequent visits and social interactions with his wife and me.  In Beating the Dementia Monster we discussed the role of social interactions in slowing the progress of Alzheimer's disease.

Then came the Covid-19 lockdown, and I have not seen him since.  On April 26, we posted about my concerns with respect to the impact of the lockdown's loneliness and isolation on people with Alzheimer's disease.  I didn't say as much, but I worried that the lockdown might accelerate Mike's disease.  I don't know if it did or not, but he died a few days ago.

ApoE4 and Dementia Without Alzheimer's Disease

The gene referred to as apolipoprotein E4 (ApoE4) is a recognized risk factor for Alzheimer's disease.  If you carry this gene, it doesn't guarantee that you'll get Alzheimer's disease, but the odds are greater.  Therefore, genetic testing companies like 23andMe and Ancestry.com will test for the #4 variant of ApoE.  If they find that you carry this gene, the companies are required by law to explain to you that this does not guarantee you will get Alzheimer's disease, but they must recommend that you to seek counseling on your path forward.

So what does ApoE4 do that's so bad?  About a year ago, we posted a list offenses, noting that each offense played its own role in a very complex disease.

Recall that, like all genes, ApoE4 is the design description for a protein.  In this case, it's a protein that helps transport cholesterol through the blood.  But what's wrong with variant #4?  Two things we noted have come up again in recent research published in the journal Nature ("APOE4 leads to blood–brain barrier dysfunction predicting cognitive decline"): promoting inflammation and damaging the blood-brain barrier.  We have been discussing both of these in recent posts.

The more we learn about inflammation, the more we realize how pervasive its effects are on many of the body's maintenance mechanisms -- and on many diseases.  But what I found interesting in the recent research linked above was how the ApoE4 protein is associated with damage to the blood-brain barrier -- most notably in the hippocampus and temporal regions.

We discussed the blood-brain barrier in the post on dietary salt.  The blood-brain barrier is part of the brain's own immune system, and it blocks the entry of pathogens into the brain.  Breakdown of the blood-brain barrier has been associated with Alzheimer's disease.

The research reported in Nature brought something new to the table.  While a correlation between breakdown in the blood-brain barrier and Alzheimer's disease seems to be established, it may be that there can also be cognitive decline here without Alzheimer's disease.

In their study population, the researchers conducted brain scans for beta amyloid and abnormal tau proteins among subjects carrying the ApoE4 gene.  (Beta amyloid plaques and accumulation of tau-related tangles are important biomarkers for Alzheimer's disease.)  They identified those individuals who did not have Alzheimer's disease.  Nevertheless, there were cases of cognitive decline in this population, suggesting that there are more ways in which this problem gene can cause dementia than just through Alzheimer's disease. 

Inflammation, Depression, and Alzheimer's Disease - A Deadly Triad

Inflammation is the body's response to just about any insult, from physical injury to infection.  It exists to serve a protective function, but quickly begins causing serious damage of its own.  In recent years, inflammation has been found to play a role in exacerbating just about anything that goes wrong in the human body, including in Alzheimer's disease.  Therefore, an important dietary target for treating Alzheimer's disease is reduction of inflammatory foods, especially refined flour and refined sugar.

Recent research increasingly associates depression with inflammation, and, according to the Alzheimer's Association Facts and Figures Report, depression is an early symptom of Alzheimer's disease.  As I wrote in Beating the Dementia Monster, one of my first symptoms was frequent, brief occurrences of mild depression.  It's not surprising that we find inflammation, depression, and Alzheimer's disease together.

Professor Edward Bullmore chairs the department of psychiatry at Cambridge University and writes on the flood of new research on inflammation.  In a recent article in The Guardian ("From Depression to Dementia, Inflammation is Medicine's New Frontier"), he discussed the link between autoimmune diseases, neurological diseases, and inflammation.

In our recent post on salt and dementia, we discussed the blood-brain barrier and the immune system in the brain that is separate from the immune system protecting the rest of the body.  Professor Bullmore contends medical science is learning that the the two immune systems communicate with each other far more than we had believed.  And so, inflammation plagues them both.  He further believes that focusing research on inflammation will lead to breakthroughs in treatment of many other diseases, because inflammation is involved in so many of them.

In February 2019 we posted regarding a link between gum disease and the advent of Alzheimer's disease.  Professor Bullmore sees an important link between gum disease and inflammation, and he believes inflammation is then the link from gum disease to Alzheimer's disease.  He cites ongoing research that may lead to improvement in how we treat Alzheimer's disease by treating gum disease.  

Dietary Salt Causes Cognitive Impairment

For several years, researchers have been studying "the gut-brain axis."  Essentially, there is a form of communication between gut microbes and the brain, and when things go wrong in the gut they can go wrong in the brain.  Also, it's easy to make the case that excess salt intake will have a negative effect on cognition because it raises blood pressure.  High blood pressure is bad for the heart and is a risk factor for Alzheimer's disease.  What's good for the heart is good for the brain.

But a December 2018 article in Scientific American (reproduce here by Pocket) discussed a separate gut-brain axis involving salt but that does not involve blood pressure.  The article's author cited research published in Nature Neuroscience about work with mice.  It found "excess dietary salt suppresses resting cerebral blood flow and endothelial function, leading to cognitive impairment. The effect depends on [certain cells] in the small intestine."  "Endothelial function" refers to the work of endothelial cells lining the blood vessels that control contraction and relaxation of the blood vessels, among other things.  Its failure contributes to a number of bad consequences for both the heart and the brain.

The research with mice points to a pathway between the gut and the brain via the immune system.  Then excessive intake of salt can impact the immune function in the small intestine with a negative effect reflected back to the brain.  A very important consequence is that blood flow may be restricted to the hippocampus and the cortex -- ground zero for Alzheimer's disease.

Prior the research on salt, there was research studying other contributions that issues in the gut can make to Alzheimer's disease.  One idea is that microbes may leak from the gut when the spectrum of gut microbes is disturbed.  The leaked microbes can promote inflammation throughout the body, including in the brain.  Inflammation in the brain plays a role in Alzheimer's disease.

The inflammation can cause impairment of the blood-brain barrier.  The blood-brain barrier protects the brain from pathogens by only allowing small molecules and ions to pass in and out of the blood vessels in the brain.  This is another work of the endothelial cells lining the blood vessels in the brain.  (Special proteins regulate the passage of certain specific molecule that must pass in and out.)  Some studies suggest that impairment of the blood-brain barrier allows beta amyloid molecules to enter the bloodstream and then be more widely distributed in the brain, thus propagating Alzheimer's disease.

Speaking for myself, I have always had fairly low blood pressure.  During periods when it seems too low my cardiologist suggested raising my intake of salt.  Maybe that's good advice, but I'm wondering what it means for neurodegeneration in light of this research.  

Coming Out of Lockdown -- What Will that Mean for Elder Care?

Unless you live in Wyoming, Utah, Oklahoma, or a few other states, you have been living in quarantine for what seems like forever.  But sooner or later a mix of improving infection statistics, economic necessity, and public frustration will lead to a relaxation of the shutdown orders.  What will that mean for people living in memory care, retirement, nursing, and other elder care facilities?  This is where the most vulnerable members of our communities live, and mortality rates are the highest.

In our city, there is one nursing home with fully 100 infections.  I've visited that facility many times, and I didn't believe there were 100 people there.  So it must be that about everyone there is infected. 

It's pretty clear that your state will not lift all restrictions simultaneously.  Restrictions will be lifted systematically to favor less hazardous activities as well as activities with economic imperatives.  Elder care facilities have the most hazard for their residents, and there is no economic imperative for opening them.  So they will likely be the last to get to wherever it is we're going with a re-opened society.

Before our shutdown order came, I was visiting elder care facilities pretty much every day, seven days per week.  I had seen one period of time when there was a scare about the flu or something, and all residents were confined to their rooms for a week or so.  What struck me about this was the terrible sense of loneliness that would pervade the living areas.  (I was told I could enter at my own risk, and I decided to risk it.)  Some of the residents receive periodic visits from family and friends, but many have no visitors at all.  They do have an opportunity to see others at meals or while traveling the halls and community areas.  But in quarantine, the only human contact residents have is when someone brings them their food, or someone comes in to bathe them or help them go to the bathroom. 

For prisons, some have tried to make the case that solitary confinement is cruel and unusual punishment.  This doesn't seem to be much different from what many elder care facility residents experience during quarantine.

Recall that human contact -- or rather, lack of it -- is a risk factor for Alzheimer's disease, and increased human contact is recommended for people who have AD.

I saw quarantines lasting a week or so, and marveled at what the residents suffered through.  And so I can't imagine what these people are going through now.  When restrictions are relaxed for the rest of us, how soon will it be safe for elder care residents to return to the level of human contact they had before?  How long will their suffering last? 

Another Possible Vaccine for Alzheimer's Disease?

As we discussed in Beating the Dementia Monster, Alzheimer's disease continues to be a black box.  There are so many hypotheses surrounding beta amyloid, tau protein, P. gingivalis, herpes, and others.  When we can finally go to press with the second edition, we will note that cancer research began in earnest in 1913, but Alzheimer's research only got going in the 1980's.  So it's not surprising that we still struggle to get a handle on the basic disease mechanisms. This has implications for progress in both disease prevention and treatment.

In two earlier posts (this one and this one) we considered the possibility of a vaccine for Alzheimer's disease.  The first article considered the possible role of P. gingivalis in the genesis of the disease, and the idea that a vaccine against this pathogen might work.  The second article concerned trials for a vaccine that might work against beta amyloid, training the body to treat it as a foreign intruder.

But what about a vaccine against tau protein?  During the perhaps 15 years of the pre-clinical stage of the disease, abnormal tau is being generated within brain cells.  But at the beginning of the MCI stage, tau is expelled from the cells and spreads throughout the brain.  This produces the tangles that are observed during autopsies.  The spreading tau appears to play a role in the advance of the disease.

This invites another idea for a vaccine.  How about a vaccine that attacks the abnormal tau protein?

At the Advances in Alzheimer’s and Parkinson’s Therapies Focus Meeting (AAT-AD/PD), held virtually from April 2 to 5, work on such a vaccine got attention.  (We discussed some other interesting takeaways from the conference on April 12 and 13.)

Presenters addressed several initiatives to develop tau vaccines.  In one case clinical trials had not gone well, and others were still trying to get off the drawing board.  But one showed promise in clinical trials. 

The most promising candidate is called "Axon peptide 108 conjugated to KLH" or AADvac1.  Basically the vaccine prompts the generation of antibodies that target one of several abnormal tau proteins.  AADvac1 has completed its phase 2 clinical trial and should -- hopefully -- go into phase 3.  The first two phases of a drug trial look for efficacy of a new drug, but they are first intended to demonstrate safety.  Phase 1 trials are fairly small, and phase 2 will involve more subjects.

In the case of AADvac1, the test subjects had "mild Alzheimer's disease."  (I don't know if that meant they had MCI or were in the mild (first) stage of Alzheimer's dementia.)  After some people dropped out, the phase 2 trial for AADvac1 had 100 subjects on the study drug and 63 on the placebo.  The trial ran for two years.

There were no problems with safety, but does the vaccine work?

Unfortunately, in the two trials there was no evident effect on cognition.  (A subset of younger test subjects may have shown some improved cognition.  "Younger" means ~65-67 years.)  On the other hand, there was pretty good evidence that the process of neurodegeneration was actually slowed.  This was evaluated through changes in blood that are associated with neurodegeneration.

The biotech company Axon Neuroscience plans to move ahead with a phase 3 clinical trial, but they believe they first need to find an international partner.

So what do we make of the fact that the drug slows neurodegeneration but does not appear to improve cognition?  We've found that we can remove amyloid plaques from Alzheimer's brains without improving cognition.  But it appears that cognition will improve somewhat if people stay on a drug long enough after removal of the amyloid to allow healing of the brain.  Will the same apply when removing the abnormal tau protein?