Alzheimer's Invisible Twin

I just got my University of Washington Brain Wellness Center monthly newsletter, and it had a fascinating article on a newly-identified brain disease.  The article (actually a press release from the National Institute on Aging) was about a "newly-defined Alzheimer's-like brain disorder."  The newly-defined disease is called Limbic-predominant Age-related TDP-43 Encephalopathy, or LATE.  (Say that three times fast.)  It mimics AD and is differentiated from AD at the autopsy.  So far, anyway.  According to the press release, the search is on for biomarkers that would help differentiate it from AD in living patients.

Apparently, LATE advances more slowly than AD, and primarily affects "the oldest of the old."  But in that group it may have a public health impact that exceeds AD.  And if it appears together with AD, dementia may advance more rapidly than with either disease alone. 

TDP-43 is the name of the protein that characterizes the disease.  Its normal role is to help regulate gene expression in the brain and other tissues.  However, it it's misfolded, it can misbehave and cause problems.

What is folding all about?  During the process of building new protein molecules (protein synthesis), chains of amino acids are jostled by water and other molecules (Brownian motion) such that electrical charges along the length of the chain are allowed to attract and repel each other to fold the new protein into a precise shape.  Or so it's hoped.  When things don't go well, you may end up with a misshapen protein that will behave very differently from what's intended.

So LATE is a new research priority.  It will be important to find biomarkers to differentiate it from AD in pools of research test subjects.  If a new drug intervention for AD is tested on a pool where many have LATE and not AD, it will invalidate the results.

Tacoma Early Stage Memory Loss Forum

On May 11, I attended the Alzheimer's Association Early Stage Memory Loss Forum in Tacoma, WA.  I had gotten an announcement email, and it looked interesting.  So I signed up.  Amy's sister was here from the east coast, so I drove over alone. There were about 40 people in attendance, mostly persons experiencing memory loss and their caregivers.  I'm not sure, but I may have been the only one who came alone. 

The attraction for me was that the first module would discuss how lifestyle changes could affect memory loss.  When I entered the room about a half hour before the program was to begin, I saw from the first slide of the PowerPoint presentation that they were going to be talking about all of the points we make in Beating the Dementia Monster.  So I approached the woman who would be the presenter for the lifestyle module and told her I might be a poster child for her presentation.  I gave her an elevator pitch, and she introduced me to people who were in charge of the whole program.  They asked if I would speak briefly at the beginning of the module, and I said that I would.  She said to keep it to less than three minutes, and I said that I could do that.

After the introductories, and after the lifestyle module began, they asked me to come up and tell my story.  Now, I really did keep my presentation to under three minutes ... but there were questions.  People had lots of questions.  So it was about 20 minutes before I was done, but everyone seemed to have gotten something from what I had to say.

It had cost me $40 to enroll, but the local Subaru dealer paid everyone's tuition!  That was nice.

This week I attended a planning meeting for a similar (but probably larger) Alzheimer's Association meeting here for November.  I will have an hour for my presentation.  I will also be speaking to a meeting of a state-wide association of retirement home professionals in September.   

Sleeping Pills for People with AD?

We know that good sleep is important in the fight against AD, and we discussed this in our post of July 13, 2018.  But people with dementia have trouble sleeping well.  I've heard some authorities describe this as a vicious circle, which makes sense.  You need good sleep to fight AD, but AD makes it much harder to get good sleep.  So why not take sleeping pills to rest better?

Hypnotics (like Ambien) and tranquilizers (like Valium) are known to aggravate AD, and so are not usually prescribed for people with AD.  Or at least my doctor won't prescribe them for me.  But is there another medication that would help us sleep better at night and feel better during the day without causing problems with AD?  Maybe there is.

A recent stage 3 (final stage) trial for the drug Suvorexant, sold under the trade name Belsomra, suggested that Suvorexant prolongs sleep, with more overall sleep time and shorter bouts of nighttime wakefulness for people with AD than with a placebo.  (Caregivers also slept better...)  Suvorexant was approved by the FDA in 2014, so we have some experience with its behavior and side effects.  This recent trial was specifically to determine if it is appropriate for people with AD.  All well and good. 

But a couple of things here.  First is that some users complain that it doesn't help them sleep, so it may be weaker than the hypnotics for some.  Also, it has been reported to cause some of the same problems reported with other drugs, such as night terrors and thoughts of suicide.   The drug was tested on AD patients for only two years, and some say it's not clear if a longer period of usage would cause problems for people specifically with AD.

The study involved 266 people with an average age of 70 who scored between 12 and 26 out of 30 on the MMSE.  When the MMSE is used as a screening tool, 24 is considered passing, but there are caveats with that.  The MMSE is not intended for diagnosing dementia, but it is sometimes used in a research setting to track changes in cognition.  To test the effect of the drug on cognition, patients received a follow-up MMSE after four weeks into the trial.  These tests did not show evidence of reduced cognition that might be attributed to the drug.  But some wondered about what would be seen for people tested when they had been on the drug longer.  That information was not available.

You can read more about this here.

I have a lot of trouble sleeping, and I really miss Ambien.  But I'm not sure about jumping into this one. 

The World Health Organization Catches Up

On May 14, the World Health Organization released their guidelines on risk reduction of cognitive decline and dementia.  Looks like they read Beating the Dementia Monster.

As a basis for the guidelines, the document acknowledged studies showing a relationship between the development of cognitive impairment and dementia with lifestyle-related risk factors.  It addressed physical inactivity, tobacco use, unhealthy diets and alcohol abuse.  It also addressed medical conditions associated with an increased risk of developing dementia, including hypertension, diabetes, high cholesterol, obesity, and depression.  Other potentially modifiable risk factors addressed included social isolation and cognitive inactivity.  They said that the existence of potentially modifiable risk factors means that prevention of dementia is possible through a public health approach, including the implementation of key interventions that delay or slow cognitive decline or dementia.

The guidelines document placed more emphasis on some areas than others.  It emphasized physical activity because the effect of physical activity on cognition is best supported by good research.  The guidelines support maintaining social connections, but the document says that the research in this area is of lower quality.  The document calls out social activity as an area of study that needs attention.  The role of diet is addressed, and the Mediterranean diet is promoted.  They don't mention the DASH diet or the MIND diet.

Supplements?  Don't waste your money.  The document says to take supplements only if your doctor directs you to.    

Cognitive training?  The quality of evidence supporting this as an intervention was said to be very low, and their recommendation was tepid at best.

One thing caught my attention.  This being the World Health Organization, they are interested in policies that will benefit countries around the world, including low and middle income countries.  However, they noted that most research on dementia is performed in upper income countries.  The obvious question is whether lifestyle differences between countries means that research conducted in upper income countries might not be valid elsewhere.  Then effective interventions would vary between countries. 

So what does the ApoE4 gene do that's so bad?

If you ask 23andMe to test your genome for AD risk, they will look first for the ApoE4 variant of the gene that codes for the apolipoprotein E protein.  There are three variants (alleles) of the gene for this protein, ApoE2, ApoE3, and ApoE4.  Cells use information encoded in the gene to construct this protein.  

The function of the apolipoprotein E protein is to, among other things, transport cholesterol through the blood, but the ApoE4 variant can cause problems on several fronts.  In Beating the Dementia Monster, we said that it could cause inflammation in the brain, and that could be part of how the AD disease process begins and progresses.

It turns out that's not all it does to cause problems.  This week's issue of ALZForum carried an interesting article on ApoE4, treating it like a criminal with a bad rap sheet.  The article highlighted several "criminal charges" regarding ways in which the protein contributes to the advent and development of AD.  The article got a little deep, but here are some takeaways.

• It acts on microglia cells to inhibit them from doing their job.  The microglia are the brain's immune system, and they help remove dead cells and waste from the brain.  The accumulation of debris in the brain is a characteristic of AD.  In fact, there's quite a bit of attention in AD research on ways in which microglia are inhibited. 
• It causes vascular problems in the brain, such as by making blood vessels leaky and breaching the blood-brain barrier.  "What's good for the heart is good for the brain," so what's bad for the cardiovascular system is bad for the brain. 
• It impairs axonal plasticity or the ability of nerve cells to make certain kinds of repairs.

 And there was more.  Quite the list!

LIght Physical Exercise Leads to Larger Brain Volume -- But not Moderate or Heavy Exercise?

This week's issue of ALZForum included information on recent research on exercise and brain health.  It's encouraging to couch potatoes and is getting wider attention.  The research claims to have found a correlation between light exercise and increased brain volume that does not appear with moderate or heavy exercise. 

The study used about 2,500 participants in the ongoing Framingham Heart Study with an average age of 53 who were cognitively normal.  Participants were wired up with accelerometers and recorders to measure how much light, moderate, and heavy exercise they got in an eight-day period.  Results were gathered from MRIs used to measure changes in brain volume.  The study did not report measuring cognition. 

Regarding moderate and vigorous activity, about half met a goal 150 minutes per week, and half did not.  Measurements of brain volumes found no meaningful difference between these two groups.  On the other hand, comparing participants who took more than 10,000 steps per day with those who took less than 5,000 steps per day found that 10,000 steps per day correlated with a brain volume that was 0.35% larger.  Based on conclusions of other studies, this in turn correlated with a brain that was effectively 1.75 years younger.  The earlier studies found that a normal brain loses 0.2% of its volume per year after age 60.

So just getting up and gardening or walking around the block can produce increased brain volume.  Does this translate into improved cognition?  The study made a number of references to the influence of exercise on Alzheimer's disease, but it did not associate their research with that.  It would have been good if, in addition to measuring brain volume, they also measured changes in cognition.

Are there other studies correlating light exercise with cognition?  In Beating the Dementia Monster, we cite research with women who just walk correlating their light exercise with signiticant delay in the onset of cognitive decline.