Aducanumab: Back from the Dead? Or a Ghost...

On October 22 we posted about the news that Biogen was applying to license Aducanumab for treatment of Alzheimer's disease type of dementia.  The monoclonal antibody was abandoned by researchers when a stage three trial was not showing sufficient positive results to justify continued pursuit.  Biogen said they had been going back over the data and believed that some of the trials were actually yielding positive results.  It was not going to cure Alzheimer's disease, but it was said to slow its progress.  Therefore, licensing and sale of the treatment were in order.  The stock market is desperate for a drug that will actually treat the disease rather than the symptoms, and Biogen's stock took off like a rocket.  The news attracted a lot of attention in popular media.

The announcement took everyone by surprise, and there was great initial jubilation.  But as time goes on, my sense is that there is some skepticism growing regarding its ultimate viability.  This week's ALZForum discussed some concerns, although they were cautiously optimistic.   

Your high school persona is a risk factor for dementia?

If you were calm or mature in high school many years ago, does that speak to your Alzheimer's disease and dementia risk today?  Maybe it does.

A recent study published in the journal JAMA Psychiatry looked at personality traits among American High School students in 1960 and related them to the incidence of development of dementia by age 70.  (The study is also discussed in this week's ALZForum.)  The researchers drew on a treasure trove of personality histories gathered in the Project Talent study of 1960.  (Here's what Wikipedia says about the original study.)  Researchers then tested 377,000 students for various traits.  (Some sources quote 440,000 students.)  They specifically evaluated for sociability, impulsivity, leadership, vigor, calm, maturity, and self-confidence.  Then in 2018 and 2019, researchers used the Medicare database to identify 82,000 of the original subjects and assess their cognitive status.

Pretty remarkable, but I'm not sure I'd want that kind of information floating around about me.  But times have changed.

What did they find?  There appears to be significant correlation between different youthful personalities and dementia risk.  Notably "vigorous" students had a 7% lower risk of dementia, while "calm" and "mature" students seemed to have a 10% lower risk.  Regardless of these factors, students with lower socioeconomic status had higher risk.

I'm not an expert on personality, but I know our ways of understanding personality have evolved over the years.  I suspect this list is outdated, since it is more common to see reference to the Big 5 traits (or the Five-Factor Model) when the slicing and dicing of personality is discussed.

The study noted that these results were consistent with other studies that looked at personality traits in later years.  A conclusion was, "Personality phenotype may be a true independent risk factor for dementia by age 70 years."  In other words, aspects of your personality are baked into your genes and subsequently influence your risk factor for dementia.  We are always trying to refine our understanding of the risk factors for Alzheimer's disease and dementia.  The study authors suggest that high school personality might be considered a new one.

Results of the HABIT® Study

In Beating the Dementia Monster, we discussed how Amy and I participated in the Mayo Clinic HABIT study -- Healthy Action to Benefit Independence & Thinking®.  The study targeted people in the mild cognitive impairment (MCI) stage of Alzheimer's disease.  The study was so engaging and popular that it has now evolved into the HABIT Program.

Amy and I spent two weeks at an assisted living facility in Seattle where we devoted ten days to engaging in four activities from a possible five.  The idea was to measure how much these activities could influence the progress of Alzheimer's disease, specifically with respect to quality of life, mood, self-efficacy, and memory-related activities of daily living.

The five possible activities involved memory compensation training (calendar and checklists), computerized cognitive training (video games), yoga, patient and partner support groups, and wellness education.  The program was conducted at different sites across the country, and each trial eliminated one of the activities.  By measuring changes in cognition over an 18 month period (following the initial two weeks), relative effects of the different activities could be measured by knowing which were omitted.  Our group omitted the computer games.

We really enjoyed our participation, but I got kicked out of the study when I started on the insulin study.   We met really nice people, and I learned a lot.

In a recent email exchange with the neuropsychologist who was principal investigator for our site, she told me about publication of the study results.  (Dr. Phatak was my first neuropsychologist at Harborview and is a reviewer on both editions of Beating the Dementia Monster.)  I was a little surprised at the outcome.  You can read the results, but my takeaways were:

• Playing video games doesn't improve mood or cognition impaired by Alzheimer's disease.  Other research suggests that it's the same with crossword puzzles and Sudoku.
• Yoga does help measurably.  This surprised me.
• Wellness education did the most to improve mood.  Mood is a factor in the progression of Alzheimer's disease. 
• Support groups were helpful with improving quality of life.  

Aducanumab: Back from the Dead

Back in March, we joined the rest of the world in declaring that Aducanumab was dead as a treatment for Alzheimer's disease.  An independent futility review found that the phase 3 (final) trial was not sufficiently promising to justify its continuation, so it was halted.  I had auditioned for the trial in 2016, but was glad not to have been accepted.  And that was that ... or so it seemed. 

But just today the word got out that Biogen and their partner, Eisai of Japan, weren't done with Aducanumab after all.  They said they will apply to the FDA for a license for the drug next year!  It's hard to tell what happened, because, so far, the big news is that Biogen's stock shot up 28%, not that there was new hope for curing Alzheimer's disease.  But it does seem that a more extensive review of the data sets justified declaring the trial a success and applying for a license.

Something that surprised me a few months ago was some grumbling I heard about Biogen being stingy about sharing the trial data.  Apparently it's customary to make data from abandoned drug trials available to other researchers, but it seems Biogen wasn't doing that very openly.  Sounds like they were still crunching the numbers.

Not everyone is sure that this is for real.  One publication outlined the doubts.  

This event was brought to my attention today by Dr. Moon (who wrote the foreword to Beating the Dementia Monster) and a neurologist who will be reviewing the new edition.

Disturbed Sleep Points to Alzheimer's Disease in Hispanics ... and Maybe the Rest of Us

News-Medical.net recently reported on a study correlating sleep disturbances in American Hispanics with the development of Alzheimer's disease.  The journal Alzheimer's and Dementia published the research.  The article was "Sleep and neurocognitive decline in the Hispanic Community Health Study/Study of Latinos."

The original publication is behind the Alzheimer's and Dementia paywall, but the summary information states this:

Introduction:  "To determine if sleep-disordered breathing, daytime sleepiness, insomnia, and sleep duration predict seven-year neurocognitive decline in US Hispanics/Latinos."

And they concluded:  "Long sleep duration predicted seven-year cognitive decline."

This was a nationwide study that included 5,247 participants between the ages of 45 and 75.  According to News-Medical's interview with the lead author, they found that prolonged periods of sleep and chronic insomnia preceded declines in memory, executive function, and processing speed.  And these often signal the onset of Alzheimer's disease and other dementias.  Hispanics have a higher probability of developing Alzheimer's disease than non-Hispanic whites.

My first question is, does this indicate that controlling these factors will reduce your risk for Alzheimer's disease, or are these symptoms of a disease that is already in motion?  Or maybe both?  Certainly in Beating the Dementia Monster, we recommended doing everything you can to optimize your sleep.  We did not, however, discuss issues that might emerge from getting too much sleep.  I understand that there's a correlation between extended sleep and depression, and there is correlation between depression and Alzheimer's disease, so maybe there's a connection there.  The study says that their work points to areas for more research.

My second question is, how does these results apply to us non-Hispanics?

The researchers specifically studied the American Hispanic population with origins throughout Latin America.  It is clear from other studies that ethnicity plays a role in the development of Alzheimer's disease, so explicitly studying a single ethnic group will help us to better understand the disease.  A recognized problem with many studies is that they intend to study the population at large, but they don't consider ethnicity in their selection of subjects.  As a consequence, the study populations may have been too heavily weighted with people of Northern European ancestry.  It's increasingly clear that research should control for this variable.

On September 3 we wrote a little about the US Pointer study, which extends the work of the Finnish FINGER study.  The Finnish study provided important information correlating lifestyle with the development of Alzheimer's disease, but it studied a very homogeneous population of Scandinavians.  The US Pointer study is one of a set of similar studies around the world that should control for ethnicity.

Still Another Study Connecting Physical Activity with Alzheimer's Prevention

This past week, the journal Alzheimer's and Dementia published the results of a study that related lifetime physical activity with the risk of developing Alzheimer's disease and dementia.  Not surprisingly to us, it found that "increased" and "always high" levels of leisure time physical activity provided a protective effect against Alzheimer's disease.  ("Always high" indicated people who were active all their lives, not always high intensity.)

The study involved 1,345 older adults who reported varying amounts of leisure time physical activity throughout their lives.  High and low levels of activity were considered, both recent and early in life.  The study concluded that "'Increased' and 'always high' levels of leisure time physical activity were associated with reduced Alzheimer's disease risk..."

One statement surprised me: There was a health benefit in Alzheimer's disease prevention by performing light and moderate [leisure time physical activities]."  So what about more aggressive activity?

I wasn't willing to pay $36 to buy the article, so I relied on the summary information I got for free.  (They didn't even say where the research was done, but the investigators were all from Columbia University.)  So did they find that there was no protective effect from more strenuous activity?  Or did they not want to report on its value in the summary material for fear of turning away people who might be intimidated by strenuous physical activity?

I will be watching to see if more information leaks out under the paywall...

 

Seeing and Believing

On July 28 of this year, we posted regarding the four syndromes of Alzheimer's disease; the memory, language, visual, and frontal syndromes.  These point to different ways that Alzheimer's disease and dementia first asserts itself, and they vary based on which part of the brain is being attacked first.  Most common and most familiar is the memory syndrome, but mine may actually have been the visual syndrome.  It is known as posterior cortical atrophy or Benson's syndrome.  Benson's syndrome is referred to as "an atypical variant" of Alzheimer's disease.  In my case, I had to stop driving because I sometimes failed to see a car in the lane I wanted to move into, or I didn't see a pedestrian in a crosswalk.  (This problem has not recurred since 2016.)

Today, Firefox offered me an interesting article on how the brain processes vision that discussed how vision changes in the elderly ("Your Brain Chooses What to Let You See").  It discussed how changes in the brain affect the way the brain processes information delivered by the eye to assess the environment for threats or access to food.  First and foremost, it must screen out distractions, so that you focus on what's important.

The principal idea was that something moving is more important than something stationary, so your brain will be interested in that first.  Also, something small that's moving may be more important than something big that's moving.  They give as an example that a raptor must distinguish a moving mouse from the windblown grass and tree branches.

One of the research findings they discussed was that elderly people have a harder time separating smaller moving objects from larger moving objects.  This is consistent with Benson's syndrome, in that evidence of Benson's syndrome includes difficulty in distinguishing the relative sizes of objects.

I will speculate that we will see something here that is similar to distinguishing memory issues in normal aging from Alzheimer's disease and other dementias.  In normal aging, the brain is atrophying.  If you're a Baby Boomer you know this, regardless of your Alzheimer's disease status.  In normal aging, the word you want to use is still in your memory, you just have trouble pulling it up for use.  It will come back to you later, but too late to have been used in the conversation.  In Alzheimer's disease, it has been erased from your memory.  You may be able to re-learn it, but it's gone.  I have met several people recently who's own names have been erased from their memories.

The authors of the article discuss limitations of seniors on their brains' ability to distinguish relative sizes of objects in motion.  I speculate that the article is referring to the consequences of normal aging.  In Benson's syndrome of Alzheimer's disease, the damage to the areas of the brain responsible for interpreting the information from the eye are much more seriously damaged, and the visual function of the brain is more seriously degraded.