Supportive listening reduces Alzheimer's risk

In Beating the Dementia Monster, we said that social isolation not only increases the risk of developing Alzheimer's disease but also of worsening it.  I cited a neurologist who told me that, in his experience, older people with cognitive challenges did best when they maintained social connections.  When I was originally diagnosed, I was told, "Don't quit your job!"  Continuing to work would maintain social connection and help resist progress of the disease.  But why should this be important?  What happens in the brain during social interaction that counters Alzheimer's disease?

I recently came across an interesting article in JAMA Neurology.  (JAMA used to be the Journal of the American Medical Association.)  The article reported on a study that found supportive listening specifically influenced cognition, while the other kinds of social support did not.  The article appeared August 16, and was entitled "Association of Social Support With Brain Volume and Cognition."

One premise of the study was that there is a relationship between cognition and, among other things, "synaptic plasticity."  Synaptic plasticity is the fundamental process of the brain by which neurons are constantly strengthening and weakening connections.  This is important to memory, and it promotes resilience, including resistance to neurodegenerative diseases.  Apparently, social activity influences synaptic plasticity in a positive way.

Another premise was that there is an association between brain volume and cognition.  So as the brain atrophies, cognition deteriorates.  The researchers looked for a relationship between changes in brain volume and cognitive test scores in the presence of different types of social support.  As we noted in Beating the Dementia Monster, all brains atrophy with age, but brains affected by Alzheimer's disease atrophy faster. 

So the question is -- Does cognition in people with different types of social support decline more slowly as their brains atrophy?  And is the rate of decline affected differently with different types of social support?

So what did the researchers do?  They took data from the very rich reserve of information generated by the Framingham Heart Study.  The study began in 1948 and continues to this day, amassing an extensive repository of data on the health of many thousands of individuals.  While the study was intended to investigate heart disease, it has yielded a treasure trove of data relevant to Alzheimer's research.  In the data, the researchers found information regarding the social activity of the subjects, specifically forms of social support.

But what kind of social support did the researchers look at?  They looked at five kinds: listening (“Can you count on anyone to listen to you when you need to talk?”), advice (“Is there someone available to give you good advice about a problem?”), love-affection (“Is there someone available to you who shows you love and affection?”), emotional support (“Can you count on anyone to provide you with emotional support?”), and sufficient contact (“Do you have as much contact as you would like with someone you feel close to, someone in whom you can trust and confide?”).

And what did they find?  Only listening (someone else listening to you) correlated with resistance to cognitive decline. 

So, if you want to keep Mom out of memory care, listen to her when she wants to talk!  

The aducanumab shock waves will radiate beyond Alzheimer's treatments

There's been a lot in the news lately, and the controversy over the FDA's approval of aducanumab/Aduhelm has receded.  But that doesn't mean that the controversy has gone away.  In fact, both the price and the way in which it was approved have invited several investigations.  These will likely impact both how the FDA manages accelerated approvals and how new drugs are priced.

When the FDA approved aducanumab, they did so without the evidence of effectiveness normally required for approval of a new drug, and their advisory committee had given it a thumbs down.  When Biogen announced their pricing of $56,000 per year for the treatment (but varying depending on how much the patient weighs), there was quite an uproar.  For one thing, there was anticipation that this could drive Medicare into an even deeper hole than what already appears to be on the horizon.  So now many players want to get into the act of critiquing how we got here.

While three members of the FDA's advisory committee quit over the controversy, the committee members together wrote an article for the New England Journal of Medicine criticizing how they were informed (or misinformed) of the FDA's strategy.  They also cast doubt on the utility of using beta amyloid plaque loading as a surrogate for effectiveness -- a substitute for showing that the treatment actually improves cognition.  At the same time, the FDA's inspector general is being tasked to investigate the appropriateness of the FDA's relationship with Biogen.  This may extend into an evaluation of the whole accelerated approval program.  The investigation was prompted by an inquiry from Rep. Katie Porter (D-CA). 

Is that enough?  No.  Two House committees, Oversight and Reform as well as Energy and Commerce, have begun collecting documents from Biogen and other entities preparatory to hearings.  And Senator Ron Wyden, chair of the Senate Finance Committee, already has an interest in how new drugs are priced at launch.  He is making noises suggesting an investigation by him will fuel interest in drug price controls.  However, the Senate has not yet responded to the letter from Elizabeth Warren and Bill Cassidy highlighting the challenges that Aduhelm presents to Medicare.

What does this mean for the career of Dr. Janet Woodcock, acting commissioner of the FDA?  In a letter to President Biden, Senator Joe Manchin (D-WVa) outlines the Aduhelm controversy, stating that it's time to put in a permanent commissioner -- someone other than Dr. Woodcock.

Fun times.

Now, some FDA officials have responded to the attention on the accelerated approval process.  In an article in JAMA (formerly the Journal of the American Medical Association) they make the claim that the program has been instrumental in getting some new cancer treatments to market.  So there's something to be said for it.  Presumably, this required judicious and thoughtful application of the process -- and not influenced by political pressure.  

A new gizmo to detect Alzheimer's disease?

How about a cell phone app that will reliably tell you if you are developing Alzheimer's dementia -- even before the disease becomes evident?  Well, earlier this month, the FDA granted Altoida, Inc. "breakthrough device status" to a cell phone app that uses AI to diagnose Alzheimer's disease.  This will allow an acceleration of the development, testing, and approval process for the device.

What does the app do?  According to a press release, it measures 800 "digital biomarkers" (whatever those are) in eleven cognitive domains.  It "collects personalized brain data by asking users to complete a 10 minute set of augmented reality and motor activities on their smartphone or tablet. With this data, the device will use artificial intelligence to predict if an individual aged 55+ with Mild Cognitive Impairment (MCI) will or will not convert to Alzheimer’s disease within 12 months."  

Now, we can see right away that whomever wrote the release could use a lesson in how Alzheimer's disease progresses.  As we wrote in Beating the Dementia Monster, Alzheimer's disease is one of many possible causes of MCI, and Alzheimer's disease begins well before the first symptoms of MCI appear.  So there are two possible things the app may be predicting.  One is if and when a case of MCI due to Alzheimer's disease might progress to dementia.  The other is to discern whether the cause of the MCI is Alzheimer's disease or one of the 30-odd other conditions known to cause MCI.  Both are possible, but it's not clear to me.

Altoida has partnered with Esai, Inc. in this and other research.  You will recall that Esai partnered with Biogen in development of Aduhelm and they continue to investigate lecanemab together.

The promise of donanemab

At the AAIC 2021 conference earlier this month, Eli Lilly presented the results of the phase 2 trial of their donanemab Alzheimer's treatment.  This is the same trial we discussed here back in January.  For me, something interesting came out of their discussion.

Like aducanumab/Aduhelm, donanemab is a monoclonal antibody that removes amyloid plaques from the brain.  It's clear from the phase 1 and 2 trials that it does this quite effectively.  And so it might be a candidate for the same (controversial) approval process that brought aducanumab into the public spotlight.

As we said in Beating the Dementia Monster, amyloid plaques can be silently building in the brain for more than a decade before cognitive problems become evident.  Then there's a tipping point, where defective tau protein associated with tangles propagates through the brain.  This event coincides with the onset of measurable cognitive decline.  So plaque accumulation appears upstream of initiation of obvious tau pathology and decline, and it may be that removal of the plaques slows this process down.

Lilly was able to present some evidence that their treatment may have improved cognition among some test subjects.  But conditional FDA approval would still rest on the hypothesis that removing the plaques stops or slows progress of the disease in a manner that measurably improves cognition.  It's not clear that it does.  

Proving efficacy will require a phase 3 trial with well-managed data.  The FDA's conditional approval process would allow use of the treatment before the phase 3 trial if the phase 2 trial showed, like aducanumab, that amyloid plaques are effectively removed.

So what's special about the donanemab trial so far?  It's that removing the plaques was shown to drive down abnormal tau accumulation, and that it stayed down after donanemab was discontinued.

When a test subject was receiving the treatment, the presence of tau was measured.  When the level fell to that of a normal subject, they switched the treatment from donanemab to a placebo and continued to measure the abnormal tau.  They found that tau levels did not increase after discontinuing the treatment for at least a year, if at all.

But the big question remains:  Does lowering amyloid and tau burdens on the brain improve cognition?  For donanemab, maybe not, although the researchers are applying some analytical techniques to further understand what may have occurred.  But bear in mind that a phase 2 trial uses a relatively small study population.  It may produce inaccurate results due to statistical vagaries -- hence the phase 3 trial with a much larger study population.  

So will Aduhelm find a competitor in donanemab?  We shall see.

Dementia Friendly Communities Conference 2021

Like last year, I am again on the conference planning committee for the Washington State dementia friendly communities conference, sponsored by University of Washington Medicine and the Dementia Action Collaborative.  To keep from boring people, I will not be a speaker this year, although we've been actively planning the event for some time.  Like last year, it will be entirely online.  Here is the information.

Alzheimer's Association International Conference 2021 News

Last year, I was able to attend the entire annual AAIC conference on-line, and I learned a lot.  This is the largest Alzheimer's conference in the world, and many new research findings and test results are revealed there.  In the past, all meetings were in-person, but covid necessitated moving the entire 2020 event on-line -- and for free!  It was great.

This year's event was held last week as a hybrid event -- on-line or in person in Denver, CO -- and it wasn't all that free.  I did register, but I had limited opportunity to participate due to my need travel to the east coast last week.  I do still have access to the plenary sessions and news releases.  I found the following were the most interesting study topics:

One:  Several studies addressed the correlation between air pollution and the development of Alzheimer's disease.  We have discussed this in the past, but the research has now gone a step further.  We knew before that there was a statistical correlation between living in an environment with elevated air pollution and the incidence of Alzheimer's disease.  But recent research presented at the meeting found that by reducing air pollution we can reduce the frequency or delay the onset of Alzheimer's disease.  

Pollutants of concern are traffic-related oxides of nitrogen and particulates.  We noted before that the particulates likely enter the brain along the path of the olfactory nerve.

Two:  The number of people living with dementia is expected to triple world-wide by 2050, but research continues to support our own premise that wise lifestyle choices can impact this prospect.  The conference highlighted education and making education more freely available in places where it's hard to come by.  Early education experience, especially that involving language, is correlated with a lesser incidence of Alzheimer's disease.  Of course, they also discussed improving air quality, and they underscored what can be done by reducing diabetes and heart disease, since those influence the incidence of Alzheimer's disease.  The latter are, in turn, affected by diet and exercise.

Three:  A panel of experts has formulated some tentative rules on the use of Aduhelm/aducanumab.  These were applauded.  The rules address who should and who should not be given the treatment, how should they be monitored, and under what conditions treatment should be stopped.  Not long ago, guidance was issued that it should only be given to people with mild symptoms of Alzheimer's disease, not severe.  The panel also suggested ruling out cases where there was evidence of stroke, and it left several situations open to further evaluation.

Four:  It's well known that African-Americans and some other minorities are under-represented in Alzheimer's research study populations, even though they have a higher incidence of Alzheimer's disease.  There is a need to increase their participation.  It turns out that people of all backgrounds are more willing to participate in a drug trial when they are invited, especially when it's by someone of their own race.  A new tool was presented that may facilitate this. 

Five:  There is growing concern over a correlation between a considerable worsening cognitive ability and a history of covid infection.  (We commented before on how this might occur.)  More study is needed, since we don't know if a covid infection will lead to a continuing acceleration of Alzheimer's disease symptoms, or if it only occurs during and shortly after the infection.

And there was more.  Click here.