Finally time to dump the amyloid hypothesis completely?

As we describe in Beating the Dementia Monster, it was Alois Alzheimer who first saw amyloid plaques and tau tangles in the brain of a deceased seamstress and hausfrau, Auguste Deter.  Since then, our focus on trying to understand the disease has been on the phenomenon of these two markers.  The conventional wisdom has been that if we can just control them, we will be controlling the disease.  If we can get rid of the amyloid plaques, we can control the disease.  If we can stop the generation of the tangles, we can control the disease.

But our experience has now shown that if we get rid of the plaques, we have neither stopped the disease nor cured it.  Yes, we can (apparently) slow it down with Aducanumab and Leqembi, but it will still get you in the end.

As we said in Beating the Dementia Monster, maybe the amyloid plaques actually have a purpose, and trying to get rid of them is the wrong thing to do.  We noted some experts believe the plaques are actually there to protect brain cells from microbes and toxins, such as p. gingivalis, the bacteria that causes gum disease.  Some researchers have been pursuing this hypothesis, but they haven't been getting headlines the way the more easily grasped amyloid narrative has.

One of the more popular and productive health YouTubers is Dr. Eric Berg.  He's a chiropractor who is very big on keto diets and intermittent fasting.  He takes sometimes serious heat from critics about the accuracy of some of the things he says on his videos, but he has a lot of followers and material.  I don't search out his viewpoint on health matters, and I take what he says with the proverbial grain of salt.  But the YouTube algorithm seems to think I should be watching all of his stuff.

Regardless of other baggage, I thought a new video captures some important elements of the shifting landscape of Alzheimer's research.  It fits with authoritative information that I've seen elsewhere and that we provided in Beating the Dementia Monster.  The video is here.

In the video, Berg explains what's wrong with the amyloid hypothesis and gives a rationale for how lifestyle changes can prevent or stall Alzheimer's disease.  He likens treating amyloid plaques to trying to put out a forest fire by putting out the match that started it.  In his discussion, he had a novel way of describing the brain's unique immune system which is separate from the system that serves the rest of the body.

One thing that disturbed me was a blanket conclusion that people with Alzheimer's disease should begin a radical daily fast, eating only one meal a day.  As we discussed before, intermittent fasting is not recommended for the elderly.  If you are older and you want to fast, talk to your health care provider first!

I'd better say this!

I have been doing a pretty radical daily fast since 2020, and I'm now 73.  You should understand that intermittent fasting is not recommended for the elderly.  Some say you're elderly when you're over the age of 65 with functional impairments or if you are otherwise over the age of 75.  But it depends on who you ask.  As I understand it, the concern is that elderly people have more trouble getting all of their nutrition, and fasting will impair that further.  This is why we have products like Ensure.  (People with eating disorders also should not fast.)

What I'm trying to do here is tell what I've done and what my experience has been.  I underscore these with stories about research and news on brain health.  In Beating the Dementia Monster, I warn strongly against starting an exercise program if you are over 50 and haven't consulted with your doctor.  I have consulted with both my primary care provider and neurologists concerning both my exercise and my fasting.  They have asked some questions, but they haven't discouraged me from doing these.  And I'm not having trouble getting all of my nutrition.  Even with the fasting, it's still a fight to keep my weight where I want it.

Nevertheless, older people must consult with medical professionals about both fasting and exercise!

A new twist on exercise, intermittent fasting, and BDNF

If you read Beating the Dementia Monster, you know research shows that exercise affects the progress of Alzheimer's disease, and it may even be able to prevent it.  (No one claims it cures it.)  The conventional thinking is that exercise prompts generation of a protein called the brain-derived neurotrophic factor, or BDNF.  BDNF has the ability to repair damaged brain cells and to prompt the formation of new neurons from stem cells.  

In 2018, we cited peer-reviewed research showing that about 400 minutes of exercise per week was optimal for impeding the progress of Alzheimer's disease, although the research said nothing about the relative intensity of the exercise.  (This led me to my current regimen of 55 minutes per day on the treadmill, six days per week.)  But the research never said how intense the exercise should be.  To get the results of the 2018 research, is walking around the block a few times enough, or must you run full speed the whole way? 

In 2020, we also cited research published in The New England Journal of Medicine stating that intermittent fasting would also encourage the generation of BDNF.  My review of what people were saying on the Internet (not a very scientific approach) found that the conventional wisdom was that a 20 hour/day fast would produce enough BDNF to be effective.  But is that true?  In any event, I've been following a 20 hour/day fast now for three years.  Some days it's more like 19 hours, but I only break the rhythm for special occasions.  (It's also hard to keep that schedule on Fridays, when Amy and I go out for lunch and do our shopping.)

My experience very definitely tells me that getting physical exercise has profoundly influenced the progress of my disease.  But I have no clue about whether the fasting has done anything.  I believe that I had largely "caught up" with normal aging by 2019 and wasn't expecting further improvement in 2020 when I began fasting.  And I have no control to compare to -- I have no twin who did the opposite of me that I can compare results with.  So who knows?  I keep fasting, because I don't want to rock the boat if it's working.

So there are two big questions: How hard to you have to exercise to get results, and does a 20 hour fast really affect the progress of neurodegenerative disease?  As it turns out, there is some interesting new research that tries to answer both questions.  However, it only tries to answer the questions from the standpoint of how much BDNF is generated.  As this article explains, intermittent fasting affects the brain in several ways other than through the production of BDNF.  Exercise, too, has positive effects beyond generation of BDNF.  Nevertheless, measuring what influences the generation of BDNF has a lot to say about how effective exercise and fasting are with respect to brain health.

I came across this research published in The Journal of Physiology that found 20 hours of fasting did little to increase the production of BDNF, but that six minute bursts of vigorous exercise did.  The six minute bursts were compared with 90 minutes of light exercise which did little.  The vigorous and light exercise were both bicycle riding.  Here's their press release.

Bear in mind that this was a small study involving only 12 subjects.  They were younger and not known to have any neurodegenerative disease.  Also, the research only measured production of BDNF.  It didn't measure the actual benefit to the brain from either fasting or different types of exercise.  Both fasting and exercise have important benefits to the brain beyond BDNF.

But I think it does tell us something helpful, particularly that the level of intensity of the exercise does seem to matter quite a bit.  I'm not planning to start doing 6 minute bursts of high intensity exercise, but the exercise I currently do is significantly more intense than the 90-minute bicycle ride they studied in the research.  It's 50 minutes on the treadmill at 3.5 mph at a 10-degree incline.  This is followed by a five minute cooldown at 2.5 mph with no incline.

All I can say is that, every morning when I wake up, I just can't believe it.  I remember back to 2015 when I was in free fall, and I thank the Good Lord for providing the wherewithal to battle this thing and hold it at bay.

Welcome Leqembi!

Yesterday, the FDA approved for use the monoclonal antibody (mab) treatment lecanemab (code named BAN2401) via their "accelerated approval process."  This is kind of like the process that got them in trouble with aducanumab, but I doubt they will face the same headwinds.  For one thing, their approval doesn't fly in the face of the advice of the Peripheral and Central Nervous System Drugs Advisory Committee.  You'll recall what happened with aducanumab.  

So now Biogen and Esai will market lecanemab as Leqembi.  How well will this go?  For starters, the wholesale price will be another $26,500 per year.  That doesn't include the periodic MRIs to check for brain swelling and microhemorrhages.  And did I mention three people died during clinical trials?  Oh -- yes I did.  What will the insurance companies say about paying for it?  What will Medicare say?  We shall see.

How do Biogen and Esai justify the price?  In this statement, they say it's based on the value of the treatment to society -- their concept of the "societal value of medicine" in relation to the "price of medicine."  If history is a guide, Elizabeth Warren and a few others will offer their thoughts on how that should work.

While the "mabs," like Aduhelm and Leqembi, go beyond treating symptoms, we don't know that they are treating the cause (or causes) and mechanisms of the disease.  We just don't really understand those very well.  And so these are not cures, they simply slow the progress of Alzheimer's disease.

Will the pros outweigh the cons for many people?  If you slow the disease enough to add a few good years to someone's life, maybe so.

Back in the news -- Aduhelm

As we mentioned in August 2021, there were to be investigations into how it was Aduhelm was approved by the FDA and how Biogen justified its unprecedented price tag.  Last week, the House Energy & Commerce and the Investigations & Reforms panels completed their investigation and issued their report.  You probably anticipated correctly that it was quite critical of both the FDA and Biogen.

Recall a couple of things.  Originally, Biogen (and its Japanese partner, Esai) said their clinical trials found the monoclonal antibody simply didn't work.  Then they reevaluated one subset of their data to find that it may actually have worked some.  So Biogen applied for approval, and the FDA put it on an unusual approval fast track.  But when it seemed ready to go, the FDA's 11-member independent advisory panel reviewed the clinical trial data themselves and voted unanimously that it not be approved.  In their view, the interpretation of the data didn't demonstrate that it worked.  But the advisory panel's judgement was not binding, and the FDA gave the treatment a conditional approval.  Three members of the FDA's advisory panel then quit in disgust.

This was (and is) a fraught time in the history of Alzheimer's research.  The disease is far more complex than anyone dreamed, and proposed drug interventions have failed, one after the other.  Yes, some drugs can give symptom relief, but none had been shown to modify the disease process, actually treating the disease.  

With millions of people succumbing to this, the sixth leading cause of death in the US, incredible pressure has been on the pharmaceutical industry and their regulators to come up with something.  I recall in 2017 seeing an article in a popular magazine saying that the FDA should simply approve an Alzheimer's drug even without completing clinical trials.  The article didn't say, but it appeared to me that the treatment in question was aducanumab (later sold as Aduhelm).  There were incredibly high hopes riding aducanumab -- and incredibly high pressure on those involved in developing any treatment that might help.

So when the FDA did provide conditional approval from questionable clinical trial results, and when Biogen started selling it at $56,000 per year (not counting the cost of regular MRIs), there was an uproar.  At that price and with the anticipated population of patients, there was fear Aduhelm would simply bankrupt Medicare.  Some in the congress vowed there would be an investigation.

Hence the investigation report released last week.  Most of the criticism fell to the FDA for a process that was "rife with irregularities."  It appeared to the investigators that the FDA was too cozy with Biogen.  The FDA and Biogen claimed that closeness was necessary in the face of such a complex scenario.  Here's what Biogen had to say. 

So what will happen?

As we've discussed before, the FDA and Medicare have severely limited the availability of Aduhelm, essentially turning current commercial usage into an extended clinical trial.  The FDA needs more evidence before giving the monoclonal antibody wider availability, and Medicare wants to know they're getting their money's worth, even after Biogen cut the price in half. 

Where do we go from here?  Hopefully the ongoing limited use of the Aduhelm will tell us how well it works.  But that's going to take some time.  As for consequences of the congressional report?  Hopefully the FDA and Biogen will go forward in a way that builds public confidence in both the regulatory process and in this generation of Alzheimer's disease treatments.

Blood tests for Alzheimer's disease? When?

It seems like every month there's a new story in the news about the advancement of another blood test for Alzheimer's disease.  A couple of tests are out there, but they're rarely used.  Yes, they're new, but why not use them more often?

We have discussed blood tests on this blog several times in the past, noting that they could shake the availability of long-term care insurance for many people.  The blood tests appear to identify the disease well before the first symptoms appear, so insurance companies will be unwilling to insure people long term who are found during screening to be already developing the disease.

Here's an interesting article from the Washington Post via Yahoo News about what's going on with this.  (Ah, The Washington Post.  Sixty years ago, I would get out of bed each morning at 4:30 or so to go deliver the Post on my paper route.) 

The Post article explains that the medical and health care communities are not ready to proceed with making the tests generally available for people with no symptoms.  The tests are being used to screen candidates for Alzheimer's drug clinical trials to ensure people with memory loss are actually suffering from the disease.  But what about use in a primary care setting?  What about primary care providers diagnosing people who may be suffering from normal pressure hydrocephalus (NPH)?  They have very similar symptoms to Alzheimer's disease, but the treatment is usually different.  NPH is often misdiagnosed as Alzheimer's disease.  Tests for NPH can be quite intrusive -- such as a spinal tap.  So why not screen out Alzheimer's disease first?

Medicare and health insurance companies are not ready to cover the blood tests.  Out of pocket, costs run from $500 to $1,200.  This is a lot cheaper than an amyloid PET scan (more than $5,000), which is the current gold standard for diagnosing Alzheimer's disease.  Of course, the final diagnosis is in the autopsy, but most people don't want to wait that long.

The article emphasizes that opinion on the tests is quite divided.  Some would make the tests freely available now, while others believe that the consequences of their use must be better understood before they're more broadly used.  No one has said anything about the possibility that the tests could disrupt the availability of long-term care insurance, but I'd bet that's a factor.