A breakthrough in understanding Alzheimer's pathology. But is it barking up the right tree?

Our niece in Hawaii, Denise, recently shared with us an article from SciTechDaily about a breakthrough in understanding how beta amyloid is generated in the brain.  On the one hand, the research provides an intriguing idea that may point to new treatments for Alzheimer's disease.  On the other hand, it relies on the amyloid hypothesis for a rationale for how the discovery could lead to the new treatments.  As we discussed in Beating the Dementia Monster, there are reasons to doubt the centrality of beta amyloid in the disease process.  

If you read Beating the Dementia Monster (and read other blog posts here), you know that the amyloid precursor protein (APP) is cut a couple of times to form different peptides -- strings of amino acids that don't qualify as proteins any more.  Some of these are amyloids.  Depending on how the protein is cut, the resulting peptides may be either innocuous or harmful.  The harmful ones clump onto brain cells, impeding the movement of information between cells and possibly killing them.  

Common sense says we should try to stop the production of amyloids and/or clean amyloids out of the brain to treat the disease.  As we've said before, Aduhelm and other treatments clean the brain of amyloid.  But improved cognition has been hard to detect.  So some (like me) are skeptical of the central role of beta amyloid in the disease process.  Yes it forms, and yes it kills brain cells, but is that important to the disease process?  Will disrupting beta amyloid formation stop the disease?  Problems with getting Aduhelm to significantly improve cognition suggests to me that gum disease and virus infection may be richer areas of investigation.

Nevertheless, it's important to understand how beta amyloid forms because it may provide additional insight into the disease.  We definitely don't understand how the disease unfolds as well as we need to.

The SciTechDaily article draws from research performed at Massachusetts General Hospital and published in the journal Cell Reports.  The research contributes to a clearer understanding of the process by which the APP is cut.

We discussed before the endoplasmic reticulum which is an organelle (kind of like an organ within the cell) that processes lipids (another name for fats) and cholesterol.  It also hosts the ribosomes where polypeptide chains are assembled from amino acids and folded into proteins.  It was known that this is where APP is cut, but the cutting process wasn't well understood. 

What the new research brings to the table is a better understanding of how an APP molecule is prepared for cutting.  During the preparation time, it's transported in a fatty sac, called a lipid raft.  The research points to the possibility that preventing the construction of lipid rafts might short-circuit the cutting process, and this might prevent the cutting of APP molecules and therefore prevent the production of beta amyloid.  Gene therapy or a drug that blocks a key protein called the "sigma-1 receptor," will decrease cutting of APP molecules in nerve cells and lower beta amyloid production.  As noted in the SciTechDaily article, several possibilities revealed by this research are being pursued. 

We'll see where this all goes -- and I hope it goes somewhere helpful.  It may be that stopping the production of beta amyloid (rather than just cleaning it out of the brain) may actually slow or stop progress of the disease better than the treatments that have been proposed and/or applied so far -- like Aduhelm.  Or maybe simply learning more about how the disease unfolds will lead us to a more fundamental Achilles heel in the disease.

Things are looking bleak for Aduhelm

It's now almost five months since Aduhelm was conditionally approved by the FDA.  Considering how many people in the United States are afflicted by the disease, are patients flocking to it?  Hardly.  Insurance companies are balking at paying the very high price (low to mid $50k/yr, depending on various factors, but not including the cost of regular MRIs), some hospitals are balking at providing it, and both the Senate and House are investigating what it means for the future of Medicare solvency.  So very few people are receiving Aduhelm.

But that's no all.  The Sept 9 issue of JAMA (formerly the Journal of the American Medical Association) carried a letter by Dr. Timothy S. Anderson, an assistant professor of medicine at Boston's Beth Israel Medial Center, claiming that the population on which the treatment was tested is substantially different from the population for which it has been approved.  What's that about?

During the small, phase 1 trial of aducanumab, researchers noted that the treatment caused microhemorrhaging of the brain in some patients.  (You will know this if you read Beating the Dementia Monster.)  This was not believed to be a great risk but still increased the risk to the patient.  Therefore, the criteria for accepting participants in the phase 3 trial were designed to exclude people with a higher risk of more serious adverse consequences from microhemorrhages.  These criteria included cardiovascular disease, prior stroke, and use of blood thinners.  This was obviously done for the safety of the trial participants.  But how did this decision affect the trial results?  

Well, guess what.  An estimated 92 per cent of Medicare patients with cognitive decline would have been excluded by these criteria.  But they are not explicitly excluded from the population for whom the treatment has been approved.  This suggests that the treatment may not have been tested on a population representing ninety per cent or more of people who might receive the treatment.

Opposition to the administration of Aduhelm is growing as noted in this story from the Boston Globe.  In fact, one chain of clinics in Washington DC has banned representatives from Biogen from even setting foot on their property!  Clinics everywhere, as a minimum, are significantly restricting the patients to whom they will administer Aduhelm.  

Philip Scheltens at VU University, Amsterdam, expressed concern that many physicians may not be properly equipped to recognize when someone is or is not an appropriate candidate for Aduhelm treatments.  He noted, “With Aduhelm and others to follow later, we have entered a new era in which treating AD patients becomes more of a precision-medicine approach, in the hands of specialists only.”

But interest in the treatment by desperate Alzheimer's patients is high.  Clinics have begun to emerge simply to provide Aduhelm treatments.  While many clinics and hospitals are reluctant to provide infusion services, and it's not clear that insurance companies are covering it, some believe that, over time, the treatment will be better accepted and funded.

More Errata...

In my post of October 24 I said, "Obviously, Actipulse needs to move ahead with a phase 3 trial."  I should have said, "... move ahead with a phase 2 trial."

Another gadget that might control Alzheimer's disease?

We are not done with new ideas about how to slow or stop Alzheimer's disease, and some of these involve electrical devices.  We wrote once before about the possibility that flashing lights might do something helpful.  And so a new idea has come along -- imposing magnetic pulses on the brain.

The underlying idea for most of these devices is that our brain waves get out of whack in Alzheimer's disease.  Since brain waves are important to the regulation of movement and storage of information in the brain, perhaps forcing the brain waves to behave better might slow or stop the disease.

The brain waves in question are called gamma waves, and they have frequencies of 25 to 135 Hz.  On the piano, middle C has a frequency of 262 Hz, and the electricity in your house has a frequency of 60 Hz.  During quiet wakefulness, some scientists have measured brain waves bouncing around between 30 and 40 Hz.  During deep sleep, the frequency drops to 4 Hz or lower -- these are delta waves.  (For a breakdown of gamma, beta, alpha, theta, and delta brain waves and what we know about them, click here.)  Of course, we discussed the importance of the slow delta waves during deep sleep in Beating the Dementia Monster. 

The concept behind the flashing light strategy was to force brain waves back into whack.  So if flashing lights would work, why not magnetic pulses?  New research published in the journal Frontiers in Neurology proposes just that.  But will it work?  Spoiler alert:  Great idea, but maybe not.

The company Actipulse Neuroscience just completed research testing whether their neurostimulator is safe.  They conducted a trial in which the devices were deployed to test participants in Mexico with training on how to use them.  The participants then used the devices at home twice a day for six months.  There were 34 participants, half of whom used a "sham" device as a control.  Sixteen using the real device actually lasted to the end of the trial with one dropping out.  Proper use of the devices was monitored remotely.  Most participants complied with their instruction.

This was a phase 1 trial, and the first purpose of a phase 1 trial is to find out if the treatment is safe using just a few participants.  Thirty-four participants will tell us whether the treatment will cause people to just drop dead, but its not enough to render reliable data regarding the effectiveness of the treatment.  It's not even enough to tell us whether the treatment causes more subtle adverse health effects.  Recall that the phase 1 trial of aducanumab (now sold as Aduhelm) rendered very positive results for effectiveness, but the phase 2 trial results were very disappointing.  (The phase 3 results were considered good enough to get conditional approval from the FDA, but their validity is in question.)

But what did Actipulse Neuroscience find in the phase 1 trial of their neurostimulator device?  It's safe with a few side effects, but it doesn't seem to help restrain Alzheimer's disease.  Here is their press release.

Since the device didn't help with controlling Alzheimer's disease during the trial, is it game over?  Thirty-four test subjects, half of whom had the sham control device, is not enough to statistically establish anything with respect to efficacy, positive or negative.  So, no.

And there are some questions in my mind.  What would happen if you ran the test longer?  Would you get better results?  What would happen if participants used the device for longer periods each day?  They tried the device in the higher regions of the gamma spectrum -- 60-135 Hz.  What would happen if they tried it in other frequency ranges?

Obviously, Actipulse needs to move ahead with a phase 3 trial with more participants.  Judging by their upbeat assessment of the results, that's just what they will do.

How about a new drug concept for treating or preventing Alzheimer's disease?

Recent research published in the journal, Nature Aging, proposes an entirely new approach to preventing and/or treating Alzheimer's disease.  It uses bumetanide, an older diuretic drug, one that's been around since 1972, to change the way the APOE4 gene can influence the development of the disease.  Researchers have found that the drug can improve cognition in mice whose genes have been edited to create a condition similar to Alzheimer's disease in humans.  They also studied health records of populations of older people who had been on the drug over an extended period of time -- they had been on it for its diuretic properties -- and compared them to those who had not been on it.  They found that people who had been on the drug had a much lower incidence of Alzheimer's disease.  Very promising.

So how would this work?  Recall that the role of genes is to describe the design of perhaps 20,000 different proteins in the body.  Messenger RNA (mRNA -- now famous for its role in the new covid vaccines) carries the design information for proteins out of the nucleus to the ribosomes, where the proteins are constructed.  

Proteins from a variety of genes, including the APOE4 gene, can encourage inflammation in the brain and other factors that create an environment in the brain where Alzheimer's disease can begin and flourish.  Proteins produced by the APOE3 gene variant, however, still perform the same function as APOE4 but without promoting Alzheimer's disease.  While many genes are associated with an increased risk for Alzheimer's disease, the APOE4 gene is most strongly correlated with the development of "sporadic" Alzheimer's disease.  That's the common form that appears later in life, generally after age 65.  (You would know this if you read Beating the Dementia Monster.)

While all of the genes you have are contained the the DNA of virtually every cell in your body, not all genes are used to produce all of the proteins in every cell.  Some cells need certain proteins, and other cells need certain other proteins.  Therefore, there must be a process of "gene regulation" to turn genes on and off.  

There are also changes that can be made to the mRNA as it travels to the ribosome that will change what the final protein looks like.  What bumetanide appears to do is change the mRNA to promote the generation of a protein that works more like APOE3 than APOE4.  Hence it should reduce the risk of developing Alzheimer's disease.

So far so good.  We have an hypothesis and some limited evidence supporting it.  What's next?  Dr. Yadong Huang, one of the originators of this hypothesis, is proposing a drug trial to begin next year.  Since the safety profile of bumetanide is already well understood, I would assume they would be able to go straight to a phase 3 trial.

Would I want to take this drug?  It probably wouldn't work for me.  According to 23andMe, I have no APOE4 genes in my genome.  I got my Alzheimer's by a different route.  And bumetanide would probably only help people whose disease began with APOE4.  

   

A new concept for pre-clinical detection of Alzheimer's disease

We wrote in Beating the Dementia Monster about the search for a reliable test that would detect the development of Alzheimer's disease well before the appearance of the first symptoms.  We reported on several promising blood tests, although none of them have yet found FDA approval.

Why should we want a test for Alzheimer's disease?  Most people say they don't want to know that they have it.  They've been told that there's no cure, so why go through the painful process of consciously confronting a monster you can't beat?  This is an understandable attitude.  (Although they should read Beating the Dementia Monster.)

But there are reasons we want to know.  Alzheimer's is a disease with a very long incubation stage.  It's perhaps 15 years before the first symptoms become evident and another five years before the advent of dementia.  But if there will be a more effective treatment and, dare we say it, a cure, it will likely be most effective if applied during that pre-clinical (or "prodromal") 15-year stage.  But that's before anyone knows anything is wrong.  

Also, for testing new drugs and treatments, we want certainty that the test subjects actually have Alzheimer's disease and with as few comorbidities as possible.  So we want them as young as possible to minimize the number of late-appearing comorbidities because these can confound test results.

While current research on a reliable test for Alzheimer's disease has focused on looking for beta amyloid in blood samples and plaques in the retina of the eye, there's a new idea building steam.

Spectral phenotyping using Fourier Transform Infrared spectromicroscopy.  What's that about?

The idea is that, during both Huntington's and Alzheimer's diseases, there are changes in cells throughout the body that can be detected by analyzing the absorption of different frequencies of infrared radiation.  These changes seem to follow a set pattern in both Huntington's disease and Alzheimer's disease.  So (I guess) shine a heat lamp (broad spectrum of infrared radiation) on a skin cell and see which frequencies are absorbed.  

The nerds among us will understand that the absorption will depend on the specific bonds between different atoms and molecules, so that the presence of certain proteins and lipds with characteristic bonds will have their own signatures.  So just apply some artificial intelligence (AI).  Show a bunch of easily accessible skin cells from people known to have Alzheimer's disease to the system, and have its AI compare them to cells from subjects who do not.  Then let the AI figure out how to predict Alzheimer's disease from skin with unknown status.  You don't have to know what elements and molecules are absorbing the radiation, just look for consistent patterns.  The claim by scientists at the Lawrence Berkeley National Laboratory is that this method predicts Alzheimer's disease very reliably. 

On reading their report, I'd say it's very promising, but they're at a relatively early stage of developing their testing method.  They've had good success, but with a small number of test subjects.  Also, most of the research on humans is with Huntington's disease and less with Alzheimer's disease.  Huntington's disease is far more a product of genetics than Alzheimer's disease, and so, in Huntington's disease, you should find a very consistent pattern of proteins in the cells that are a consequence of the Huntington's gene.  Of course, the rare young onset form of Alzheimer's disease is also a product of genetics, and so I would expect their method to work well there.  But I'm having trouble seeing from what I read in their reporting how this is supposed to work with the much more common old onset form of Alzheimer's disease. 

And I can't get past the damage a test will do to the cost/availability of long-term care insurance.  Once a pre-clinical person is known to have Alzheimer's disease, how will that affect the willingness of an insurance company to take them on -- and at what price?  (Of course, our systems of funding healthcare are in flux, so people may not see this as a problem in a few years.)

Errata Redux

No one has ever accused me of being fun, no less a funraiser.  Therefore my reference to myself in my last blog entry as a great funraiser is a typo...  I was, instead, a fundraiser. 

The 2021 Walk to End Alzheimer's is now history -- and I was #3 funraiser!

Today was the Kennewick, WA Walk to End Alzheimer's, and I was awarded recognition as the #3 fundraiser for our area!  Some of you contributed to that, and I thank you.

I was also a planning committee member and event photographer.  I took two camera's, and Amy helped with shooting.  I probably have around 500 pictures I now need to load on the computer and edit.  I brought my drone, but the walk course was relatively near the airport, and I had trouble navigating the process to allow the drone to fly.  I did get approval from the FAA to fly in the park between 1 and 3 p.m. and no higher than 200 feet.  But I couldn't navigate the technology to tell the drone I was approved.  (The drone has interlocks to keep it from flying in restricted air space without approvals.)

As a consequence of all of this, I didn't actually walk the whole course...  But I've been working up to it, I was busy the whole time, and I have a lot yet to do to make the whole event a success for everyone.

Again, I am so grateful for all who contributed.

And BTW, it's not too late.  For another month or so, you can still contribute to my "walk."  Who knows, maybe I can still bump #2?  He or she wasn't very far above me.  If you want to help me rise in the ranks, click here.

Errata

In my last post I said that a drug trial had lowered HDL in order to treat heart disease.  The post should have said they raised HDL.

Angst

The aducanumab debacle (and it is a debacle) continues to inspire soul searching in the research community.  The focus is on whether the ability of a treatment to clean beta amyloid from the brain is valid evidence that the treatment is effective.  In other words, does simply getting rid of amyloid treat the disease?  Moreover, is simply showing that a treatment gets rid of amyloid strong enough evidence to approve the treatment for public use? 

I just read this fascinating article.  It's long and gets kind of deep into the issue, but here's what I got from it.

We have a long history of choosing the wrong therapeutic target when testing a new treatment candidate.  An example offered was treatments to raise HDL ("good cholesterol") as a treatment for heart disease.  We know that people with higher levels of HDL are less prone to heart disease.  So why not use drugs to raise its level in the blood stream?  A couple of candidate drugs went to trial.  How did that work out?  Well, they raised HDL without reducing or preventing anyone's heart disease.  In one case more people on the drug died of heart disease than those on the placebo.  Not a good showing.

The takeaway is that you need to understand the disease mechanisms before you know how to treat it.  And we do not understand Alzheimer's disease well at all.

In Alzheimer's disease we see anther correlation with an uncertain causal relationship.  There's a strong correlation between the presence of beta amyloid plaques and degeneration of the brain.  In Beating the Dementia Monster, we discussed possible pitfalls in assuming a direct causal relationship between the plaques and the disease.  I recalled what one researcher told me.  He said it's as though we correlate the presence of fast food wrappers in the trash with someone's heart disease.  Maybe if we just remove the fast food wrappers from the trash she will get better.  His point was that this may be what we have been doing with aducanumab.  

The authors of the article discussed an idea in this vein that was interesting to me.  In Beating the Dementia Monster, we discussed the origin of beta amyloid from the amyloid precursor protein (APP).  No one knows the purpose of the protein, but it's cut multiple times by some enzymes, notably one called secretase.  Different variants of secretase cut the APP molecule differently.  Ideally, if the APP molecule is cut appropriately (by the right variant), the fragments (peptides) are water soluble.  If they are not, insoluble fragments accumulate on brain cells as those famous plaques. 

I said in the book that the soluble fragments disappear innocuously from the scene, but maybe that's not right.  An idea being proposed is that it's not the presence of the insoluble fragments that are a feature of the disease process, but rather the reduced production of the soluble fragments.  When too many insoluble fragments are being produced not enough soluble ones are produced.  Just getting rid of the insoluble ones won't help. 

But who knows?  These proposals underline how poorly we understand the disease.  More work is needed to increase our understanding.

One More Week

It's one week until our Walk to End Alzheimer's, and I am so very grateful to all of you who have pledged to sponsor me!  I'm just over halfway to my goal, and I'm hoping for a late surge of sponsors.

If you're willing to donate, you may click here.  If you're uncomfortable with monetary transactions over the Internet, note that there's a "Mail-In Donation" form that you can download.  It's near the top of the page.  Also, your donation can be anonymous.

Recall that, behind the governments of the United States and China, the Alzheimer's Association is the biggest sponsor of Alzheimer's research in the world.  And the Walk is their biggest source of funds.  Alzheimer's research is important to me, and this is how I make my contribution to seeing that it continues.

Exciting News on the MIND Diet

We have been waiting for news on the big MIND diet study (the MIND Diet Trial) being pursued by Rush University, the Harvard TC Chan School of Public Health, and Brigham and Women's hospital.  We have written about this study several times, and we discussed it in Beating the Dementia Monster.  We expected it to be the definitive study of the power of diet intervention to affect the course of Alzheimer's disease.  We had hoped to see some results by April of this year, but, probably due to covid-19, we haven't seen anything yet.

In the absence of the Mind Diet Trial results, another large study was published on September 14 in the Journal of Alzheimer's Disease.  While different in design from the Mind Diet Trial, it is a very credible study of 597 people who had died, many with evidence of dementia.  With their consent and cooperation, the study tracked the eating habits of these people over a number of years, tested their cognition, and then evaluated their brains in subsequent autopsies.  The results provide additional support for the MIND diet as one way of limiting the advance of Alzheimer's disease.

The study used data from the Rush Memory and Aging Project which has been ongoing for many years.  Their analysis of study data controlled for age, sex, education, APOE4 status, late-life cognitive activities, and total energy intake.  

The study data was very dependent on self-reporting of dietary habits, and there was concern that dementia could have affected the quality of this data.  Each participant was scored with respect to their adherence to the diet, so that these compliance scores could be compared to their cognitive test scores and other measures.  The concern was that people suffering from advancing dementia might not accurately record what they ate.  The researchers did a credible job of showing this was not a factor.

So what did they find?

According to the published research, "a higher MIND diet score was associated with better global cognitive functioning proximate to death, and neither the strength nor the significance of association changed substantially when AD pathology and other brain pathologies were included in the model ... The MIND diet-cognition relationship remained significant when we restricted our analysis to individuals without mild cognitive impairment at the baseline [when the study began] or in people diagnosed with postmortem diagnosis of AD..."

So one of the things they're saying here is that among people who followed the MIND diet more carefully, cognition did not deteriorate to the extent expected based on the amount of atrophy of the brain found in their autopsies.  Brains atrophied, but those who adhered best to the MIND diet still hung onto an unexpected level of good cognition.  This is consistent with some of the surprises that came from the Nun Study that we discussed in Beating the Dementia Monster.  They're also saying that the MIND diet was helpful to people who already had Alzheimer's disease at the beginning of the study, but it was also helpful to people who developed the disease during the years of the study.

Their final conclusion: "[The] MIND diet is associated with better cognitive functioning independently of common brain pathology, suggesting that the MIND diet may contribute to cognitive resilience in the elderly."

Speaking as one of the elderly, I must say this is really good news, and I anticipate that these results will be supported when we hear from the MIND Diet Trial people.  I have been applying the MIND diet now for several years, and I'm sure that it's contributing to my well-being.  But don't forget the importance of the multi-domain approach!  You still need to get exercise, make sure you sleep well, stay socially active, and control your stress.  These are all important!