The amyloid fraud controversy -- what it is and what it isn't

Since the news broke that some of what we thought we understood about the role of beta amyloid in Alzheimer's disease may have been based on fraudulent work, the scandal has spread widely in the media.  I've read a number of articles about it, and they have often misunderstood the significance of the event.  And so, a couple of points:

-- The amyloid hypothesis is not fundamentally based on the fraudulent research.  Discarding the research does not simply negate subsequent research and clinical trials based on the hypothesis. 

-- Discarding the apparently fraudulent research does create an awkward situation for the amyloid hypothesis.  Failures of clinical trials for treatments such as Aduhelm and BAN2401 will be looked at under an entirely different light. 

-- The research purported to have identified a unique species of beta amyloid, Aβ*56, that might have had a special role in Alzheimer's disease.  But, with or without Aβ*56, amyloid plaques do form in the brains of people with Alzheimer's disease, and they have some role in the disease.  Treatments like Aduhelm and BAN2401 do remove the plaques.

Nevertheless, so much research has been based on the assumption that Aβ*56 exists and plays a role in the development of Alzheimer's disease, researchers now feel much less confident in many of the treatments under development.  Our greatest faith has been placed on the proposition that monoclonal antibodies eating up amyloid plaques will alter the progression of the disease, and this is the basis for these treatments.  So there is anxiety that our most promising treatments have been barking up a wrong tree.

In Beating the Dementia Monster, we cautiously expressed skepticism about the amyloid hypothesis.  The illusion of Aβ*56 may explain why Aduhelm struggled so hard to demonstrate effectiveness.  I'm thinking the members of the FDA's advisory panel who quit when Aduhelm was approved are likely feeling very vindicated right now.

In Beating the Dementia Monster, we cited several other hypotheses that deserve attention from researchers.  An outspoken amyloid skeptic wrote this long but excellent article on the controversy.  In fact, it's the best writing I've seen since this terrible news broke.  One point he makes -- a very important point -- is that interest in the amyloid hypothesis supported by the belief in Aβ*56 has distracted researchers from pursuing other avenues that might have produced better results for those suffering from the disease and their families. 

And, as we did in our last post, he quotes Harvard's Dennis Selkoe in saying, "I hope that people will not become faint-hearted as a result of what really looks like a very egregious example of malfeasance that’s squarely in the Aβ oligomer field. But if current phase 3 clinical trials of three drugs targeting amyloid oligomers all fail, the Aβ hypothesis is very much under duress.” 

Photoshopping our way to an amyloid train wreck.

I love Photoshop.  If I do someone's portrait, and there are abnormal skin conditions (for example, too much red or a transient blemish) it is so easy make the person look so much better.  In a landscape photograph, there may be some power lines that can be removed to make the image much more pleasing.  However, I sometimes get grief from people for "cheating" to make the subject look the way they would in different lighting or a few days later.  Or simply for doing manually what your phone, camera, or computer would have done automatically to the image.

But in the world of photojournalism and creating images as part of a scientific or historic record, altering an image, at least manually, is forbidden.  If you were fortunate enough to be the only person who photographed an unexpected event, the wire service isn't going to be willing to buy the image from you without confidence that you didn't alter it.  Fortunately, image editing software often leaves artifacts in the image that give away the fact that it was altered. 

You may have read that the world of Alzheimer's research has been rocked by the revelation of some apparent fraud in the study of the role of amyloids in the disease.  My sister sent me a link to this article in the journal Science which first broke the story, but it's been all over the news since.  The upshot is that, in 2006, a researcher published research purporting to show the role of a previously unknown species (or "oligomer") of the amyloid peptide, Aβ*56 (pronounced “amyloid beta star 56”).  This prompted more than a decade of new research investigating the role of Aβ*56 in Alzheimer's disease.

One problem.  Everyone uncritically took the word of the original researchers regarding their finding -- even though no one was able to show that Aβ*56 actually existed.  I read some comments by some who tried.  When they couldn't find anything resembling Aβ*56, they either just moved on to something else or they were left puzzled.  It didn't seem to occur to anyone that it could be fraud.

The article in Science tells the story of some who doubted the narrative and looked into it.  The researchers had used a technique called the "Western blot" to separate different species of amyloid for individual study.  To apply this technique, researchers create a scan using staining, immunofluorescence, and radioactivity.  This should provide a fingerprint of the peptide or protein being isolated.

In closely examining the Western blot images used to make the claim for the existence of Aβ*56, the investigators found evidence that the images had been manipulated, perhaps with image editing software.  Suddenly the suspicions of a few were finding validation.  The original research (published in the very prestigious journal Nature) had not been seriously questioned up until now.  We will see how the story unfolds from here, but it doesn't look good for the researchers or for the reputation of the University of Minnesota.

If you read Beating the Dementia Monster, you know that I'm something of an amyloid skeptic.  I suspect that we will eventually find out that beta amyloid plays a role in the development of Alzheimer's disease, but it is not a central role.  (But who am I?)  So the first question that jumped into my mind when I read about this was, "Does this kill the amyloid hypothesis?"  Well, probably not.  If Aβ*56 is a species of beta amyloid, then the hypothesis that it plays a special role in Alzheimer's disease is a "species" of the amyloid hypothesis.  If Aβ*56 can go away without beta amyloid persisting, than so can its hypothesis -- probably.  The Science article contains the following observation:

"[Harvard University’s Dennis] Selkoe adds that the broader amyloid hypothesis remains viable. 'I hope that people will not become faint-hearted as a result of what really looks like a very egregious example of malfeasance that’s squarely in the Aβ oligomer field,' he says. But if current phase 3 clinical trials of three drugs targeting amyloid oligomers all fail, he notes, 'the Aβ hypothesis is very much under duress.'”

So ... stay tuned

What's up with the MIND diet?

It's been, like, forever since we began our vigil for the results of the MIND Diet Trial.  This was a collaboration between Rush University, the Harvard TH Chan School of Public Health, and Brigham and Women's Hospital.  We were promised results by April 2021.  But what have we so far?  Not much.  I'm sure this is a casualty of covid-19, but we're not getting updates from anyone.  ClinicalTrials.gov was updated in March 2022, but I couldn't figure out what was updated.  

You will recall from Beating the Dementia Monster that the MIND diet is a modification of the popular Mediterranean and DASH diets, both of which have been correlated with improved brain health.  (MIND stands for "Mediterranean-DASH Intervention for Neurodegenerative Delay.")  There have been some important and very positive trials of the MIND diet, but the scientific consensus is that the earlier results must be replicated in a randomized trial.  That was going to be the MIND Diet Trial that we're still waiting on.

So, in the absence of single randomized controlled trial (the gold standard), what do we actually have that might still be good evidence of the superiority of the MIND diet for the brain?  My sister sent me this article documenting a review of the existing literature of what we know about the diet's effectiveness.  It's not exactly what we're looking for, but it's still pretty substantial.

The authors searched through 135 studies and found 14 articles that met their criteria for credibility.  All of the studies found the MIND diet was superior to both the Mediterranean and DASH diets when it came to brain health.  The authors specifically concluded, "All of the included studies indicated that adherence to the MIND diet was positively associated with specific domains, but not all, of cognition and global cognitive function ... in older adults. MIND diet was superior to other plant-rich diets including Mediterranean, Dietary Approaches to Stop Hypertension [DASH], Pro-Vegetarian and Baltic Sea diets, for improving cognition. Adherence to the MIND diet may possibly be associated with an improved cognitive function in older adults. MIND diet may be superior to other plant-rich diets for improving cognition." 

What sets the MIND diet apart that might explain its apparent superiority?  The best I can make of it is how the MIND diet stays away from cheese, butter, margarine, and red meat.

Of course, I haven't been waiting for the study results to decide whether to apply this diet or not.  I've been following it since 2016, and so it's just what I do.

How much has it helped me?  I have no way of knowing.  All I do know is that applying the whole Dementia Toolkit has helped me immensely.

More evidence: It's all about lifestyle!

Forty percent of dementias in the United States are preventable.  When I tell people that, they look shocked.  Most people have been told that it's all in your genes, and your genetic makeup is your death sentence.  But readers of this blog know this is just not true.  In Beating the Dementia Monster, we listed the modifiable lifestyle factors that are the biggest drivers of Alzheimer's disease and discussed how you can deal with each.  

About two years ago, we discussed an article in the prestigious journal, The Lancet, which was regarded as the definitive analysis of lifestyle and dementia.  It was the work of a commission set up to evaluate what can be done to prevent dementia.  It found that 40% of dementias were preventable, and 12 risk factors could be modified to prevent dementia.  These are:

- physical inactivity, 
- excess alcohol consumption, 
- obesity, 
- smoking, 
- hypertension, 
- diabetes, 
- depression, 
- traumatic brain injury, 
- hearing loss, 
- few years of education, 
- social isolation, and 
- air pollution.  

The commission determined that hearing loss, education, and smoking are most significant.

The evidence supporting the Lancet Commission's conclusions continue to pour in.  A recent study published in JAMA (formerly Journal of the American Medical Association) came to very similar conclusions.  It was entitled "Variation in Population Attributable Fraction of Dementia Associated With Potentially Modifiable Risk Factors by Race and Ethnicity in the US."  The research team was led by Mark Lee, a PhD candidate at the University of Minnesota.

Lee began with the same risk factors from the Lancet Commission report and then determined what portion of dementia in different cohorts is explained by modifiable risk factors.  Cohorts were Hispanic, non-Hispanic White, non-Hispanic Black, and non-Hispanic Asian.  In all cohorts, high blood pressure, obesity, and lack of exercise were most closely correlated with dementia.  

Also, lifestyle differences between cohorts corresponded to different levels of risk due to modifiable factors.  The study used self-reporting in survey responses to establish the cohorts.  Based on the survey responses, the study attributed the 12 risk factors to 46.7 percent of dementia risk in Hispanic, 45.6 percent in Black, 39.4 in non-Hispanic whites, and 35.8 percent in non-Hispanic Asian populations. 

But there's a problem with these 12 risk factors.  Many of them correlate with each other in ways that suggest they are not unique.  We've said before that there may be commonality between hearing loss and social isolation -- hearing loss may simply be a form of social isolation.  And then physical inactivity, obesity, hypertension, and diabetes are often found together.  Fewer years of education was more characteristic of some cohorts than others.  Do these commonalities indicate that they are all manifestations of something underlying a given set of correlated risk factors?

No matter how you slice and dice it, if you want to do your best to prevent or deal with Alzheimer's disease, making good lifestyle choices is your best bet.   And the dementia toolkit we provide in Beating the Dementia Monster is your best guide on making the best choices.

Whither BAN2401?

In Beating the Dementia Monster, we discussed promising drug trial results for another Alzheimer's disease treatment called BAN2401, or lecanemab.  Like aducanumab, the "mab" at the end signals that it's a monoclonal antibody.  As an antibody, it's supposed to attack amyloid plaques and remove them from the brain.  "Monoclonal" indicates that that millions, or likely billions, of the antibodies have been grown in the laboratory from a single cell.  The process began with amyloid antibodies from mice which were then "humanized" -- the protein sequence was copied from the mouse antibody into an antibody that could be administered to humans.

Lecanemab is thought to be a next generation treatment past aducanumab/Aduhelm and therefore more effective.  In phase 1 trials, memory and cognition appeared to improve if the patient was kept on the treatment long enough.  Both Aduhelm and lecanemab have been shown to remove amyloid plaques from the brain.  But Biogen is still trying to prove that leads to a positive effect on the decline of both memory and cognition with Aduhelm.  The hope is that lecanemab will be more effective than Aduhelm.

So where does lecanemab stand today?  Last year, partners Biogen and Esai received "Breakthrough Therapy" designation for lecanemab which provides for an accelerated approval pathway.  By the end of the year, the FDA granted "fast track" designation.  This is the same controversial path that Aduhelm followed.  The treatment was approved for use by the public under certain limited circumstances, but there were doubts regarding whether that was appropriate.  This occurred when Biogen had trouble showing that, even though the treatment removed plaques, it was not clear that it was slowing the decline of memory and cognition.  But there is great hope that lecanemab will fare better in ongoing trials.

The phase 3 trail is in progress now with results expected this summer.  The news is that the FDA has granted the treatment "priority review" status.  This means that, depending on trial results, they could provide some form of approval by January 2023.  Move over Aduhelm.   

Handwriting and drawing to predict cognitive impairnent?

In Beating the Dementia Monster, I wrote about my deteriorating handwriting.  My signature deteriorated dramatically, and sometimes I could hardly sign my name at all.  I often ripped up checks when my signature was simply unrecognizable.  Like many of the symptoms of my disease, this behavior has waxed and waned over the past seven years.  Sometimes I take the time to just practice signing my name to try getting my handwriting back.

I've written about similar issues with my voice.  In 2019, I participated in research to develop biomarkers for various neurodegenerative diseases based on human voice.  Last I heard, the research was ongoing, but it looked probable that a computer might evaluate someone's voice for clues and identify incipient disease.

So can the same be done with handwriting?  Just based on my personal experience where I can perceive a correlation between a deterioration in my ability to write and the progress of my disease, I would very definitely say yes.  There must be.

Researchers in Japan and the United States have collaborated on research to determine if they can estimate someone's score on the Montreal Cognitive Assessment (MoCA) based on a computer analysis of how they draw.  We discussed the MoCA in Beating the Dementia Monster, noting that it includes some drawing challenges, such as drawing a clock.  A perfect score is 30 points.  A score of less than 26 indicates mild cognitive impairment or worse.  People with Alzheimer's dementia may score an average of 16.  (The more commonly used mini-mental status (or state) exam includes similar challenges and is scored similarly.)

So could the researchers estimate an MoCA score?  Yes, with a respectable level of accuracy.  Their research was published in the journal JMIR Formative Research.  It used cohorts of both impaired and cognitively normal subjects in both the United States and Japan, showing similar results across varying cultures. 

So what did they measure?  Drawing speed, drawing speed variability, pauses between drawings, pen pressure, and both vertical and horizontal pen inclinations.  And what did they find?  With low MoCA scores, there tended to be higher variability in drawing speed, a higher pause duration/drawing duration ratio, and lower variability in the pen’s horizontal inclination.  From these results, they could estimate MoCA scores, apparently with greater accuracy than with the speech analysis techniques.

I know that I'd do horribly with this test.  I wonder how well it would predict my MoCA score knowing how much my memory and cognition have improved since 2015 while my handwriting hasn't.

What's the opposite of BDNF? And can covid generate it?

We've had a lot to say recently about the brain-derived neurotrophic factor -- BDNF.  According to Merriam-Webster, a "factor" is a substance that "functions in or promotes the function of a particular physiological process or bodily system."  Are there other factors that might function in a bodily system in a negative way?  How about one that cancels the good things that BDNF is doing for us?

Enter eosinophil chemotactic protein, or CCL11.  [Ominous music]  

About a year ago we discussed an emerging picture of covid infections disturbing memory function.  We said that, in the brain, a covid infection can prompt a strong inflammatory response characterized by a "cytokine storm."  We said that cytokines are proteins that coordinate the body's immune response and promote inflammation.  Inflammation is a two-edged sword -- it helps with fighting infection (among other things) but also does its own damage.  Inflammation in the brain may be a part of the body's response to infection, but it's also part of the Alzheimer's disease process.  CCL11 is a particular cytokine that emerges when someone undergoes chemotherapy for cancer (think "chemo brain") and also during a covid infection.

According to research recently published in the journal Cell, the CCL11 cytokine is doing the opposite of what the BDNF does -- suppressing the generation of new neurons from stem cells in the hippocampus.  Logically, it's responsible for both chemo-brain and the brain fog that has been reported in covid cases.  (This suggests to me that it could aggravate Alzheimer's disease.)  So we see similar brain fog in chemotherapy patients and people infected with covid.

Here's an easier reading article from Wired magazine.  Note that the research is, again, based on work with mice.  Mice are not people, and results with mice can be misleading.  Nevertheless the research appears to explain covid brain fog.