Notes on the Alzheimer’s Disease Amyloid Beta Scandal from a Neuroscientist/CEO

Is this scandal good for the Alzheimer’s field?

Summary:

A scientist falsified research and this helped push Alzheimer’s Disease research in the wrong direction. The exposure is good for the field because it will open it up to more diverse research and treatment options.


Do I know what I’m talking about?

I am a Ph.D. neuroscientist (see Google Scholar) and neurotechnology CEO.


What happened?

Science Magazine and researchers figured out that some important research in the Alzheimer’s field was fabricated. A reigning theory of Alzheimer Disease is now facing serious questions.


What is the theory that is taking a hit?

From a very high-level, the theory states that toxic proteins clump together (beta-amyloid/toxic oligomers”) and damage the brain in Alzheimer’s patients.

No one is disputing the fact that there are beta-amyloid clumps but their importance and potential as a therapeutic target is under scrutiny.


Insider Context:

In the Alzheimer’s Disease field, the “amyloid/toxic oligomer” theory has been dominant. For those outside of this perspective, there has been quiet resentment against the “amyloid mafia”* that has dominated funding in the field.

To get an idea of how dominant this perspective has been → the NIH spent about $1.6 billion on projects that mention amyloids this year, about half its overall Alzheimer’s funding.

Looking back over the past few decades of Pharmaceutical clinical trials, $40+ billion has been spent on Alzheimer’s trials which revolve around the “amyloid/toxic oligomer” theory.


How can I learn more about this scandal?

Find the Primary Article here and a great summary here.

But also check out this summary by the Alzheimer's forum. You can see a fascinating discussion being played out in the comments section with respected scientists contributing.


What do the commenters say?

The commenters’ central theme is that “ toxic oligomer research” would have progressed the same whether or not these papers were fabricated and in general the “toxic oligomer” research should continue as is.


My take

I agree that there is a huge body of brilliant “amyloid/toxic oligomer” research.

I disagree that the field would have progressed the same way without these falsified papers.


Why?

“Amyloid/Toxic oligomer” took a dominant role with the support of these discredited papers. It ate up funding that could have gone into alternative perspectives.

Without these high-profile discredited papers, other perspectives may have gained more traction earlier.

The Science Article articulates this nicely: “Scientists who advance other potential Alzheimer’s causes, such as immune dysfunction or inflammation, complain they have been sidelined…”.

Derek Lowe over at Science has a great line regarding this: “We have to put money and effort down on other hypotheses and stop hammering, hammering, hammering on beta-amyloid so much. It isn’t working.”


Why am I hopeful?

This scandal will open up more room for new voices in the field. With new perspectives, we can develop novel treatments.


Why is a different perspective needed?

Every single Alzheimer’s drug trial has been a disappointment.

The failure rate is over 99% for new drugs. Even the drugs that get approved are not inspiring confidence (see the drama involving aducanumab).


There is a core conceptual problem with all “Alzheimer’s Disease” research

Alzheimer’s disease is at best an umbrella diagnosis.

We call a lot of different dementias “Alzheimer’s Disease” for outdated historical reasons. It's clinically convenient but it is not biologically helpful. In reality, Alzheimer’s Disease has many different biological root causes for any given patient.

In order to treat patients, we need to develop therapies that target their biological root causes.

Therefore, diverse perspectives are needed to develop a variety of treatment options to help patients.


What will the “Alzheimer’s Disease” field look like in 10 years?

Alzheimer’s Disease will shift towards the Cancer model of increased personalization linked with targeted treatment. The blunt current assessments and treatments will be replaced.

In the future, patients will have imaging, automated cognitive assessments, and blood screening fused into a single exam to reveal the root biological cause driving their individual symptoms.

At my company, BrainKey, we are building the platform that fuses these technologies into a single exam in order to uncover the root biological drivers for each patient. We believe that this multimodal fusion approach enhances the value of any single exam in isolation. The fusion approach will be the standard neurological assessment of the future and it will help with the development of novel therapeutics.

We set up BrainKey to help physicians understand their patient’s brain health. But we’ve already been able to use the platform to gain additional insights into the biological root causes of Alzeimer’s disease. These insights have further convinced me that the “Amyloid/Toxic oligomer” theory needs to make space for a diverse biological perspective.


Conclusion

As a field, we need to move beyond the “Amyloid/Toxic oligomer” theory of Alzheimer’s Disease. We need a diverse biological perspective. This means opening up the field to competing theories and expanding the types of biological data we examine. Only by doing this will we be able to develop and deliver therapeutics which target the biological root causes of a patient's symptoms.




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Owen Phillips, PhD, CEO of BrainKey










Comment:

I believe that everyone involved in Alzeimer’s disease research really wants to help patients. I sympathize with the pressure involved. If you feel anger towards any researcher, please note that most researchers are just barely getting by on tiny salaries that are not guaranteed to be there next year. Check out this article in Science about the situation in general for academics.

The “Amyloid/Toxic oligomer” theory was a strong one, with real justification for pursuing it. It should still be investigated. However, it gained too much traction at the expense of other theories. As a field, I hope we can rally and collaborative open science will come out of this scandal.




Notes

Below are some notes, links and extended (less organized) discussion.

There is a lot here and could fill a number of good conversations late into the evening so even with all this, it’s just scratching the surface.




Extended Discussion

The “Amyloid/Toxic oligomer” theory has attracted so much attention and money because it has made Alzheimer’s Disease look like it’s possible to cure with a “magic bullet”. This is wishful lottery thinking. Over the past two decades, over $40 billion has been spent on clinical trials for Alzheimer’s alone but the failure rate is over 99%(1).

Just like cancer, Alzheimer’s Disease and by extension dementia, is not a single disease. There are in excess of 100+ types of dementia recognized and I would argue that we will identify many more in the next five years as we move away from outdated techniques built around visually assessing a patient in person to a biologically driven quantitative one.

There won’t be a single winner-take-all drug in Alzheimer’s Disease. Just like with cancer there will be a broad range developed.

I often tell people that the Alzheimer’s field is 10 years behind where Cancer is as a field. To understand what I mean, see how tailored the approach is for Breast Cancer and the varied treatment options and compare that to Alzheimer’s Disease.


Some Market Sizing Notes:

  • Dementia is in the same zone as cancer in terms of # of people affected: 40% of people get cancer in their lifetimes, 1 in 3 aged 65+ will get some form of dementia
  • The % of the population affected is growing: % of US population +65 to grow from 17% (2020) to 22% (2050)
  • With an average life expectancy of 8-10 years post-diagnosis for Alzheimer’s patients, the pain point is substantial and arguably bigger than for a cancer diagnosis
  • The economic pain point is huge and growing rapidly: dementia-related spending in US is $322 billion for 2022, expected to be $1 trillion by 2050 (see The Lancet)



Personal Story

I’ve learned firsthand that the identification and treatment options for “Alzheimer’s patients” is incredibly frustrating. My mom has had the “Alzheimer’s Disease” diagnosis thrown at her with very little offered to help her. But, we (my company - BrainKey ) were able to dig deeper into the biology driving her symptoms and identified that she had a treatable type of dementia.

My mom’s story demonstrates how important it is to go deeper and understand the individual patient’s biology so that you can design and deliver the best possible treatment for the patient.





Extended Notes:


Regarding the “Amyloid Mafia”

The Alzheimer Conundrum: Entanglements of Dementia and Aging Margaret Lock

Good new summary on the scandal and what it means

Lancet on aducanumab

*See this Nature Article from 2018

*No disrespect to Dr. Alois Alzheimer → https://de.wikipedia.org/wiki/Alois_Alzheimer / https://www.tuepedia.de/wiki/Alois_Alzheimer


Regarding a quantified assessment of a patient

You need to know the patient’s symptoms (cognitive exam), you need to know what is driving the immediate symptoms (imaging + blood biomarkers*) and you need to know the environment that led to those symptoms (genes, gene expression/methylation).

*Often the thought is that there are no blood biomarkers for Alzheimer’s Disease - but this appears wrong (see https://www.nia.nih.gov/news/blood-test-can-predict-presence-beta-amyloid-brain-new-study-finds).

Further, if you are thinking about the problem from outside the amyloid/toxic oligomers theory a whole world of powerful indicators of neurological status open up.


Imaging

Brain MRI imaging offers the most biological information about a patient’s brain currently possible. Advances are making imaging acquisition better, faster and cheaper and companies are building fantastic AI tools to extract more information from these images.


Some great companies

Big players such as Siemens/GE

New ones such as https://hyperfine.io/

Imaging Analysis

BrainKey (obviously) https://www.brainkey.ai/

Coretech AI https://www.cortechs.ai/


Possible Emerging Technologies:

Eye exam as a cheaper alternative to brain imaging

Kernel made some cool hardware: https://www.kernel.com/

EEG (personally I don’t like it, but I’m open to being wrong!)

Classic Imaging such as CT (convenient but uses radiation and the images aren’t as good as MRI)


Blood

Risk Genes (single genes such as APOE4 but also polygenetic assessments (there are already over 365 genes identified that are associated with various dementias - BrainKey has started offering a polygenic score based on an imaging phenotype)

Abnormal Gene expression

Blood biomarkers such as amyloid-beta (yes, it’s still important) and newer markers such as neurofilament light chain and a host of inflammatory markers


Automated Cognitive Assessment

See companies such as https://modality.ai/ and https://altoida.com/


Video for Movement:

CSF BioMarker: Lumipulse just got FDA approval for an amyloid marker but it has the downside of requiring a CSF lumbar puncture. These are not fun and I don’t see these as routine in 10 years unless it is a particularly challenging case. https://www.fda.gov/news-events/press-announcements/fda-permits-marketing-new-test-improve-diagnosis-alzheimers-disease.

https://www.science.org/content/article/potential-fabrication-research-images-threatens-key-theory-alzheimers-disease






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