On JLO, RFK, the NIH, TNF, Karl Herrup and innovation - a longer post.
Summary
The amyloid hypothesis did not yield the desired results. Innovation in neurodegenerative will have to come from the left field. The angle of inflammation and myelination is probably the most obvious choice.
INmune Bio and XPro are that left field. To allow the immune system of the CNS to respond appropriately, allowing the glial cells to do their normal job of nurturing neurons, synapses, and axons, one needed to ensure that they could do so. Traditional TNF inhibitors do not allow remyelination and do not do so.
XPro does. The overwhelming preclinical work, as well as the Phase 1 data, leads to that conclusion.
On JLO and The Typ
On the last day of 1999, as I was heading over to my grandparents for lunch while at university, the world was heading into New Year’s eve waiting for the Y2K virus to shut down computers worldwide. Jennifer Lopez’s ‘Waiting for tonight’ was a hit back then. My grandparents are from the quaint university city of Leuven. I am from the north side of Brussels, where we have our own monument called the Atomium, representing an iron atom and innovation, built by André Waterkeyn for the 1958 World Exhibition. The French have their Eiffel Tower. We Belgians like our Atomium at least as much.
Later that same year, my grandfather on father’s side died of old age and Parkinson’s disease. He was a genius. For years during his career, his signature would appear on Belgian state bills. One of those represented that monument that I like so much.
Years later, my grandmother on mother’s side died of old age and Alzheimer’s disease. I’d like to help change the course of at least some of those histories. I have no intention to end up in any of these scenario’s. All this to say I have an interest in writing this, as so many other people in the world do. Hence the existence of The Typ.
JLO apparently hasn’t aged much since 1999. She’s also a sports and healthy nutrition fanatic. Perhaps there’s something there. But we are all genetically different and can’t all follow such a strict regimen.
Is there, perhaps, a ‘botox’ for the brain?
On RFK, Rob Howard, Charles Piller and amyloid groupthink
This week, RFK JR stated something on Alzheimer’s disease that wasn’t so wrong: "20 years ago NIH scientists did a study on amyloid on Alzheimer's in which they said it was caused by amyloid plaque. After that, NIH shut down studies of any other hypothesis. Twenty years later we now know that those studies were fraudulent. NIH has funded 800 studies on a fraudulent hypothesis and we've lost 20 years in figuring out how to a cure for Alzheimer's. And that's just one example. I could give you hundreds. We need to end that."
UCL Prof. Rob Howard reposted it stating: “To my surprise, I’m completely in agreement with Kennedy when he calls for funding for replication studies. The fraudulent NIH Alzheimer’s research definitely impeded the search for treatments. The Field has totally failed to address this and focus on replication makes sense. […] But he’s absolutely correct to point out that the Alzheimer’s field has been rocked by high profile scientific fraud and doesn’t seem to (a) be able to acknowledge this, and (b) have a plan to fix things. […]”
Rob Howard was also an early and outspoken critic of Cassava Sciences. Credit to whom credit is due.
Just last week, Charles Piller opined in the NYT:
“For decades, Alzheimer’s research has been shaped by the dominance of a single theory, the amyloid hypothesis. It holds that amyloid proteins prompt a cascade of biochemical changes in the brain that cause dementia. The supremacy of that hypothesis has exerted enormous pressure toward scientific conformity.
Even many of the most hardened skeptics of the hypothesis believe that amyloids have some association with the disease. But since the early 2000s, doctors, patients and their loved ones have endured decades of therapeutic failures stemming from it, despite billions of dollars spent in grants and investments. Its contradictions — such as the presence of massive amyloid deposits found in the brains of deceased people who had no symptoms of Alzheimer’s — have long exasperated critics and prompted doubts among many supporters.
Still, the hypothesis retains enormous influence. Nearly every drug approved for Alzheimer’s dementia symptoms is based on it, despite producing meager results. The anti-amyloid antibody drugs approved in the United States cost tens of thousands of dollars per patient per year, yet they slow cognitive decline so minutely that many doctors call the benefits imperceptible. The drugs are also not benign, posing risks of death or serious brain injury, and they can shrink the brain faster than Alzheimer’s itself.
The entrenchment of the amyloid hypothesis has fostered a kind of groupthink where grants, corporate riches, career advancement and professional reputations often depend on a central idea largely accepted by institutional authorities on faith. It’s unsurprising, then, that most of the fraudulent or questionable papers uncovered during my reporting have involved aspects of the amyloid hypothesis. It’s easier to publish dubious science that aligns with conventional wisdom.”
In an earlier opinion piece, he had written: “Ultimately, solutions to Alzheimer’s could arrive much faster if the amyloid hypothesis wasn’t reinforced with quasi-religious zeal by many of the field’s most powerful scholars. “There is an entrenched echo chamber that involves a lot of big names,” Dr. Schrag said. “It’s time for the field to move on.”
If this is correct, would it then make sense that the amyloid-related groupthink prevents other more innovative ideas to surface? Is it an investment thesis? Can innovation in Alzheimer’s disease truly come from the left field?
I think INmune Bio’s Phase 1 results already answered those questions, for those who want to look and understand them. But we need a properly powered randomized trial testing cognition to corroborate that for the outside world.
How Not To Study A Disease? (Karl Herrup)
How does the scientific world see the Alzheimer’s research landscape? I believe an answer to that can be found in a book that Alzheimer’s researcher Karl Herrup (academic page) had written in 2021 entitled ‘How Not to Study a Disease: The Story of Alzheimer's’. Comprehensive short interviews on that book can be found here, here (videos) or here (article). In my opinion, they are more insightful than this blog post, so worth a look.
Karl Herrup’s book highlights several key points about Alzheimer’s research, which I will try to summarize below (somewhat rearranged).
Amyloid Plaques in Cognitively Healthy Individuals / Focusing On Amyloid Plaques Makes No Sense
Aloïs Alzheimer’s had identified amyloid plaques and phosphorylated tau tangles in the brain of the first woman with Alzheimer’s ever described in scientific literature.
However, approximately 30% of cognitively healthy older adults also have significant amyloid plaques in their brains. One-quarter to one-third of cognitive healthy individuals have amyloid levels high enough to meet the diagnostic criteria for Alzheimer’s—yet they show no signs of dementia or even mild cognitive impairment.
That fact should raise important questions to which the amyloid hypothesis of dementia has no answer:
How can someone have the biological markers of Alzheimer’s but remain cognitively intact?
These individuals serve as a natural experiment to test the amyloid cascade hypothesis, which posits that amyloid buildup is the primary driver of Alzheimer’s. Could the presence of plaques in healthy individuals suggest that amyloid alone may not be sufficient to cause the disease?
Testing the Amyloid Hypothesis
One possibility is that these plaque-positive individuals are on the verge of developing Alzheimer’s. This seems unlikely given the data. For example, among 72-year-olds, 30% may have significant amyloid deposits, but far fewer develop dementia within a year. Studies tracking individuals with MCI and amyloid plaques show that only about 20% progress to Alzheimer’s within a year, and it takes three to four years for half of them to reach that stage. Even among those with amyloid, the progression to dementia is slow, suggesting that the brain can tolerate amyloid buildup for years without significant cognitive decline.
Individuals without amyloid plaques however do progress to Alzheimer’s much more slowly (which I hope to cover in an upcoming blog post provisionally entitled ‘amyloid is (also) a cytokine)’. Only 7% of plaque-negative individuals with MCI developed dementia within a year, and over half remained dementia-free after six years. While amyloid increases the risk of Alzheimer’s by three to four times, its impact is less dramatic than other risk factors, such as carrying the APOE4 gene. Overall, the data suggest that amyloid plays a role in Alzheimer’s but is not the sole or immediate cause of the disease.
In 2011, an article was published entitled ‘Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association Workgroups on Diagnostic Guidelines for Alzheimer’s Disease’ which again pushed the field in the wrong direction.
About 1 in every 10 people over the age of 65, i.e. 10% of the elderly, have some symptoms of Alzheimer’s disease. The other 90 percent have normal cognition, but about a third of the people in this cognitively normal group have significant levels of plaques in their brain, which does not make sense if they would be categorized as having preclinical Alzheimer’s disease.
Add to this that, for years, there has not been a universally agreed-upon definition of Alzheimer’s disease. Dementia also often overlaps with other conditions. For example, Parkinson’s disease and Huntington’s disease can lead to dementia in their advanced stages. Other recognized forms of dementia include vascular dementia, HIV-related dementia, Lewy body disease, frontotemporal dementia, and progressive supranuclear palsy.
Challenges to the Amyloid Cascade Hypothesis
The slow progression from amyloid buildup to dementia challenges the idea that amyloid triggers a rapid, destructive cascade. If amyloid were the primary driver, the transition to dementia would likely occur more quickly. Instead, the data suggest that other factors may be at play, potentially involving a third element that independently contributes to both amyloid accumulation and dementia.
Mouse Models and Their Limitations
Mouse models of Alzheimer’s were developed during a period of intense focus on the amyloid hypothesis. These models were designed to replicate amyloid buildup in the brain, and early studies showed that removing amyloid plaques could reverse memory deficits in mice. However, these findings may not translate to humans.
In humans, Alzheimer’s involves progressive, irreversible brain damage, with up to 25% of the brain lost by the disease’s end. In contrast, memory deficits in amyloid-laden mice are mild and fully reversible, often resolving within days of treatment. This rapid recovery suggests that the memory problems in mice are not caused by the same degenerative processes seen in human Alzheimer’s. While these models are useful for studying amyloid, they do not accurately replicate the progressive and irreversible nature of the human disease.
Implications for Alzheimer’s Research
The limitations of mouse models highlight the need for caution when interpreting their results. While they provide insights into amyloid’s role, they do not fully capture the complexity of Alzheimer’s in humans. Effective treatments for mouse models may not address the underlying causes of human Alzheimer’s, particularly the irreversible loss of brain function. This underscores the importance of developing more accurate models and exploring alternative hypotheses to better understand and treat the disease.
Medications and Alzheimer’s risk
Research additionally suggests that certain medications may lower the risk of Alzheimer’s disease, which seems completely unrelated to the amyloid hypothesis. Notably, long-term use (two years or more) of nonsteroidal anti-inflammatory drugs (NSAIDs) has been strongly linked to a reduced risk of developing Alzheimer’s. This connection is particularly intriguing because inflammation is now established as a hallmark of Alzheimer’s disease, as well as of other neurodegenerative diseases.
Inflammation and Alzheimer’s Disease
Genetic studies have identified a network of genes associated with inflammation that are also linked to Alzheimer’s. Among the 29 genes tied to sporadic Alzheimer’s, several are involved in immune system processes. This supports the idea that inflammation plays a central role in the disease.
Inflammation is typically a protective response. For instance, when an infection occurs, immune cells gather to eliminate the threat, causing redness, swelling, and warmth—classic signs of inflammation. However, sometimes the immune system overreacts, attacking the body’s own tissues, as seen in conditions like rheumatoid arthritis. Similarly, in Alzheimer’s, the brain exhibits chronic, low-grade inflammation.
Microglia, the brain’s immune cells, appear to malfunction in Alzheimer’s, contributing to this inflammatory response. Other glial cells may be malfunctioning too. For more insight, see my earlier blog post: ‘It’s the (micro)glia, stupid!’
Genetic, microscopic, and epidemiological studies all point to inflammation as a key factor in the disease’s progression. For example, individuals who took high doses of NSAIDs for extended periods were found to have a significantly lower risk of Alzheimer’s, with some studies showing up to a 50% reduction.
The Role of Myelin
Myelin, a fatty substance that insulates nerve fibers, is crucial for efficient brain communication. It enhances the speed and efficiency of electrical signals along axons, much like insulation on a wire.
Interestingly, the brain regions most affected by Alzheimer’s are also those with the most myelin.
Myelin production continues into a person’s 30s, but by the mid-40s, it begins to decline, particularly in areas where it was last added. This loss occurs more rapidly in individuals with Alzheimer’s. Modern imaging techniques allow scientists to track myelin changes over time, revealing a correlation between myelin levels and cognitive performance.
Genetics and Myelin Maintenance
Many genes associated with Alzheimer’s risk are involved in myelin production and maintenance. For example, oligodendrocytes, the cells responsible for creating myelin, must produce vast amounts of membrane to insulate axons effectively.
Exploring Myelin’s Role in Alzheimer’s Disease
Myelin, the insulating layer around nerve fibers, plays a critical role in maintaining healthy brain function. Its deterioration can explain many of the symptoms associated with Alzheimer’s. If we wanted to explore the relationship between myelin and Alzheimer’s to develop new treatments, where should we focus our efforts according to the neighborhood model (shown above)? The model suggests that the loss of myelin would have two major effects. First, the support system for neurons in the affected area would weaken, leading to the breakdown of myelin around axons (represented by graying in the figure). Second, the loss of myelin itself would disrupt brain function. Without proper insulation, the speed of electrical signals along axons would decrease, and the energy required for communication would increase.
A Myelin-Based Approach to Treatment
Notably, the discussion of myelin and its role in Alzheimer’s does not require mentioning amyloid or Aβ peptides. This demonstrates that the neighborhood model offers a plausible, testable pathway for understanding and treating age-related dementia without relying on amyloid-centric theories. The myelin-based approach identifies several potential targets for immediate testing in clinical trials, providing a fresh perspective on Alzheimer’s research.
Glial Inflammation as Another Target
The neighborhood model also highlights microglial inflammation as a promising area of focus. While initial efforts to target inflammation with broad-spectrum anti-inflammatory drugs like naproxen and celecoxib have yielded inconclusive results, the model suggests a more refined approach. Instead of general anti-inflammatories, researchers could explore drugs that specifically block the (micro)glial response. This targeted strategy could offer a more effective way to address the inflammatory processes implicated in Alzheimer’s.
Adding Plaques and Tangles to the Equation
While amyloid plaques and tau tangles are well-known features of Alzheimer’s, researchers have identified up to 40 other proteins within plaques and tangles, many of which are linked to immune system activity. This supports the idea that inflammation is a significant driver of the disease.
Despite the compelling evidence, therapeutic approaches targeting inflammation have received far less attention and funding compared to those focused on the amyloid hypothesis.
"But in fact, the inflammation hypothesis folks never argued that plaques or tangles should be excluded from the story of Alzheimer’s disease. Far from it. In fact, they argued that one very likely trigger for the inflammatory reaction was the plaques and the tangles themselves. This meant that the inflammation-based model was actually a combined model."
NIH funding: Amyloid Research and Funding Priorities
The NIH budget has systematically become bigger over the years. The 2018 numbers show that “Neuroscience” accounted for about 65 percent of the total NIA budget, of which most went to Alzheimer’s disease or dementia research.
While industry-sponsored research has extensively covered amyloid-related studies, one might expect the National Institute on Aging (NIA) to focus on laying a broad foundation for future Alzheimer’s research beyond amyloid. However, this has not been the case. Although the NIA funds valuable aging research, its Alzheimer’s funding has heavily prioritized amyloid and tau studies. This focus has overshadowed other promising approaches, creating an imbalance in research priorities. In essence, the emphasis on amyloid has disproportionately influenced the direction of Alzheimer’s research, which may not be the most effective way to study such a complex human disease.
In conclusion, Karl Herrup suggests adjusting government funding of Alzheimer’s disease research, and adjusting the role of the pharmaceutical industry.
On TNF and Xpro
Existing approved TNF inhibitors have showed an ability to reduce risk of developing Alzheimer’s, but have an abundance of side effects, among others with regards to immunological dysfunction. A major development here has come through the insight into TNF as a master regulator of inflammation.
TNF is a unique cytokine.
INMB informs us that there are two types of TNF, the good TNF (transmembrane TNF) and the bad TNF (soluble TNF). TNF is, in fact, first produced as a transmembrane protein that preferentially activates the TNF receptor 2. Once cleaved, it becomes soluble, and then preferentially activates TNF receptor 1. TNFR2 activation promotes cell survival, neurogenesis and CNS autoimmunity. TNFR1 activity does the opposite; it promotes cell death, aberrant neuroplasticity and exacerbation of the inflammatory response.
To my knowledge, other cytokines do not work in a similar manner. And this may also be why TNF acts as the master regulator of inflammation.
As traditional TNF inhibitors do not distinguish between both, they may drive unwanted effects. For that reason, XPro was developed as a selective TNF inhibitor.
The scientific research underlying XPro is abundant (contrary to that of other AD players in the investment space). In more exact scientific words, taken from one of the more than 80 papers on Xpro:
“Our observation that XPro1595 treatment does not change the MRNA expression pattern of the other key inflammatory cytokines within the hippocampus or peri-lesional region is important given that both IL-1B and IL-6 promote both pro- and anti-inflammatory signaling following trauma. Reducing their expression may prevent their contribution to brain repair mechanisms, while increasing their expression may exacerbate the extent of the injury.”
On Innovation and the Left Field
In light of the above, innovation in Alzheimer’s disease, and probably neurodegenerative diseases as a whole will have to come form the left field.
Who are the academic innovators focusing on glial activation and inflammation, each with their own labs or research organizations: Prof. Beth Stevens, Prof. Malù Tansey, Prof. Shane Liddelow, Lesley Probert, PhD, Prof. Kate L. Lambertsen, Prof. Andrew Miller, Prof. Kirsty Dixon, Howard Fillit, MD, Karl Herrup, PhD, and others.
On The Typ, I try to focus on some of their research.
Conclusion
RFK JR may have been right when he said that too much funding has gone to work that did not amount too much. However, anti-amyloid antibodies did yield some results.
Innovation in neurodegenerative will have to come from the left field. The angle of inflammation and myelination is probably the most obvious choice.
INmune Bio and XPro are that left field. To allow the immune system of the CNS to respond appropriately, allowing the glial cells to do their normal job of nurturing neurons, synapses, and axons, one needed to ensure that they could do so. Traditional TNF inhibitors do not allow remyelination and do not do so.
XPro does. The overwhelming preclinical work, as well as the Phase 1 data, lead to that conclusion.
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