| To: Ian@SI who wrote (52146) | 8/5/2025 3:14:17 PM | | From: Ian@SI | | | | | to believe that Tau causes Alzheimer’s disease, you have to believe that a few million years of evolution has produced and retained a protein, which is deadly and causes the most undesirable death. Personally I find that very unlikely. Evolution has done a much better job with almost every other protein and probably with every other protein. |
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| To: Ian@SI who wrote (52147) | 8/5/2025 3:40:40 PM | | From: Art Bechhoefer | | | | It's one thing to believe tau causes Alzheimer's and another thing altogether to state that tau tangles are associated with AD. To date, there are no FDA approved drugs to clear tau, though there is at least one drug in phase 2 clinical trials that looks promising. The approved AD drugs, which treat only beta amyloid plaques, have limited success, and then only for early stage AD. I would not assume that a drug to treat tau tangles is unlikely to be successful, especially when at least one drug is already in phase 2.
Art |
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| To: Art Bechhoefer who wrote (52148) | 8/5/2025 4:09:49 PM | | From: Ian@SI | | | | Art, I’ve updated my data as it was a month or two old. I had misunderstood the 98 number of failures.
I suspect that Gemini‘s response below is only covering the data up until 2022. I’m too lazy to look at the detailed references that came with that response. :-). Ian
Based on a comprehensive review of clinical trials for Alzheimer's disease, the figure of 98 failures, specifically for Phase II and III trials targeting amyloid-beta and tau, has been cited in a significant scientific review article published in 2022. This number, which included both Phase II and III trials, reflected the state of research up to that point.
These failures, often resulting from futility analyses, underscore the immense challenge of developing effective treatments for Alzheimer's disease. A futility analysis is a statistical check during a trial to see if it's likely to succeed. If the chance of success is too low, the trial is stopped early.
The key takeaways from these numerous failures are:
* High Failure Rate: The vast majority of trials, particularly those focused on the amyloid-beta and tau hypotheses, have not yielded a successful drug.
* Futility as a Major Cause: A large number of these trials were terminated early based on futility analyses, indicating that the drugs were unlikely to show a meaningful benefit to patients.
* Re-evaluation of the Hypotheses: The consistent failures have led researchers to question the long-standing amyloid and tau hypotheses as the sole drivers of the disease, prompting a shift toward exploring other therapeutic targets and more complex disease mechanisms.
It's important to note that the exact number can fluctuate as new trials begin, fail, or succeed. However, the number 98 represents a key milestone in the history of Alzheimer's research and highlights the monumental challenges that the field has faced. |
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| To: Ian@SI who wrote (52149) | 8/5/2025 4:21:56 PM | | From: Ian@SI | | | | I also asked Gemini how rapid the researchers were migrating to different approaches to identifying a cause and solutions to the Alzheimer’s disease problem. Gemini answer follows.
The shift in Alzheimer's disease research from the dominant amyloid and tau hypotheses to a focus on pathogens is a significant and growing trend. It represents a fundamental re-evaluation of the disease's underlying causes, driven by the consistent failure of amyloid-targeting clinical trials.
Here's a breakdown of the significance of this migration of thought:
1. The Limitations of the Amyloid and Tau Hypotheses:
For decades, the "amyloid cascade hypothesis" has been the prevailing theory. It posits that the accumulation of amyloid-beta (Aß) plaques in the brain is the primary cause of Alzheimer's, leading to the formation of tau tangles, neurodegeneration, and cognitive decline. The vast majority of research and drug development has been based on this model.
However, the repeated failure of numerous clinical trials (including the 98 mentioned previously) to effectively treat or reverse the disease by clearing Aß and tau has cast serious doubt on this hypothesis. While some recent anti-amyloid drugs have shown a modest effect in slowing cognitive decline, they haven't been the "cure" that researchers hoped for. This has led many in the scientific community to believe that Aß and tau are not the root cause, but rather a downstream effect or even a protective response to a more fundamental problem.
2. The Rise of the Pathogen Hypothesis:
The "pathogen hypothesis" is gaining traction and offers a compelling alternative. This theory suggests that Alzheimer's is a response to an infection in the brain caused by various pathogens, including:
* Bacteria: Spirochetes, such as those that cause Lyme disease, and bacteria involved in gum disease (Porphyromonas gingivalis) have been found in the brains of Alzheimer's patients.
* Viruses: Herpes viruses, particularly HSV-1 (which causes cold sores), have been linked to Alzheimer's pathology.
* Fungi and Parasites: There is also a growing body of evidence linking other microbes to the disease.
The pathogen hypothesis re-frames the role of Aß. Instead of being the primary villain, Aß is seen as an antimicrobial peptide—part of the brain's innate immune system that clumps around invading pathogens to neutralize them. The plaques, in this view, are essentially graveyards of dead microbes and the Aß proteins that encased them. Over time, a chronic, low-grade infection leads to a persistent immune response, causing inflammation, and ultimately, the neurodegeneration characteristic of Alzheimer's.
3. The Significance of the Shift:
This change in perspective is significant for several reasons:
* New Therapeutic Avenues: It opens up entirely new avenues for treatment. Instead of just targeting Aß and tau, researchers can now focus on developing antimicrobial and anti-inflammatory drugs. Clinical trials are beginning to test whether antibiotics, antivirals, and other anti-pathogenic therapies can slow or prevent the disease.
* Reframing the Disease: The pathogen hypothesis offers a more comprehensive explanation for the complex pathology of Alzheimer's. It accounts for the presence of Aß and tau, the role of inflammation, and the disease's association with genetic risk factors (like APOE4, which may make individuals more susceptible to microbial infections).
* Increased Funding and Research: The failures of amyloid-targeting trials and the growing body of evidence supporting the pathogen hypothesis have led to an increase in funding and research dedicated to this new area. Organizations like the Infectious Diseases Society of America (IDSA) have established grants specifically for research into the microbial pathogenesis of Alzheimer's.
In conclusion, the migration of researchers away from the exclusive focus on the amyloid and tau hypotheses toward the pathogen hypothesis is a major paradigm shift. It is not an abandonment of the amyloid and tau research, but rather a re-contextualization of their role within a broader, more complex picture of the disease.
This shift offers new hope for more effective treatments by targeting the potential root cause rather than just the symptoms or downstream effects. |
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| To: Art Bechhoefer who wrote (52148) | 8/5/2025 4:41:55 PM | | From: Ian@SI | | | | Here’s a quick response from Gemini to my first question on Tau tangle research.
Attempts to develop drugs targeting tau tangles have been a significant part of Alzheimer's research, especially as the failures of amyloid-targeting drugs became more apparent. However, the path has been similarly challenging.
Attempts that have made it to Phase 2 or Phase 3:
* LMTM (Hydromethylthionine mesylate): This tau aggregation inhibitor developed by TauRx reached Phase 3 trials.
* Gosuranemab (BIIB092): A monoclonal antibody designed to clear tau from the brain, it advanced to Phase 2 trials.
* **Tilavonemab (ABBV-8E12): Another monoclonal antibody targeting tau, which also reached Phase 2 trials.
* Semorinemab (RO7109575): This antibody from Genentech and AC Immune made it to Phase 2.
* Tideglusib: A GSK-3ß inhibitor, which is an enzyme involved in tau phosphorylation, that went into Phase 2 trials.
* ACI-35: A vaccine targeting phosphorylated tau, which has been in Phase 2 trials.
It is difficult to provide a precise, up-to-the-minute number for all tau-specific trials as new studies are constantly being registered, initiated, or terminated. However, based on available data from scientific reviews and clinical trial registries, a number of tau-targeting drugs have reached late-stage development.
Failures between Phase 1 and Phase 3
The number of failed trials is substantial. A significant portion of the tau-targeting drugs that reached Phase 2 or 3 have ultimately failed to demonstrate clinical efficacy.
* Gosuranemab: Was terminated after a Phase 2 trial failed to show a benefit in slowing cognitive decline.
* Semorinemab: A Phase 2 trial for this drug failed to meet its primary efficacy endpoint.
* Tilavonemab: A Phase 2 trial for this drug was also stopped due to futility.
* LMTM: The Phase 3 trials for this drug failed to meet their primary endpoints.
* Tideglusib: Clinical trials were terminated after it failed to show a significant benefit.
These examples represent some of the most notable failures, but they are not exhaustive. Many other tau-related compounds, including various aggregation inhibitors, microtubule stabilizers, and other antibodies, have also been discontinued in earlier phases (Phase 1 or 2) due to a lack of efficacy, safety concerns, or futility. The experience with tau-targeting drugs is mirroring the amyloid story, where many promising candidates in preclinical studies have not translated into successful treatments for patients. |
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| To: Ian@SI who wrote (52151) | 8/5/2025 4:50:26 PM | | From: Ian@SI | | | | …. And one last comment from me With no AI assistant help.
Even if these failed attempts do destroy the brain’s immune system, I suspect that most Alzheimer’s patients And their families would welcome any reduced time and suffering For the patient. Not exactly a cure that the FDA will ever approve it may be something that the Alzheimer’s patient would want if they only had sufficient awareness. |
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