Our newest research-advisor Prof. Randall J. Bateman, MD.
Lecanemab Target
Pat & Dennis Bender Early Dementia Diagnosis & Prognosis Fund
J. Dennis Bender
Office, Home & Cell Phone: 859-391-5226
5726 La Jolla Blvd. – Suite 311
La Jolla, CA 92037-7345
&
Office - 100 Riverside Pl. - Suite 303
Covington, KY 41011-5711
We support the development of improved diagnostic methods for the early detection and diagnosis of MCI, Alzheimer’s, vascular and other dementias, their likely prognosis, and best treatment options. We focus on the development of Bayesian-based medical-decision-support systems, comparative-effectiveness research, and the better utilization of these for the above. (After incorporating in KY as a 501(c)(3) in 2002, we dissolved that entity for a simplified form of two entirely self-financed, private philanthropies utilizing a Vanguard Charitable Trust for making annual-research-grants for early-dementia-detection and its correct differential-diagnosis and likely-prognosis. They will continue on, after I am long gone, either mentally or physically. Prof. Randall Bateman is the first of our fund’s research advisors, KMK Law is our legal advisor. See: https://www.alz.org/alzheimers-dementia/research_progress/earlier-diagnosis )
www.JDBender.com – EMS/eVTOL & Educational Experimental Aviation Fund (Vanguard Charitable Trust)
www.JDBender.org – Dementia Diagnosis Fund (Vanguard Charitable Trust)
“Lecanemab targets a particular-molecular-cascade, the plasma-contact-system, which drives-amyloid-beta-toxicity. . . Protofibrils are the step before amyloid-beta forms fibrils and are considered to be the most-toxic-form, although the mechanism behind why it's so toxic is not understood. . . We looked at lecanemab and found it can block-the-activation-of-the-contact-system. . . The blood–brain-barrier can break-down in Alzheimer's, so things from the blood can move into the brain and deposit there. Fibrin then interacts-with-amyloid-beta, the major-pathogenic-protein-in-AD. . . The plasma of Alzheimer's-patients showed irregular-levels-of-these-enzymes-and-proteins that are part of the intrinsic-clotting-system compared to those of normal-controls. . . amyloid-beta has different-forms. It's normally-soluble, and it's a very-tiny-molecule. "But over time, and in different situations, it can start to aggregate, becoming bigger and bigger. . . HK also ‘bound-tightly’ to amyloid-beta-protofibrils, with ‘weaker’-binding to other amyloid-beta-species, confirming that amyloid-beta-protofibrils bind to HK and FXII.”
This is a very-promising new discovery and exactly why I spend every-day reading the newest medical-research-reports and my many daily Google Keyword alerts, much to the detriment of everything else I should be doing instead.
Fibrin-clots can form through ‘intrinsic-clotting,’ which takes place through the ‘contact-system,’ as I’ve previously reported on. Amyloid-beta can activate the contact-system. Here is an overview of how it might work in AD. The contact system has two "arms," the first of which is involved with clotting, and the second with inflammation, Norris said. In fact, it's the plasma-contact-system that links vascular- and inflammatory-pathways.
The contact-system also causes-inflammation. Bradykinin, a potent inflammatory-molecule, is released by binding to high-molecular-weight kininogen (HK). In addition to inflammation, bradykinin can cause edema and blood-brain-barrier-permeability. Amyloid-beta-protofibrils promoted-the-activation-of-the-contact-system.
The researchers introduced lecanemab into the picture and found it "dramatically-inhibited" the contact-system-activation induced-by-amyloid-beta-protofibrils. Lecanemab also prevented accelerated-intrinsic-coagulation in normal-human-plasma mediated-by-amyloid-beta-protofibril.
The hypothesized-mechanisms for why amyloid (lecanemab's-target) is toxic to the brain does incorporate important AD-related-brain-changes that have been observed in other studies, including inflammatory/immune-changes and vascular-related-changes, as I previously reported.
(Read on McDuff: See my earlier Beta Amyloid Protofibrils in AD for all the gory details.)
How Does Lecanemab Work in Alzheimer's?
Batya Swift Yasgur, MA, LSW - September 15, 2023
Lecanemab (Lequembi, Esai), an amyloid-beta-directed-antibody-therapy, is approved by the US Food and Drug Administration (FDA) for the treatment of Alzheimer's-disease (AD). But exactly how the drug clears amyloid-beta wasn't clear.
Now new research suggests the drug, which was approved by the FDA in January, targets a particular-molecular-cascade, the plasma-contact-system, which drives-amyloid-beta-toxicity.
Investigators tested the effectiveness of various forms of amyloid-beta in activating the plasma-contact-system and found that amyloid-beta-protofibrils, known to be the most-toxic-form-of-amyloid-beta, promoted the activation of this molecular-cascade and that lecanemab-inhibited-pathway-activation.
"In our study, we looked at lecanemab and found it can block-the-activation-of-the-contact-system, which could be one of the reasons that it works so well for AD," study Co-Investigator Erin Norris, PhD, Research Associate Professor, Rockefeller University, New York City, told Medscape Medical News.
The study was published online August 28 in the Proceedings of the National Academy of Science.
Unknown Mechanism "Many years ago, we started looking at the involvement of vascular dysfunction in AD," Norris said. "We wanted to see whether or not irregular-blood-clotting or problems-with-blood-flow was problematic in Alzheimer's-patients."
The researchers found that fibrin, a major component involved in blood-clotting, can extravasate into the brain.
Norris explained that fibrin-clots can form-in-two-different-ways. One is through the normal-process that occurs when there's an injury-and-bleeding. The second is through intrinsic-clotting, which takes place through the contact-system.
"We started looking into this system and found that the plasma of Alzheimer's-patients showed irregular-levels-of-these-enzymes-and-proteins that are part of the intrinsic-clotting-system compared to those of normal-controls," said Norris.
"This paper was an extension of years studying this pathway and these mechanisms. It was also inspired by the approval-of-lecanemab and its release-for-use-in-Alzheimer's-patients," she added.
In previous research, the same researchers found that amyloid-beta has different-forms. "It's normally-soluble, and it's a very-tiny-molecule," Norris said. "But over time, and in different situations, it can start to aggregate, becoming bigger and bigger."
Implications Beyond Alzheimer's Postmortem-tissue-analysis has found fibrillar-plaques that are "clumped-together." These are insoluble and hard-to-get-rid-of, she said. "Protofibrils are the step before amyloid-beta-form- fibrils and are considered to be the most-toxic-form, although the mechanism behind why it's so toxic is not understood," she added.
Previous research has already shown that amyloid-beta can activate the contact system. The contact system has two "arms," the first of which is involved with clotting, and the second with inflammation, Norris said. In fact, it's the plasma contact system that links vascular and inflammatory pathways.
The plasma-contact-system leads to the clotting-of-fibrin, Norris continued. It activates-factor-XII (FXII), which leads to blood-clotting by binding-to-coagulation-factor-XI (FXI).
Although it's been known that amyloid-beta can activate the contact-system, the particular form of amyloid-beta implicated in this cascade has not been identified. And so, the researchers incubated-amyloid-beta42 with human-plasma, testing various types of amyloid-beta — monomers, oligomers, protofibrils, and fibrils — to see which would activate-the-contact-system.
Amyloid-beta-protofibrils promoted-the-activation-of-the-contact-system, as evidenced by several reactions, including activation-of-FXII, while other forms of amyloid-beta did not. HK also "bound-tightly" to amyloid-beta-protofibrils, with "weaker"-binding to other amyloid-beta-species, the authors report, confirming that amyloid-beta protofibrils bind to HK and FXII.
Bradykinin-levels were increased-by-amyloid-beta-protofibrils, which also induced-faster-clotting compared with other-forms-of-amyloid-beta.
The researchers introduced lecanemab into the picture and found it "dramatically-inhibited" the contact-system-activation induced-by-amyloid-beta-protofibrils. For example, it blocked-the-binding-of-FXII-to-amyloid-beta. By contrast, human-IgG (which the researchers used as a control) had no-effect.
Additionally, lecanemab also prevented accelerated intrinsic coagulation in normal human plasma mediated by amyloid-beta-protofibril.
Senior Author Sidney Strickland, PhD, the Zachary and Elizabeth M. Fisher Professor in Alzheimer's and Neurodegenerative Disease, Rockefeller University, told Medscape Medical News: "One of the strong-motivators for conducting this study was the fact that this drug, which is effective-in-AD, targets this specific-form of amyloid-beta; but no one knows why it's more-toxic. We thought we could see if we could tie it to what we're working-on, and we found it ties in beautifully."
The findings have implications that go beyond AD, Strickland said. "The contact-system is implicated in lots of different pathologies, including sickle-cell-anemia, sepsis, inflammatory-bowel-disease, and so on." Blocking the contact system might be a helpful approach in these conditions too.”
Innovative, Plausible, but Still Preliminary Commenting for Medscape Medical News, Heather M. Snyder, Phd, Vice-President of Medical and Scientific Relations at the Alzheimer's Association, called the investigation "innovative," with ideas that are "certainly-plausible." However, "at this time, the work is preliminary and not conclusive."
The hypothesized-mechanisms for why amyloid (lecanemab's-target) is toxic to the brain "does incorporate important AD-related-brain-changes that have been observed in other studies, including inflammatory/immune-changes and vascular-related-changes," said Snyder, who was not involved with the current study.
However, "additional studies that look both in model systems and in humans are needed to further illuminate these relationships," Snyder said.
The study was supported by grants from the National Institutes of Health as well as the Robertson Therapeutic Development Fund, Samuel Newhouse Foundation, John A. Herrmann, and the May and Samuel Rudin Family Foundation. Norris, Strickland, and Snyder have declared no relevant financial relationships.
PNAS. Published online August 28, 2023. Full text - Batya Swift Yasgur MA, LSW, is a freelance writer with a counseling practice in Teaneck, NJ. She is a regular contributor to numerous medical publications, including Medscape and WebMD, and is the author of several consumer-oriented health books as well as Behind the Burqa: Our Lives in Afghanistan and How We Escaped to Freedom (the memoir of two brave Afghan sisters who told her their story).
My Old Keywords & Key-Phrase Search Routine: [Hyphenated-phrases(-), bold & italics were used in my old customized-inverted-file-search-routine, but are now totally-obsoleted by ChatGPT, Google search, PubMed online, etc. Over 9,000+ of my old research-documents were all annotated in this way for use with that previous, customized-keyword/phrase, search-routine that I created for searching my own personal-document files. It was designed to avoid having to use just the then, very-common, single-keyword search routines. For example, such as just searching on “watching” and “TV” separately, it focused on compound-keywords or entire-phrases, such as: “watching-TV” or “sedentary-watching-TV,” which is very-different from just individually searching for the single keywords “watching” and “TV” together. Most of the then existing-search-routines and many still do today don’t allowing for using standard Boolean-logic nomenclature in searches, such as “watching” AND “TV, rather than “watching” OR “TV.” I implemented my own custom-coded alternative to those old single-OR-based-keyword-search-routines, but now we have a much-better alternative based on AI and related technologies, so it is no longer necessary, just an old-habit now to try to break.]
[Keywords and compound-keywords (tags) are highlighted-and-hyphenated in italic-and-bold; place-names, organizations and titles are in bold; media-names put in italic. Instead of underlining, I’ve been hyphenating entire phrases – called long-tail-keywords. This odd style was being tried to enhance ease-of-spotting items-of-interest in my specific website-achieved documents. Now generative-AI and similar have eliminate this time-consuming distraction.]
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