Rapid amyloid-β clearance and cognitive recovery by modulating BBB transport
nature.com
nature.com
Unkike monoclonal antibodies of dubious effectiveness like elecanemab, donanemab and cie; this work upstream of the plaques. If a compromised BBB is a cause and not a symptom of another underlying cause this has a chance of doing something positive in the clinic. And that is also why this substance is an interesting leads for ALS and parkison.
Can we stop with that? These drugs were shown to slow down cognitive decline in phase 3 RCTs. Of course, the effect is not as strong as we'd like it to be. But "dubious" it isn't.
Aducanumab was approved for medical use in the United States by the Food and Drug Administration (FDA) in June 2021,[8] in a controversial decision that led to the resignation of three advisers to the FDA in the absence of evidence that the medication is effective.[9][10][11] The FDA stated that it represents a first-of-its-kind treatment approved for Alzheimer's disease and that it is the first new treatment approved for Alzheimer's since 2003.[2] Aducanumab's approval is controversial for numerous reasons including ambiguous clinical trial results regarding efficacy, the high cost of the medication and the very high rate of serious adverse events.[12][11] The FDA considers it to be a first-in-class medication.[13]
In November 2020, a panel of outside experts for the FDA concluded that a pivotal study of aducanumab failed to show strong evidence that the medication worked, citing questionable efficacy and multiple red flags found with the data analysis.[14] There were also significant health risks associated with the medication; brain swelling or brain bleeding was found in 41% of patients enrolled in the studies.[15]...
This was a debacle. The entire process (as far as I can see) did no one any good whatsoever - not Alzheimer's patients (first in line), not Biogen, not the FDA. All that talk about how the approval was a "transformational breakthough" (Biogen's PR) is, well, "inoperative" as they used to say in the Nixon administration. In fact, I would argue that the Aduhelm saga has ended up doing a lot of actual damage. It set a precedent, the "Well, they approved this, so why not that?" kind that just sits around causing trouble year after year. Biogen, for example, says that they are now devoting their energies to their second anti-amyloid antibody therapy, lecanemab (Leqembi), but sourpuss that I am, I'm not impressed with that one, either. That's because I think that it is unlikely to actually make a difference to Alzheimer's patients, their families, or their caregivers, while at the same time exposing those patients to risks that are a lot easier to quantify than the drug's possible benefits....
I any case the debate is not on whether the drugs have an impact on the disease (which they do, unequivocally), but on whether the risk/benefit ratio is good enough (on which I'm also not sold, but that's not the question in our discussion).
from https://www.sciencedirect.com/science/article/pii/S227458072...
Our review of the trial publications found high quality evidence of statistically significant group differences, but also recognized that there are mixed views on the clinical relevance of the observed differences and the value of therapy for individual patients. ...
If patients are treated, then confirmation of AD by positron emission tomography or cerebrospinal fluid analysis and monitoring for risk of amyloid-related imaging abnormalities was recommended, as done in the clinical trials, although it would strain Canadian resource capacity.But to me, the fact that these anti amyloid drugs show even modest effect on cognition puts the burden of proof back on the amyloid skeptics, since removing amyloid changes at least somewhat the course of the disease.
New Alzheimer's Treatment Clears Plaques from Brains of Mice Within Hours - https://news.ycombinator.com/item?id=45600581 - Oct 2025 (113 comments)
New nanotherapy clears amyloid-β, reversing symptoms of Alzheimer's in mice - https://news.ycombinator.com/item?id=45528308 - Oct 2025 (137 comments)
Extract suitable for layfolk:
> Current therapeutic approaches have often focused on improving transport efficiency by tuning ligand affinity, particularly in transferrin receptor-targeting strategies, which have demonstrated that mid-affinity interactions can outperform high-affinity binding by avoiding lysosomal routing and promoting transcytosis. While such strategies have opened a new chapter in neuropharmaceutical design, they largely remain transport-centric, concerned with getting molecules into the brain rather than repairing the transport systems themselves. In contrast, the approach presented here seeks to correct the pathological shift in endothelial trafficking, re-establishing a healthy balance between receptor recycling and degradation.
> Experimental evidence confirms that treatment initiates a rapid clearance phase within hours, marked by a substantial reduction in cerebral amyloid load and concurrent elevation of plasma Aβ, consistent with restored vectorial efflux. Pathological imaging reveals depletion of insoluble aggregates across the isocortex, while functional assays demonstrate normalization of transporter stoichiometry and re-coupling of the neurovascular unit. Multiplex immunohistochemistry confirms reactivation of vesicular trafficking from the luminal surface toward the parenchyma, representing a spatial inversion of pathological amyloid dynamics. Most notably, these structural and molecular restorations translate into long-lasting cognitive preservation, with treated animals performing indistinguishably from wild-type controls in complex spatial learning tasks over extended observation periods. The conceptual advance here lies in moving beyond the paradigm of “overcoming the [blood-brain] barrier” toward “repairing the barrier.”
> Looking ahead, the translational journey will require accounting for interspecies differences in receptor glycosylation and membrane composition, as well as vascular pathologies such as cerebral amyloid angiopathy and pericyte loss, which are incompletely recapitulated in murine models. Strategies integrating spatiotemporal mapping of clearance dynamics with human-specific in vitro models, computational simulations under physiological shear stress, and tailored ligand designs informed by patient-specific LRP1 polymorphisms will be essential. The potential extends beyond AD to Parkinson’s, amyotrophic lateral sclerosis, and other disorders where vascular transport failure accelerates neurodegeneration.
We're building BetterBrain around this insight—catching vascular and metabolic risk factors that compromise BBB integrity years before severe pathology. Not replacing breakthrough therapies like this, but complementing them by intervening earlier in the cascade. (www.betterbrain.com/insurance if anyone would like to try - its $0 with most insurance plans)
In other news, we have shown that taking a shingles vaccine will reduce your odds of getting Alzheimer's.
I am extremely dubious that yet another treatment for amyloid-beta that works on mice, will do anything useful in humans.
Just an idle thought, no sources needed or expected, but you'd think that if you actually GOT shingles it'd be the same effect as not getting shingles because you did get the vaccine?
I think they're saying that the only thing the shingles vaccine should cause is the immune response to it, which you should also get from getting shingles, so does getting shingles have the same effect?
Seems like a valid question to me.
Of course real research or sources needed, but just some idle curiosity to update my mental map of what's going on.
The way that the vaccine preserves us is by reducing the odds of there being a shingles infection in the first place.
That said, this is only my guess. We do not actually know the mechanism by which the vaccine helps. Nor do I have any evidence or data supporting my guess.