Preprint of the Paper Summarizing the Leucadia Therapeutics Hypothesis and Evidence on the Cause of Alzheimer's Disease

The Leucadia Therapeutics staff has been working for a few years now to prove the founder's hypothesis on the cause of Alzheimer's disease. In this view, the primary problem is impaired drainage of cerebrospinal fluid. As the drainage path through the cribriform plate is blocked by slow ossification of channels, metabolic waste builds up in the olfactory bulb, the closest region of the brain. This is where Alzheimer's pathology initially starts, before spreading. The team has gathered an imposing amount of human anatomical data, and their eventual goal is to unblock the drainage path via an implant placed in the cribriform plate.

Cerebrospinal fluid (CSF) clears the brain's interstitial spaces, and disruptions in CSF flow or egress impact homeostasis, contributing to various neurological conditions. Here, we recast the human cribriform plate from innocuous bony structure to complex regulator of CSF egress with an apical role in Alzheimer's disease etiology. It includes the pathological evaluation of 70 post-mortem samples using high-resolution contrast-enhanced micro-CT and cutting-edge machine learning, a novel ferret model of neurodegeneration, and a clinical study with 560 volunteers, to provide conclusive evidence of a relationship between cribriform plate aging/pathology and cognitive impairment.

Interstitial spaces within the medial temporal lobe and basal forebrain are cleared by CSF flow that drains through olfactory structures to the olfactory bulb, directly above the cribriform plate. We characterized CSF flow channels from subarachnoid spaces under the olfactory bulb to the nasal mucosa through subarachnoid evaginations that subdivide into tiny tubules that connect to an elaborate conduit system within the cribriform plate. These conduits form an internal watershed that runs from the crista galli's vault to a bony manifold within the olfactory fossa's back wall, connecting with large apertures in between.

We found that the cross-sectional area of apertures limits CSF flux through the cribriform plate, which declines with increasing age. Subjects with a confirmed post-mortem diagnosis of Alzheimer's disease had the smallest CSF flux capacity, which reduces CSF-mediated clearance in upstream areas and leads to the accumulation of toxic macromolecules that seed AD pathology.

We surgically occluded apertures in adult ferrets and found that this manipulation induced progressive deficits in spatiotemporal memory and significant atrophy of the temporal lobe, olfactory bulbs, and lateral olfactory stria. Finally, we explored human cribriform plate aging/pathology and cognition in a clinical study with 560 participants (20-95 years old). We evaluated cribriform plate morphology with CT and Deep Learning, assessed memory with a novel touch screen platform, tested olfactory discrimination, and asked questions about family history and relevant life events, like broken noses. Deep learning algorithms effectively parsed subjects and established the feasibility of predicting Alzheimer's disease years before a clinical presentation of cognitive impairment.



Btw, this is probably the only good news about AD research. I guess they might plan human studies to unblock those passages for operator with early diagnosed stages of AD and see how much it helps

Posted by: Cuberat at October 6th, 2021 7:05 AM


A nice result, but their stock continues to crater down the tubes...

Aubrey dGrey was recently talking about the perverse financial situation most of these "went public too fast" longevity companies find themselves in

And here is Unity with a result BUT.....Small sample size + very competitive space for AMD + dwindling cash....

Posted by: David Petrov at October 6th, 2021 11:00 AM

Just read through the study as best I could :

I was a little disappointed though, because I thought they did cognitive testing on 500+ people and took a picture of the bones behind their noses and tried to see if there was a correlation between cognitive scores and how obfuscated the bones were.... but I didn't see that. Am I missing something? All the tests seemed to show a correlation between cognitive scores and ... age?

I'm frustrated by this...

Posted by: GREGORY S SCHULTE at October 6th, 2021 11:41 AM
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