Leucadia Therapeutics has a novel approach to treating Alzheimer’s disease.
Having looked into this company, it is interesting that the concept of effective nasal breathing can reduce degenerative neurological conditions. we can all start nasal breathing long before we have any neurological condition which are associate with poor nasal breathing.Alzheimer’s disease (AD) is increasingly recognised as a condition closely linked to the failure of cerebrospinal fluid (CSF) clearance pathways. One of the most significant structures involved in this clearance is the cribriform plate, a perforated region of the ethmoid bone that forms the roof of the nasal cavity and provides an essential outlet for CSF drainage.
The Cribriform Plate as a CSF Drainage Pathway
CSF is responsible for clearing insoluble metabolites and neurotoxic waste products from the interstitial compartments of the brain. While a proportion of CSF flows through the ventricular system and rejoins subarachnoid spaces below the cerebellum, a major fraction percolates through the allocortex—including the hippocampus, parahippocampal gyrus, and basal forebrain. From here, fluid travels anteriorly along the olfactory system, passes through the olfactory bulbs, and drains via the cribriform plate into lymphatic vessels of the nasal mucosa.
This ancient route of CSF egress, often referred to as the olfactory CSF conduit (OCC), predates neocortical expansion by hundreds of millions of years. It is particularly important because it drains regions of the medial temporal lobe and basal forebrain—areas consistently among the first affected by AD pathology.
Ageing and Morphological Changes in the Cribriform Plate
With advancing age, the apertures of the cribriform plate undergo ossification and other structural changes that restrict CSF flow. This reduced permeability diminishes the removal of amyloid-β (Aβ) and other toxic metabolites, leading to their accumulation in upstream brain regions. Post-mortem studies and high-resolution micro-CT imaging have confirmed that patients with AD exhibit markedly reduced aperture cross-sectional area and impaired CSF flux capacity compared with age-matched controls.
Histological investigations reveal a specialised cribriform glymphatic system (CGS), consisting of subarachnoid evaginations that descend into the plate’s apertures and surround olfactory nerves as they pass into the nasal cavity. These structures appear to regulate CSF outflow while protecting the brain against upward migration of pathogens. In AD patients, however, these fine structures are disrupted, supporting the hypothesis that defective clearance across the cribriform plate contributes to early disease processes.
Experimental and Clinical Evidence
Evidence for the central role of cribriform plate pathology in AD is now derived from several complementary approaches:
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Post-mortem studies: Detailed micro-CT analysis of human cribriform plates shows progressive aperture occlusion with age, particularly pronounced in AD patients.
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Animal models: Surgical occlusion of cribriform plate apertures in adult ferrets induces progressive deficits in spatial memory, atrophy of the hippocampus and olfactory bulbs, and behavioural changes reminiscent of early AD.
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Clinical studies: In a cohort of over 500 volunteers aged 20–95, deep learning applied to CT imaging of the cribriform plate correlated patterns of aperture occlusion with cognitive decline and impaired olfactory discrimination. These results suggest that cribriform plate imaging may predict cognitive impairment years before overt clinical symptoms appear.
Multifactorial Influences on CSF Egress
A variety of environmental and genetic factors may accelerate or exacerbate cribriform plate occlusion. These include:
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Head trauma, which can distort the delicate bony architecture of the ethmoid and impair CSF drainage.
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Inflammatory processes, such as those affecting the nasal epithelium (including post-viral anosmia as observed in COVID-19).
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Vascular and metabolic conditions, such as diabetes, obesity, and atherosclerosis, which alter vascular support for CSF clearance.
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Genetic influences, including mutations associated with familial AD and structural predispositions inherited through craniofacial morphology.
Notably, individuals with Down syndrome (trisomy 21) show altered ethmoid bone morphology and early-onset AD pathology, suggesting that cribriform plate anatomy may contribute to their heightened risk.
Clinical Implications
The emerging view is that impairment of CSF egress through the cribriform plate represents an apical event in AD pathogenesis. The failure to clear metabolite-laden CSF from the medial temporal lobe and basal forebrain allows toxic proteins such as amyloid-β to accumulate, seeding the characteristic plaques and tangles of the disease.
This reconceptualises the cribriform plate not as a passive bony partition but as a critical regulator of CSF outflow and brain homeostasis. Interventions aimed at preserving or restoring CSF flux across the plate may therefore provide novel strategies for early diagnosis, prevention, and treatment of AD.
