Posted by New data suggest that the aggregation of misfolded native proteins initiates and drives the pathogenic cascade that leads to Alzheimer’s disease (AD) and other age-related neurodegenerative disorders. We propose a unifying single toxin theory of brain neurodegeneration that identifies new targets and approaches to the development of disease-modifying treatments. An extensive body of genetic evidence suggests soluble aggregates of beta-amyloid (Aβ) as the primary neurotoxin in the pathogenesis of AD. New insights from fluid biomarkers, imaging, and clinical studies provide further evidence for the decisive impact of toxic Aβ species in the initiation and progression of AD. Understanding the distinct roles of soluble and insoluble amyloid aggregates on AD pathogenesis has been the key missing piece of the Alzheimer’s puzzle. Data from clinical trials with anti-amyloid agents and recent advances in the diagnosis of AD demonstrate that the driving insult in biologically defined AD is the neurotoxicity of soluble Aβ aggregates, called oligomers and protofibrils, rather than the relatively inert insoluble mature fibrils and amyloid plaques. Amyloid oligomers appear to be the primary factor causing the synaptic impairment, neuronal stress, spreading of tau pathology, and eventual cell death that lead to the clinical syndrome of AD dementia. All other biochemical effects and neurodegenerative changes in the brain that are observed in AD are a response to or a downstream effect of this initial toxic insult by oligomers. Other neurodegenerative disorders follow a similar pattern of pathogenesis, in which normal brain proteins with important biological functions become trapped in the aging brain due to impaired clearance and then misfold and aggregate into neurotoxic species that exhibit prion-like behavior. These aggregates then spread through the brain and cause disease-specific neurodegeneration. Targeting the inhibition of this initial step in neurodegeneration by blocking the misfolding and aggregation of healthy proteins has the potential to slow or arrest disease progression, and if treatment is administered early in the course of AD and other neurodegenerative disorders, it may delay or prevent the onset of clinical symptoms.
The authors emphasize the importance of early diagnosis and intervention, ideally in the preclinical phase, in which treatment may allow for the maintenance of brain health and normal brain function.
The early phase of the disease was targted in the “6-Month Study to Evaluate the Safety & Potential Efficacy of Trappsol Cyclo in Patients With Early Alzheimer’s Disease (EAD501)” clinical trial by CTD (NCT05607615; leader: Karen Mullen). Intravenous administration over at least 4 hours by IV infusion Trappsol Cyclo either 500 mg/kg or 1000 mg/kg HPBCD every 4 weeks for enrolled patients with evidence of progressive cognitive decline in the last year. The study has not been concluded as yet. The mechanism should be understood.
The combination of the anti-amyloid antibodies (aducanumab ,lecanemab and ndnanemab) with CDs is also an option.
Tolar, M.; Hey, J.A.; Power, A.; Abushakra, S. The Single Toxin Origin of Alzheimer’s Disease and Other Neurodegenerative Disorders Enables Targeted Approach to Treatment and Prevention. Int. J. Mol. Sci. 2024, 25, 2727. https://doi.org/10.3390/ijms25052727