The Six Stage Nutritional Cascade Model: A Mechanistic Framework for Upstream Neurodegeneration

Abstract Neurodegenerative diseases such as motor neuron disease, Parkinson’s disease, and dementia share upstream biological disturbances that emerge long before clinical symptoms. Current models often describe isolated mechanisms—oxidative stress, mitochondrial dysfunction, inflammation—without integrating how these processes interact or evolve over time. This paper proposes a unified Six‑Stage Nutritional Cascade Model that maps the sequential upstream events linking nutritional status to neurobiological decline. The model synthesises evidence across lipid biology, barrier integrity, mitochondrial energetics, neuronal signalling, and microglial activation to outline a coherent mechanistic pathway. The cascade begins with barrier integrity failure, followed by lipid transport disruption, mitochondrial stress, neuronal signalling impairment, microglial over-activation, and finally a degenerative feedback loop that accelerates pathology. This framework highlights how nutritional deficits and metabolic disturbances can modulate each stage, potentially influencing disease onset and progression. The model offers a structured, biologically plausible foundation for hypothesis generation, biomarker development, and upstream intervention research. While theoretical, it provides a clear mechanistic scaffold for future empirical validation and cross‑disease comparison