A Biophysical Framework for Neurodegeneration: Prioritizing Protein Homeostasis Over Aggregate Toxicity

Neurodegenerative research has long hypothesized that aggregated proteins such as amyloid‑β (Aβ), tau, and α‑synuclein (αSyn) are intrinsically toxic and are directly associated with the etiologies of Alzheimer’s disease (AD) and Parkinson’s disease (PD). However, emerging scientific evidence challenges this view. Plasma p‑tau217 shows weak correlation with cognitive severity, αSyn seed amplification assays provide only binary diagnostic support, and anti‑amyloid monoclonal antibodies yield modest short-term benefit while increasing amyloid-related imaging abnormality (ARIA) risk. Postmortem pathology and fluid biomarkers explain only a limited amount of variance in clinical outcomes, undermining their role as surrogate endpoints. We propose a biophysical framework in which aggregation reflects a supersaturation-driven phase transition that signals depletion of soluble, functional monomers rather than the emergence of toxic species. Within this paradigm, amyloid plaques, neurofibrillary tangles, and Lewy bodies represent tombstones of lost protein function, and neurodegeneration occurs when monomer supply falls below neuronal demand. This shift has practical implications for biomarker interpretation, staging, and therapeutic design. Future directions include quantifying monomer flux using stable-isotope labeling kinetics (SILK), integrating supply and demand ratios, and prioritizing mechanism-testing trials that restore protein homeostasis rather than indiscriminately clear aggregates. By reframing pathology as a marker of stress rather than a maker of disease, this approach may enable more effective precision therapeutics based on human biology.