Alzheimer’s disease is widely depicted as a linear cascade from amyloid-β accumulation to Tau pathology and neurodegeneration. We propose instead that the disease unfolds through discrete molecular, cellular and network phases organized around biological inflection points. At these thresholds, stress-driven loss of homeostasis produces qualitative shifts in cellular behavior that alters disease progression.
These altered states spread across local tissue-domains, accumulate as a mosaic across the brain, and progressively engage vulnerable centres of information processing that control cognitive performance. The induction of amyloid-associated Tau phosphorylation marks a pivotal inflection point, separating amyloid-dominated tissue states from domains in which neuronal Tau stress responses have emerged. This framework helps reconcile the dissociation between pathology and symptoms, clarifies the shared architecture of familial and sporadic disease and reframes Alzheimer’s disease as a disorder shaped by biological thresholds, timing, and progressive erosion of homeostatic resilience.
UKDRI at London University College, London, UK VIB at University of Leuven, , Belgium Neurodegenerative Diseases Department, University College London, London, UK De Strooper, B., Karran, E. Inflection points and transitions in Alzheimer’s disease. Nature (2026). https://doi.org/10.1038/s41586-026-11110-5 DOI: https://doi.org/10.1038/s41586-026-11110-5
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