Bart De Strooper and Edward Karran propose a new framework for understanding Alzheimer’s disease, suggesting it progresses through distinct phases marked by biological ‘inflection points’ rather than a simple linear cascade. These inflection points represent thresholds where loss of homeostasis causes shifts in cellular behavior, altering disease progression.
The researchers argue that the conventional view of Alzheimer’s—amyloid-β accumulation leading to Tau pathology and neurodegeneration—is an oversimplification. Instead, they posit the disease unfolds through discrete molecular, cellular, and network phases organized around these inflection points. These altered states spread across brain tissue, accumulating as a mosaic and impacting areas controlling cognitive function.
A pivotal inflection point, according to De Strooper and Karran, is the induction of amyloid-associated Tau phosphorylation. This marks a separation between tissue dominated by amyloid and areas where neuronal Tau stress responses have begun to emerge. This framework aims to reconcile the disconnect often observed between pathological changes and the appearance of symptoms, and also offers a unified explanation for both familial and sporadic forms of the disease.
The authors state this new understanding reframes Alzheimer’s disease as a disorder shaped by biological thresholds, the timing of these thresholds, and the progressive erosion of the brain’s ability to maintain stability (homeostatic resilience).
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