Alzheimer’s disease and cancer as opposing failures of APP signaling network homeostasis: from pleiotropic components to multi-target therapeutics

The inverse epidemiological relationship between Alzheimer’s disease (AD) and cancer has been previously explained by a “Cleavage Pathway Imbalance” in amyloid precursor protein (APP) proteolysis. Here we expand this model into a dynamic, multi-dimensional APP signaling network that integrates extracellular cues, intracellular adaptors, organelle-contact dynamics, and proteolytic events. In AD, the network undergoes catastrophic post-mitotic collapse, driven by endolysosomal dysfunction, impaired autophagy, and downstream mitochondrial failure, resulting in synaptic degeneration. In cancer, the same network is hijacked to sustain proliferative, invasive, and immunoevasive programs. Crucially, network components such as BACE1 and ADAM10 act as neurodegenerative drivers in the brain yet as oncogenic promoters in peripheral tissues. We advocate a shift from reductionist single-pathway inhibition to rational, multi-target strategies that restore system-wide network homeostasis. Embracing this context-aware, network-based framework is essential for developing safer and more effective therapeutics for these two major age-related disorders.