The Amyloid Precursor Protein as a Universal Survival Molecule: A Critical Perspective on APP-Suppressing Therapies for Alzheimer's Disease

Abstract The amyloid precursor protein (APP) is best known in Alzheimer’s disease (AD) research as the source of the neurotoxic amyloid-β (Aβ) peptide. Consequently, therapeutic strategies now entering clinical trials seek to reduce Aβ production by directly suppressing APP expression itself, most notably through RNA interference (RNAi). However, a growing body of evidence reveals that APP is not a passive substrate for pathology but a deeply conserved, pro-survival molecule deployed by the brain and body in response to every form of catastrophic insult—from synaptic fatigue and traumatic axonal injury to systemic wound healing and bone fracture. This manuscript argues that APP must be understood as a universal “connector” and “mender,” a molecule evolved to detect and bridge any disconnect that threatens the integrity of the nervous system. A linear, toxin-focused view of APP risks catastrophic harm by disarming the brain’s own first responder. We offer an integrative, evolutionary critique of broad-spectrum APP suppression, highlight the early clinical warning signs, and propose that the brain’s own survival logic must be fully accounted for before silencing one of its most ancient guardians. Keywords: Amyloid precursor protein, Alzheimer’s disease, APP suppression, RNA interference, mivelsiran, ALN-APP, neuroprotection, evolution, systems biology, amyloid cascade hypothesis