Abstract / Summary
With the accelerating process of global aging, Alzheimer’s disease (AD) has become an enormous public health burden worldwide. However, its pathogenesis is still not fully understood beyond the classic amyloid-β (Aβ) and tau hypotheses. This review aims to fill this critical knowledge gap by proposing the “Iron-Mitochondria-Oligodendrocyte Axis (IMOA)” as a novel metabolic paradigm for deciphering the complex biological mechanisms underlying AD. Specifically, we explicitly aim to address whether this axis functions as a causal, permissive, or modulatory pathway during the early and progressive stages of the disease. We systematically summarize the reciprocal regulatory interactions within this axis, with a focus on how brain iron dyshomeostasis preferentially impacts mitochondria in oligodendrocytes, which are characterized by high metabolic demand. Notably, the IMOA framework highlights disordered iron metabolism as a potential modulatory factor of neurodegeneration by linking iron imbalance to impaired energy metabolism. Excessive intracellular iron induces mitochondrial dysfunction, insufficient energy supply, and reactive oxygen species (ROS) overproduction, thereby triggering oligodendrocyte ferroptosis and myelin degeneration. These events further aggravate neuronal energy depletion, forming a potentially self-sustaining pathological cascade that may operate synergistically with or upstream of Aβ and tau pathologies. This framework not only bridges the logical disconnect between protein accumulation and neuronal degeneration in the Aβ and tau hypothesis but also provides promising targets for multi-target therapeutic strategies. The IMOA offers valuable insights for improving the temporal and spatial precision of AD diagnosis and intervention. Collectively, targeting the IMOA may represent a transformative strategy for developing precision diagnostics and combination therapies to halt or delay the progression of AD.