Crosstalk and Convergence in Alzheimer's Disease: Integrating Brain Injury, Neuroinflammation, and Precision Medicine for Next-Generation Therapeutics.

Alzheimer's Disease (AD) is a complex disorder whose underlying biology is not fully explained by traditional single-pathway models. For several decades, research has largely focused on the roles of amyloid-β and tau in the formation and deposition of plaques and neurofibrillary tangles associated with AD pathology and neurodegeneration. Despite this sustained focus, therapeutic strategies targeting amyloid-β and tau alone have shown limited success in altering the natural course of the disease. Accordingly, there is a clear need for an adaptive and integrative framework that better captures the heterogeneity and dynamic nature of disease progression over time. This review proposes conceptualizing Alzheimer's disease as a neural circuit disorder that emerges from sustained crosstalk among multiple interacting pathways, including brain injury, neuroinflammation, mitochondrial and metabolic dysfunction, neurovascular dysfunction (impaired supply chain), synaptic dysfunction, and individual vulnerability. Evidence is presented to illustrate (1) how the traumatic and chronic nature of brain injury predisposes the brain to persistent inflammation and neurodegeneration; (2) how astrocytic and microglial activation states contribute to synaptic dysfunction and neuronal damage; and (3) how pathological interactions among amyloid pathology, tau dysregulation, and immune signaling collectively exacerbate neuroinflammatory responses and accelerate disease progression in AD.