The Central Role of Neuronal Cell Death in Alzheimer's Disease Pathobiology.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder in which amyloid β accumulation, tau pathology, chronic neuroinflammation, and metabolic stress converge to drive synaptic dysfunction and neuronal loss. Rather than resulting from a single mechanism, increasing evidence indicates that neurodegeneration in AD is mediated by the coordinated activation of multiple regulated cell death pathways. These pathways include apoptosis, necroptosis, pyroptosis, ferroptosis, and autophagy-dependent cell death, each characterized by distinct molecular mediators and execution programs. Evidence from human brain tissues, animal models, and in vitro systems demonstrates that core pathological drivers such as amyloid β and tau pathology, oxidative stress, and sustained neuroinflammation engage these death pathways in a spatially, temporally, and cell-type-dependent manner across neurons and glial populations. In this review, we synthesize the current knowledge on regulated cell death mechanisms in AD, emphasizing their molecular signatures, cellular specificity, and stage-dependent involvement, together with recent advances in immunohistochemical, imaging, and biofluid-based approaches for detecting neuronal death. By integrating evidence across molecular, cellular, and system levels, this review positions regulated cell death as a unifying framework for understanding neurodegeneration and developing pathway-specific biomarkers and combinatorial neuroprotective strategies.