Regulated neuronal death in Alzheimer's disease: Crosstalk and convergence of apoptosis, pyroptosis, senescence, and ferroptosis.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by memory loss and cognitive impairment. Despite its rapidly increasing global prevalence, effective disease-modifying therapies remain limited. Neuronal loss is a central pathological hallmark of AD, yet classical proteinopathy frameworks centered on amyloid-β (Aβ) deposition and tau hyperphosphorylation do not fully explain the extent and dynamics of neurodegeneration. Convergent upstream pressures-including Aβ/tau-associated proteotoxicity, mitochondrial dysfunction and oxidative stress, glucose hypometabolism/brain insulin resistance, and chronic neuroinflammation-lower the threshold for regulated neuronal death programs. Evidence from human postmortem brains and experimental AD models implicates multiple death modalities, including apoptosis, inflammasome-associated pyroptosis, cellular senescence with a senescence-associated secretory phenotype (SASP), and ferroptosis driven by iron-dependent lipid peroxidation. These signatures are often mixed and show region- and stage-dependent patterns, reflecting context- and model-specific drivers rather than mutually exclusive pathways. A crosstalk-and-convergence view highlights shared hubs-oxidative stress, mitochondrial failure, inflammasome/cytokine signaling, and SASP-mediated chronic inflammation-that connect these modalities through feed-forward loops, helping to explain the limited durability of single-pathway interventions. This review summarizes recent advances across these four pathways, discusses their mechanistic interplay, and outlines translational considerations (blood-brain barrier delivery, target specificity, and limited clinical evidence). We also highlight priorities for future work, including single-cell/spatial profiling, multi-omics integration, and biomarker-guided stratification to enable rational combination strategies.