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

Abstract

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.