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Neuronal loss is a central pathological hallmark of AD, yet classical proteinopathy frameworks centered on amyloid-\u03b2 (A\u03b2) deposition and tau hyperphosphorylation do not fully explain the extent and dynamics of neurodegeneration. Convergent upstream pressures\u2014including A\u03b2\/tau-associated proteotoxicity, mitochondrial dysfunction and oxidative stress, glucose hypometabolism\/brain insulin resistance, and chronic neuroinflammation\u2014lower 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\u2014oxidative stress, mitochondrial failure, inflammasome\/cytokine signaling, and SASP-mediated chronic inflammation\u2014that 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\u2013brain 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.<\/jats:p>","DOI":"10.1177\/13872877261430002","type":"journal-article","created":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T19:09:07Z","timestamp":1773256147000},"page":"32-55","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":5,"title":["Regulated neuronal death in Alzheimer's disease: Crosstalk and convergence of apoptosis, pyroptosis, senescence, and ferroptosis"],"prefix":"10.1177","volume":"111","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-0213-3518","authenticated-orcid":false,"given":"Yang","family":"Zhang","sequence":"first","affiliation":[{"name":"Chengdu University of Traditional Chinese Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongmei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Operating Room, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hua","family":"Xiao","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2026,3,11]]},"reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24076518"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)32205-4"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2023.08.021"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24021059"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24010107"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10495-023-01848-y"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1021\/acschemneuro.3c00343"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23041989"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-023-01484-7"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2024.1400544"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2025.1551273"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1002\/alz.12452"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mito.2023.05.007"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2021.617588"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.metop.2025.100400"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-023-01486-5"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0709259105"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2006.09.106"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/s42003-021-02551-x"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.14336\/AD.2025.0484"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/srep13313"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1007\/s43440-023-00466-4"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurot.2025.e00618"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-024-02722-0"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1186\/s40035-024-00447-4"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2024.109941"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10571-025-01579-5"},{"key":"e_1_3_3_29_2","article-title":"Systematic review of human post-mortem immunohistochemical studies and bioinformatics analyses unveil the complexity of astrocyte reaction in Alzheimer\u2019s disease","volume":"48","author":"Viejo L","year":"2021","unstructured":"Viejo L, Noori A, Merrill E, et al. 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