Alzheimer's disease (AD) is a neurodegenerative disease characterized by the deposition of amyloid-β protein forming senile plaques, excessive phosphorylation of tau protein forming neurofibrillary tangles, and progressive loss of neurons. The increasing number of patients places a substantial burden on both patients and society. Abnormal activation of programmed cell death (PCD) is the core pathological mechanism of neuronal loss in AD, and as an important regulators of gene expression, long noncoding RNAs (lncRNAs) can regulate various forms of PCD, including apoptosis, autophagy, pyroptosis, ferroptosis, and necroptosis, through multiple molecular mechanisms, playing an important role in the occurrence and development of AD. This paper systematically reviews the pathological mechanisms of different types of PCD in AD. It summarizes the molecular mechanisms by which lncRNAs intervene in PCD through the competing endogenous RNA (ceRNA) network in AD, aiming to provide novel insights into therapeutic targets for AD.

1. KamathamPT, ShuklaR, KhatriDK, et al. Pathogenesis, diagnostics, and therapeutics for Alzheimer's disease: breaking the memory barrier[J]. Ageing Res Rev, 2024, 101: 102481. doi：10.1016/j.arr.2024.102481

2. ZhengQ, WangX. Alzheimer's disease: insights into pathology, molecular mechanisms, and therapy[J]. Protein Cell, 2025, 16(2): 83-120. doi：10.1093/procel/pwae026

3. PszczołowskaM, WalczakK, MiśkówW, et al. Mitochondrial disorders leading to Alzheimer's disease—perspectives of diagnosis and treatment[J]. Geroscience, 2024, 46(3): 2977-2988. doi：10.1007/s11357-024-01118-y

4. WangM, YuF, ZhangY, et al. Programmed cell death in tumor immunity: mechanistic insights and clinical implications[J]. Front Immunol, 2024, 14: 1309635. doi：10.3389/fimmu.2023.1309635

5. MoujalledD, StrasserA, LiddellJR. Molecular mechanisms of cell death in neurological diseases[J]. Cell Death Differ, 2021, 28(7): 2029-2044. doi：10.1038/s41418-021-00814-y

6. CanoyRJ, SyJC, DeguitCD, et al. Non-coding RNAs involved in the molecular pathology of Alzheimer's disease: a systematic review[J]. Front Neurosci, 2024, 18: 1421675. doi：10.3389/fnins.2024.1421675

7. XiongZ, SunC, HuangS. LncRNA-driven programmed cell death networks: new therapeutic targets for neurological disorders[J]. Front Mol Neurosci, 2025, 18: 1635119. doi：10.3389/fnmol.2025.1635119

8. ParkW, WeiS, KimBS, et al. Diversity and complexity of cell death: a historical review[J]. Exp Mol Med, 2023, 55(8): 1573-1594. doi：10.1038/s12276-023-01078-x

9. TianX, SrinivasanPR, TajikniaV, et al. Targeting apoptotic pathways for cancer therapy[J]. J Clin Invest, 2024, 134(14): e179570. doi：10.1172/jci179570

10. ChenY, LiX, YangM, et al. Research progress on morphology and mechanism of programmed cell death[J]. Cell Death Dis, 2024, 15(5): 327. doi：10.1038/s41419-024-06712-8

11. WangH, LiuX, WangC, et al. Natural active botanical metabolites: targeting AMPK signaling pathway to treat metabolic dysfunction-associated fatty liver disease[J]. Front Pharmacol, 2025, 16: 1611400. doi：10.3389/fphar.2025.1611400

12. MeiJ, ZhangS, CuiX, et al. The dual role of autophagy in cartilage degradation: from mechanisms to targeted therapeutics[J]. Front Cell Dev Biol, 2026, 14: 1737547. doi：10.3389/fcell.2026.1737547

13. García-JuanM, VillaM, Benito-CuestaI, et al. Reassessing the AMPK-MTORC1 balance in autophagy in the central nervous system[J]. Neural Regen Res, 2025, 20(11): 3209-3210. doi：10.4103/nrr.nrr-d-24-00733

14. LiorN, ChenD, DanF, et al. The connection between autophagy and Alzheimer's disease[J]. Inflamm Res, 2025, 74(1): 1-18. doi：10.1007/s00011-025-02118-0

15. TangT. Pyroptosis in Alzheimer's disease: mechanisms and therapeutic potential[J]. Cell Mol Neurobiol, 2025, 45(1): 57. doi：10.1007/s10571-025-01579-5

16. HanJ, ZhangZ, ZhangP, et al. The roles of microglia and astrocytes in neuroinflammation of Alzheimer's disease[J]. Front Neurosci, 2025, 19: 1575453. doi：10.3389/fnins.2025.1575453

17. KielanB, PałaszA, KrystaK, et al. Ferroptosis as a form of cell death—medical importance and pharmacological implications[J]. Pharmaceuticals (Basel), 2025, 18(8): 1183. doi：10.3390/ph18081183

18. SunD, WangL, WuY, et al. Lipid metabolism in ferroptosis: mechanistic insights and therapeutic potential[J]. Front Immunol, 2025, 16: 1545339. doi：10.3389/fimmu.2025.1545339

19. LeeJ, SeoY, RohJL. Emerging therapeutic strategies targeting GPX4-mediated ferroptosis in head and neck cancer[J]. Int J Mol Sci, 2025, 26(13): 6452. doi：10.3390/ijms26136452

20. ChenY, XiaoW, QianC, et al. System Xc-pathway as a potential regulatory target in neurological disorders[J]. Front Pharmacol, 2025, 16: 1701320. doi：10.3389/fphar.2025.1701320

21. EskanderG, AbdelhamidSG, WahdanSA, et al. Insights on the crosstalk among different cell death mechanisms[J]. Cell Death Discov, 2025, 11(1): 56. doi：10.1038/s41420-025-02328-9

22. ZhangL, LiuJ, DaiZ, et al. Crosstalk between regulated necrosis and micronutrition, bridged by reactive oxygen species[J]. Front Nutr, 2022, 9: 1003340. doi：10.3389/fnut.2022.1003340

23. JurcăuMC, Andronie-CioaraFL, JurcăuA, et al. The link between oxidative stress, mitochondrial dysfunction and neuroinflammation in the pathophysiology of Alzheimer's disease: therapeutic implications and future perspectives[J]. Antioxidants (Basel), 2022, 11(11): 2167. doi：10.3390/antiox11112167

24. AnzovinoA, CanepaE, AlvesM, et al. Amyloid beta oligomers activate death receptors and mitochondria-mediated apoptotic pathways in cerebral vascular smooth muscle cells; protective effects of carbonic anhydrase inhibitors[J]. Cells, 2023, 12(24): 2840. doi：10.3390/cells12242840

25. SendtnerN, SeitzR, BrandlN, et al. Reactive oxygen species across death pathways: gatekeepers of apoptosis, ferroptosis, pyroptosis, paraptosis, and beyond[J]. Int J Mol Sci, 2025, 26(20): 10240. doi：10.3390/ijms262010240

26. ZhaoP, YinS, QiuY, et al. Ferroptosis and pyroptosis are connected through autophagy: a new perspective of overcoming drug resistance[J]. Mol Cancer, 2025, 24(1): 23. doi：10.1186/s12943-024-02217-2

27. LiB, LiuJ, ZhangD, et al. Evodiamine promotes autophagy and alleviates oxidative stress in dry eye disease through the p53/mTOR pathway[J]. Invest Ophthalmol Vis Sci, 2025, 66(3): 44. doi：10.1167/iovs.66.3.44

28. ChenZ, LiJ, PengH, et al. Meteorin-like/Meteorin-β protects LPS-induced acute lung injury by activating SIRT1-P53-SLC7A11 mediated ferroptosis pathway[J]. Mol Med, 2023, 29(1): 144. doi：10.1186/s10020-023-00714-6

29. ZengL, ZhaoK, LiuJ, et al. Long noncoding RNA GAS5 acts as a competitive endogenous RNA to regulate GSK-3β and PTEN expression by sponging miR-23b-3p in Alzheimer's disease[J]. Neural Regen Res, 2026, 21(1): 392-405. doi：10.4103/nrr.nrr-d-23-01273

30. HaoY, XieB, FuX, et al. New insights into LncRNAs in Aβ cascade hypothesis of Alzheimer's disease[J]. Biomolecules, 2022, 12(12): 1802. doi：10.3390/biom12121802

31. DongLX, ZhangYY, BaoHL, et al. LncRNA NEAT1 promotes Alzheimer's disease by down regulating micro-27a-3p[J]. Am J Transl Res, 2021, 13(8): 8885-8896.

32. ZhangYY, BaoHL, DongLX, et al. Silenced lncRNA H19 and up-regulated microRNA-129 accelerates viability and restrains apoptosis of PC12 cells induced by Aβ25-35 in a cellular model of Alzheimer's disease[J]. Cell Cycle, 2021, 20(1): 112-125. doi：10.1080/15384101.2020.1863681

33. RenH, QiuW, ZhuB, et al. The long non-coding RNA BDNF-AS induces neuronal cell apoptosis by targeting miR-125b-5p in Alzheimer's disease models[J]. Adv Clin Exp Med, 2024, 33(3): 233-245. doi：10.17219/acem/168241

34. ZhouY, GeY, LiuQ, et al. LncRNA BACE1-AS promotes autophagy-mediated neuronal damage through the miR-214-3p/ATG5 signalling axis in Alzheimer's disease[J]. Neuroscience, 2021, 455: 52-64. doi：10.1016/j.neuroscience.2020.10.028

35. TangZB, ChenHP, ZhongD, et al. LncRNA RMRP accelerates autophagy-mediated neurons apoptosis through miR-3142/TRIB3 signaling axis in Alzheimer's disease[J]. Brain Res, 2022, 1785: 147884. doi：10.1016/j.brainres.2022.147884

36. 贾玉梅, 朱才丰, 杨坤, 等. 艾灸督脉对APP/PS1双转基因小鼠mTOR/TFEB通路介导的自噬溶酶体功能及lncRNA H19表达的影响[J]. 针刺研究, 2022, 47(8): 665-672.JiaYM, ZhuCF, YangK, et al. Effect of moxibustion on autophagy lysosome function mediated by mTOR/TFEB pathway and lncRNA H19 expression in APP/PS1 double transgenic mice[J]. Acupuncture Research, 2022, 47(8): 665-672.

37. RenganathanA, MinayaMA, BroderM, et al. A novel lncRNA FAM151B-DT regulates degradation of aggregation prone proteins[J]. Mol Psychiatry, 2025, 30(12): 5637-5651. doi：10.1038/s41380-025-03277-6

38. 刘江华, 潘娴, 吴永贵. 基于Aβ代谢和NLRP3/Caspase-1/GSDMD信号通路探讨开心散对阿尔茨海默病小鼠神经元损伤的影响[J]. 中成药, 2026, 48(2): 431-438.LiuJH, PanX, WuYG. Study on the effect of Kaixin Powder on neuronal damage in Alzheimer's disease mice based on Aβ metabolism and NLRP3/Caspase-1/GSDMD signaling pathway[J]. Chinese Herbal Medicines, 2026, 48(2):431-438.

39. DuanR, WangSY, WeiB, et al. Angiotensin-(1-7) analogue AVE0991 modulates astrocyte-mediated neuroinflammation via lncRNA SNHG14/miR-223-3p/NLRP3 pathway and offers neuroprotection in a transgenic mouse model of Alzheimer's disease[J]. J Inflamm Res, 2021, 14: 7007-7019. doi：10.2147/jir.s343575

40. WangY, LiY, ZhouL, et al. Identification and validation of pyroptosis-related genes in Alzheimer's disease based on multi-transcriptome and machine learning[J]. Front Aging Neurosci, 2025, 17: 1568337. doi：10.3389/fnagi.2025.1568337

41. LinP, WangJ, LiY, et al. LINC00472 regulates ferroptosis of neurons in Alzheimer's disease via FOXO1[J]. Dement Geriatr Cogn Disord, 2024, 53(3): 107-118. doi：10.1159/000537883

42. BalusuS, HorréK, ThruppN, et al. MEG3 activates necroptosis in human neuron xenografts modeling Alzheimer's disease[J]. Science, 2023, 381(6663): 1176-1182. doi：10.1126/science.abp9556

43. XiongZ, SunC, HuangS. LncRNA-driven programmed cell death networks: new therapeutic targets for neurological disorders[J]. Front Mol Neurosci, 2025, 18: 1635119. doi：10.3389/fnmol.2025.1635119

44. TsvetkovP, CoyS, PetrovaB, et al. Copper induces cell death by targeting lipoylated TCA cycle proteins[J]. Science, 2022, 375(6586): 1254-1261. doi：10.1126/science.abf0529

45. ZhengN, ZhouQ, ChenZ, et al. Cuproptosis: mechanisms and links with Alzheimer's disease[J]. J Neurophysiol, 2025, 134(6): 1853-1876. doi：10.1152/jn.00370.2025

46. MaJ, ZhangY, SunZ, et al. LncRNA PVT1 promotes cuproptosis through transcriptional activation of FDX1 in colorectal cancer[J]. Redox Biol, 2025, 85: 103722. doi：10.1016/j.redox.2025.103722

47. LiuX, NieL, ZhangY, et al. Actin cytoskeleton vulnerability to disulfide stress mediates disulfidptosis[J]. Nat Cell Biol, 2023, 25(3): 404-414. doi：10.1038/s41556-023-01091-2

48. ZhouQ, ZhengN, ChenZ, et al. The emerging role of disulfidptosis in Alzheimer's disease[J]. European Journal of Pharmacology, 2025: 178085. doi：10.1016/j.ejphar.2025.178085

49. LacyKAD, LiangX, ZhangL, et al. RNA modifications can affect RNase H1-mediated PS-ASO activity[J]. Mol Ther Nucleic Acids, 2022, 28: 814-828. doi：10.1016/j.omtn.2022.05.024

50. WinkleM, El-DalySM, FabbriM, et al. Noncoding RNA therapeutics-challenges and potential solutions[J]. Nat Rev Drug Discov, 2021, 20(8): 629-651. doi：10.1038/s41573-021-00219-z

51. SelaM, ChenG, KadoshH, et al. AI-validated brain targeted mRNA lipid nanoparticles with neuronal tropism[J]. ACS nano, 2025, 19(41): 36106-36128.

52. Mohan KumarD, TalwarP. Neurotherapeutics across blood-brain barrier: screening of BBB-permeable and CNS-active molecules for neurodegenerative disease[J]. Front Pharmacol, 2025, 16: 1616144. doi：10.3389/fphar.2025.1616144

53. XuQ, LiuD, ZhuLQ, et al. Long non‐coding RNAs as key regulators of neurodegenerative protein aggregation[J]. Alzheimers Dement, 2025, 21(2): e14498. doi：10.1002/alz.14498