阿尔茨海默病相关认知障碍药物靶点研究进展

doi:10.3969/j.issn.1003-9198.2026.02.003

摘要/Abstract

摘要： 近年来研究发现,AD导致的认知障碍可能是由多种机制共同引发的。本文总结了AD相关认知障碍的发病机制,包括β-淀粉样蛋白假说、Tau蛋白假说、神经炎症假说、突触损伤、神经元功能失调、神经可塑性改变以及APOE基因,并进一步探讨疾病可能的起源及相关药物治疗靶点。最后,本文提出未来需全面整合AD不同的致病机制,多靶点治疗模式可能是AD相关认知障碍防治的新方向。

关键词: 认知障碍, 阿尔茨海默病, 神经退行性疾病, 治疗靶点

Abstract: Recent studies have found that cognitive impairment caused by Alzheimer’s disease (AD) may result from multiple mechanisms acting in concert. This article summaries the pathogenesis of cognitive impairment related to AD, including the β-amyloid hypothesis, Tau protein hypothesis, neuroinflammation hypothesis, synaptic injury, neuronal dysfunction, and neuroplasticity changes, as well as the APOE gene. And further explores the possible origins of the disease and related drug therapeutic targets. Finally, this paper proposes that future efforts need to comprehensively integrate the different pathogenic mechanisms of AD, and a multi-target therapeutic model may be a new direction for the prevention and treatment of AD-related cognitive impairment.

Key words: cognitive impairment, Alzheimer’s disease, neurodegenerative diseases, therapeutic target

中图分类号:

R 749.16

孙阳, 郭莹. 阿尔茨海默病相关认知障碍药物靶点研究进展[J]. 实用老年医学, 2026, 40(2): 116-120.

SUN Yang, GUO Ying. Research progress on drug targets for Alzheimer’s disease-related cognitive impairment[J]. Practical Geriatrics, 2026, 40(2): 116-120.

参考文献

[1] MAGANA-RAMIREZ C M, GILLEN D L, HOM C L, et al. Neuropsychiatric symptoms and emerging dementia in people with down syndrome and older adults[J]. Alzheimers Dement, 2025, 21(11):e70871.
[2] TAKEDA T, UMEHARA H, MATSUMOTO Y, et al. Schizophrenia and cognitive dysfunction[J]. J Med Invest, 2024, 71(3/4): 205-209.
[3] LEE N, YOUN K, KWON H, et al. Fucoxanthin suppresses amyloid-β and pyroglutamate-3-Aβ accumulation by modulating the PI3K/AKT/GSK-3β signaling pathway[J]. Food Funct, 2025, 16(23): 9102-9117.
[4] CHOE K, ALI J, PARK H Y, et al. The mGluR2/3 agonist xanthurenic acid improves memory, attention, and synaptic deficits by modulating glutamate release in Alzheimer’s disease model[J]. Acta Pharmacol Sin, 2025. DOI: 10.1038/s41401-025-01671-y.
[5] JIANG S, HIJAZI S, SÁRKÁNY B, et al. Pathological tau alters head direction signaling and induces spatial disorientation[J]. Cell Rep, 2025, 44(12): 116610.
[6] CHOI D J, MURALI S, KWON W, et al. Astrocytic Sox9 overexpression in Alzheimer’s disease mouse models promotes Aβ plaque phagocytosis and preserves cognitive function[J]. Nat Neurosci, 2025. DOI: 10.1038/s41593-025-02115-w.
[7] ZHOU Y, SONG W M, ANDHEY P S, et al. Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer’s disease[J]. Nat Med, 2020, 26(1):131-142.
[8] YU C, WANG W, SHI L, et al. 27-Hydroxycholesterol triggers microglial senescence subsequent to iron over-loading contributes to brain aging, suppressed by Deferoxamine[J]. NPJ Aging, 2025. DOI: 10.1038/s41514-025-00303-3.
[9] ZHAO H, LI F, XU S, et al. Restoration neurite growth by removing the blockage of endosome trafficking in Alzheimer-like mice[J]. Neurotherapeutics, 2025. DOI: 10.1016/j.neurot.2025.e00777.
[10] LIU Z, MENG X, LU R, et al. PBX1 improves cognition and reduces amyloid-β pathology in APP/PS1 mice by transcriptionally activating the CRTC2-CREB pathway[J]. Aging Cell, 2025: e70311.
[11] LUO H, MARRON FERNANDEZ DE VELASCO E, KIM J, et al. Membrane-associated estrogen receptor α prevents the amyloid β-induced suppression of GIRK channel activity in hippocampal neurons from female mice[J]. Biol Sex Differ, 2025, 16(1): 90.
[12] LIU L R, LI L, LU L L, et al. Ceftriaxone alleviates mitochondrial damage through the inhibition of extrasynaptic NMDA receptor-mediated changes in intracellular calcium levels to improve cognitive deficits in APP/PS1 mice[J]. Alzheimers Res Ther, 2025, 17(1): 253.
[13] GUO Z, NI H, LU Y, et al. TNEA regulates hippocampal oscillation by improving inhibitory synaptic plasticity to ameliorates cognitive impairment in Alzheimer’s disease[J]. Adv Sci: Weinh, 2025, 11:e10885.
[14] WANG J L, SHA X Y, SHAO Y, et al. Elucidating pathway-selective biased CCKBR agonism for Alzheimer’s disease treatment[J]. Cell, 2025. DOI: 10.1016/j.cell.2025.10.034.
[15] MAIOLI S, NALVARTE I, ANKARCRONA M, et al. Bioenergetics and lipid metabolism in Alzheimer’s disease: from cell biology to systemic health[J]. J Intern Med, 2025, 299(1):20-43.
[16] CHEN C, MO M, ÅKERMAN M, et al. Dynamic associations of cholinesterase inhibitors and memantine with cognitive trajectories in individuals with Alzheimer’s or mixed dementia: a real-world analysis using the quality registry SveDem[J]. Alzheimers Res Ther, 2025, 17(1): 256.
[17] LI L L, WANG R Z, WANG Z, et al. Safety and short-term outcomes of lecanemab for Alzheimer’s disease in China: a multicentre study[J]. Brain, 2025, 11:awaf427
[18] NASRALLAH I M, POLACEK C, FRECH F H, et al. Early Alzheimer’s disease patient care pathway and health system readiness: a framework for integrated care[J]. Alzheimers Dement: N Y, 2025, 11(4):e70162.
[19] KNOPMAN D S, JONES D T, GREICIUS M D. Failure to demonstrate efficacy of aducanumab: an analysis of the EMERGE and ENGAGE trials as reported by Biogen, December 2019[J]. Alzheimers Dement, 2021, 17(4): 696-701.
[20] ALQAHTANI S M, AL-KURAISHY H M, AL-GAREEB A I, et al. Pharmacological modulation of the PI3K/AKT/GSK3β axis: a new frontier in Alzheimer’s disease treatment[J]. Inflammopharmacology, 2025. DOI: 10.1007/s10787-025-02000-9.
[21] LEE H J, KANG S, JIN LEE Y, et al. Genetic knockdown of DYRK1A attenuates cognitive impairment, Aβ pathology, tauopathy and neuroinflammatory responses in mouse models of AD[J]. Front Immunol, 2025, 16: 1661791.
[22] WANG X, SUN G, FENG T, et al. Sodium oligomannate therapeutically remodels gut microbiota and suppresses gut bacterial amino acids-shaped neuroinflammation to inhibit Alzheimer’s disease progression[J]. Cell Res, 2019, 29(10):787-803.
[23] XIAO S, CHAN P, WANG T, et al. A 36-week multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase 3 clinical trial of sodium oligomannate for mild-to-moderate Alzheimer’s dementia[J]. Alzheimers Res Ther, 2021, 13(1):62.
[24] LI H, BRZOSTEK O, SHERMAN J, et al. Cyclic nucleotide phosphodiesterase 1 and cognitive impairment: mechanistic insights and therapeutic implications[J]. Biomed Pharmacother, 2025, 193: 118796.
[25] SUN T, LI Z, XIAO B, et al. Recent development in PDE4D-targeted inhibitors for Alzheimer’s disease therapy[J]. Eur J Med Chem, 2025, 302(Pt 3):118383.
[26] XIONG C, TANG Y, CHEN J, et al. Transplantation of hiPSC-derived pericytes rescues Alzheimer’s disease phenotypes in APOE4/4 mice through IGF2-rich apoptotic vesicles[J]. Transl Neurodegener, 2025, 14(1): 57.
[27] WANG X, WANG D, LIU J, et al. Systemic delivery of liposome-loaded microRNA-195 ameliorates spatial memory impairment in a rat model of chronic cerebral hypoperfusion[J]. Int J Biol Macromol, 2026, 336:149290.
[28] KUEHN J F, ZHANG Q, HESTON M B, et al. Fecal short-chain fatty acids vary by sex and amyloid status[J]. Alzheimers Dement, 2025, 21(11):e70877.
[29] JIA L, XIAO L, SONG X, et al. Postbiotics alleviate cognitive impairment and neuroinflammation via gut-brain axis and TLR4/MyD88/NLRP3 pathway[J]. Food Res Int, 2025, 222(Pt 2): 117708.
[30] BAEK H I, KWON S Y, NOH H J, et al. Efficacy and safety of Lactobacillus delbrueckii subsp. lactis CKDB001 supplementation on cognitive function in mild cognitive impairment: a randomized, double-blind, placebo-controlled clinical trial[J]. Nutrients, 2025, 17(20):3313.
[31] TONG P, LI X, LI S, et al. Integrated metabolomics, transcriptomics and network pharmacology analysis to reveal the mechanisms of Danggui Buxue Tang in treating Alzheimer’s disease[J]. Phytomedicine, 2025, 150: 157591.
[32] 蔡美云, 庄文欣, 吕娥, 等. 山奈酚通过抑制p38 MAPK通路减轻6-羟多巴胺(6-OHDA)诱导的PC12细胞炎症[J]. 细胞与分子免疫学杂志, 2020, 36(7): 583-589.
[33] 张云, 高博, 许海军. 柴胡皂苷D基于PI3K/AKT/FoxO1调节神经炎症发挥抗抑郁作用[J]. 实用药物与临床, 2021, 24(5): 395-399.