探索Lecanemab与无创神经调控技术在阿尔茨海默病源性MCI治疗中的协同作用：一项综述
Explore the Synergistic Effect of Lecanemab and Non-Invasive Neuromodulation Technology in the Treatment of Alzheimer’s Disease-Related MCI: A Review
摘要: 阿尔茨海默病(AD)是高发神经退行性疾病，轻度认知障碍(MCI)作为疾病早期阶段，是临床干预的关键窗口期。现阶段AD治疗手段以对症处理为主，尚无有效逆转病程的方案，单一疗法存在明显局限。靶向 β-淀粉样蛋白的单克隆抗体Lecanemab可清除脑部病理沉积物、延缓疾病进展；经颅磁刺激、经颅直流电刺激等无创神经调控技术，能够调节脑神经网络活动、改善认知功能。本文系统梳理AD及AD源性MCI的流行病学特征、主流发病机制、临床诊断标准，分别阐述Lecanemab的药理作用、临床疗效与安全性，以及各类无创神经调控技术的应用现状。在此基础上分析两类疗法的潜在协同机制：Lecanemab作用于病理层面改善脑内微环境，无创神经调控技术作用于功能层面修复神经活动，二者可形成互补效应。本文进一步在挑战与展望部分构建2 × 2析因设计的假设性临床试验方案，明确入排标准、分层干预方案、多维度结局指标与全程安全性监测体系，具象化联合治疗的临床实施路径。目前二者联合应用的研究仍处于空白阶段，联合治疗的作用机制、远期疗效与安全性仍需大量临床试验验证。本文旨在为AD源性MCI的综合治疗提供新思路，为后续基础研究与临床实践提供参考。
Abstract: Alzheimer’s disease (AD) is a prevalent neurodegenerative disease. Mild Cognitive Impairment (MCI), as the early stage of AD, is a critical window for clinical intervention. Current treatments for AD mainly relieve symptoms, and there is no effective therapy to reverse the disease progression, while single treatment strategies have obvious limitations. Lecanemab, a monoclonal antibody targeting β-amyloid protein, can clear pathological deposits in the brain and delay the progression of AD. Non-invasive neuromodulation technologies such as transcranial magnetic stimulation and transcranial direct current stimulation can regulate the activity of brain neural networks and improve cognitive function. This paper systematically reviews the epidemiological characteristics, mainstream pathogenesis and clinical diagnostic criteria of AD and AD-related MCI, and expounds the pharmacological effects, clinical efficacy and safety of Lecanemab, as well as the application status of various non-invasive neuromodulation technologies. On this basis, the potential synergistic mechanism of the two types of therapies is analyzed: Lecanemab improves the intracerebral microenvironment at the pathological level, and non-invasive neuromodulation technology repairs neural activity at the functional level, and the two can produce complementary effects. A hypothetical clinical trial protocol with 2 × 2 factorial design is constructed in the challenge and prospect section, specifying enrollment criteria, hierarchical intervention regimens, multi-dimensional outcome indicators and full-process safety monitoring plan, to concretize the implementation path of combined therapy. At present, researches on their combined application are still blank, and the mechanism, long-term efficacy and safety of combined treatment need to be verified by a large number of clinical trials. This study aims to provide new ideas for the comprehensive treatment of AD-related MCI and offer references for subsequent basic research and clinical practice.
文章引用：李卓岭, 杨东东. 探索Lecanemab与无创神经调控技术在阿尔茨海默病源性MCI治疗中的协同作用：一项综述[J]. 临床个性化医学, 2026, 5(4): 262-272. https://doi.org/10.12677/jcpm.2026.54248

参考文献

[1] 中华医学会神经病学分会痴呆与认知障碍学组, 陈晓春, 潘晓东, 等. 阿尔茨海默病源性轻度认知障碍诊疗中国专家共识2024 [J]. 中华神经科杂志, 2024, 57(7): 715-737.
[2] 张赫, 郑焱. β淀粉样蛋白级联假说相关的阿尔茨海默病发病机制及防治策略研究进展[J]. 中国医学科学院学报, 2019, 41(5): 702-708.
[3] van Dyck, C.H., Swanson, C.J., Aisen, P., Bateman, R.J., Chen, C., Gee, M., et al. (2023) Lecanemab in Early Alzheimer’s Disease. New England Journal of Medicine, 388, 9-21.
https://doi.org/10.1056/nejmoa2212948
[4] Jia, L.F., Quan, M.N., Fu, Y., et al. (2020) Dementia in China: Epidemiology, Clinical Management, and Research Advances. The Lancet Neurology, 19, 81-92.
https://doi.org/10.1016/s1474-4422(19)30290-x
[5] Xu, J., Wang, J., Wimo, A., Fratiglioni, L. and Qiu, C. (2017) The Economic Burden of Dementia in China, 1990-2030: Implications for Health Policy. Bulletin of the World Health Organization, 95, 18-26.
https://doi.org/10.2471/blt.15.167726
[6] Jia, J.P., Wei, C.B., Chen, S.Q., et al. (2018) The Cost of Alzheimer’s Disease in China and Re‐Estimation of Costs Worldwide. Alzheimer’s & Dementia, 14, 483-491.
https://doi.org/10.1016/j.jalz.2017.12.006
[7] Jia, L.F., Du, Y.F., Chu, L., et al. (2020) Prevalence, Risk Factors, and Management of Dementia and Mild Cognitive Impairment in Adults Aged 60 Years or Older in China: A Cross-Sectional Study. The Lancet Public Health, 5, e661-e671.
https://doi.org/10.1016/s2468-2667(20)30185-7
[8] Glenner, G.G. and Wong, C.W. (1988) Alzheimerʼs Disease: Initial Report of the Purification and Characterization of a Novel Cerebrovascular Amyloid Protein. Alzheimer Disease & Associated Disorders, 2, 134.
https://doi.org/10.1097/00002093-198802020-00010
[9] Hardy, J. and Allsop, D. (1991) Amyloid Deposition as the Central Event in the Aetiology of Alzheimer’s Disease. Trends in Pharmacological Sciences, 12, 383-388.
https://doi.org/10.1016/0165-6147(91)90609-v
[10] Long, J.M. and Holtzman, D.M. (2019) Alzheimer Disease: An Update on Pathobiology and Treatment Strategies. Cell, 179, 312-339.
https://doi.org/10.1016/j.cell.2019.09.001
[11] Vassar, R., Bennett, B.D., Babu-Khan, S., Kahn, S., Mendiaz, E.A., Denis, P., et al. (1999) β-Secretase Cleavage of Alzheimer’s Amyloid Precursor Protein by the Transmembrane Aspartic Protease BACE. Science, 286, 735-741.
https://doi.org/10.1126/science.286.5440.735
[12] Voytyuk, I., De Strooper, B. and Chávez-Gutiérrez, L. (2018) Modulation of γ-and β-Secretases as Early Prevention against Alzheimer’s Disease. Biological Psychiatry, 83, 320-327.
https://doi.org/10.1016/j.biopsych.2017.08.001
[13] Nelson, P.T., Alafuzoff, I., Bigio, E.H., Bouras, C., Braak, H., Cairns, N.J., et al. (2012) Correlation of Alzheimer Disease Neuropathologic Changes with Cognitive Status: A Review of the Literature. Journal of Neuropathology & Experimental Neurology, 71, 362-381.
https://doi.org/10.1097/nen.0b013e31825018f7
[14] Salloway, S., Sperling, R., Fox, N.C., Blennow, K., Klunk, W., Raskind, M., et al. (2014) Two Phase 3 Trials of Bapineuzumab in Mild-to-Moderate Alzheimer’s Disease. New England Journal of Medicine, 370, 322-333.
https://doi.org/10.1056/nejmoa1304839
[15] Honig, L.S., Vellas, B., Woodward, M., Boada, M., Bullock, R., Borrie, M., et al. (2018) Trial of Solanezumab for Mild Dementia Due to Alzheimer’s Disease. New England Journal of Medicine, 378, 321-330.
https://doi.org/10.1056/nejmoa1705971
[16] Sevigny, J., Chiao, P., Bussière, T., Weinreb, P.H., Williams, L., Maier, M., et al. (2016) The Antibody Aducanumab Reduces Aβ Plaques in Alzheimer’s Disease. Nature, 537, 50-56.
https://doi.org/10.1038/nature19323
[17] Ostrowitzki, S., Lasser, R.A., Dorflinger, E., Scheltens, P., Barkhof, F., Nikolcheva, T., et al. (2017) A Phase III Randomized Trial of Gantenerumab in Prodromal Alzheimer’s Disease. Alzheimer’s Research & Therapy, 9, Article No. 95.
https://doi.org/10.1186/s13195-017-0318-y
[18] Spillantini, M.G. and Goedert, M. (2013) Tau Pathology and Neurodegeneration. The Lancet Neurology, 12, 609-622.
https://doi.org/10.1016/s1474-4422(13)70090-5
[19] 闫丽爽, 李全, 张健, 等. 小檗碱防治阿尔茨海默病作用机制研究进展[J]. 中华中医药学刊, 2025, 43(10): 195-201.
[20] He, Z.H., Guo, J.L., McBride, J.D., et al. (2018) Amyloid-β Plaques Enhance Alzheimer’s Brain Tau-Seeded Pathologies by Facilitating Neuritic Plaque Tau Aggregation. Nature Medicine, 24, 29-38.
https://doi.org/10.1038/nm.4443
[21] Hanseeuw, B.J., Betensky, R.A., Jacobs, H.I.L., Schultz, A.P., Sepulcre, J., Becker, J.A., et al. (2019) Association of Amyloid and Tau with Cognition in Preclinical Alzheimer Disease: A Longitudinal Study. JAMA Neurology, 76, 915-924.
https://doi.org/10.1001/jamaneurol.2019.1424
[22] Liu, C.C., Zhao, N., Fu, Y., et al. (2017) ApoE4 Accelerates Early Seeding of Amyloid Pathology. Neuron, 96, 1024-1032.e3.
https://doi.org/10.1016/j.neuron.2017.11.013
[23] Reiman, E.M., Arboleda-Velasquez, J.F., Quiroz, Y.T., et al. (2020) Exceptionally Low Likelihood of Alzheimer’s Dementia in APOE2 Homozygotes from a 5,000-Person Neuropathological Study. Nature Communications, 11, Article No. 667.
[24] Serrano-Pozo, A., Qian, J., Monsell, S.E., Betensky, R.A. and Hyman, B.T. (2015) APOEε2 Is Associated with Milder Clinical and Pathological Alzheimer Disease. Annals of Neurology, 77, 917-929.
https://doi.org/10.1002/ana.24369
[25] Hashimoto, T., Serrano-Pozo, A., Hori, Y., Adams, K.W., Takeda, S., Banerji, A.O., et al. (2012) Apolipoprotein E, Especially Apolipoprotein E4, Increases the Oligomerization of Amyloid β Peptide. The Journal of Neuroscience, 32, 15181-15192.
https://doi.org/10.1523/jneurosci.1542-12.2012
[26] Hori, Y., Hashimoto, T., Nomoto, H., Hyman, B.T. and Iwatsubo, T. (2018) Role of Apolipoprotein E in β-AmyloidoGenesis: Isoform-Specific Effects on Protofibril to Fibril Conversion of Aβ in Vitro and Brain Aβ Deposition in Vivo. Journal of Biological Chemistry, 293, Article 7267.
https://doi.org/10.1074/jbc.aac118.003576
[27] Serrano-Pozo, A., Das, S. and Hyman, B.T. (2021) APOE and Alzheimer’s Disease: Advances in Genetics, Pathophysiology, and Therapeutic Approaches. The Lancet Neurology, 20, 68-80.
https://doi.org/10.1016/s1474-4422(20)30412-9
[28] Lin, Y.T., Seo, J., Gao, F., et al. (2018) APOE4 Causes Widespread Molecular and Cellular Alterations Associated with Alzheimer’s Disease Phenotypes in Human iPSC-Derived Brain Cell Types. Neuron, 98, 1141-1154.e7.
https://doi.org/10.1016/j.neuron.2018.05.008
[29] Buciuc, M., Wennberg, A.M., Weigand, S.D., Murray, M.E., Senjem, M.L., Spychalla, A.J., et al. (2020) Effect Modifiers of TDP-43-Associated Hippocampal Atrophy Rates in Patients with Alzheimer’s Disease Neuropathological Changes. Journal of Alzheimer’s Disease, 73, 1511-1523.
https://doi.org/10.3233/jad-191040
[30] Wu, J., Ishikawa, M., Zhang, J. and Hashimoto, K. (2010) Brain Imaging of Nicotinic Receptors in Alzheimer’s Disease. International Journal of Alzheimer’s Disease, 2010, 1-11.
https://doi.org/10.4061/2010/548913
[31] Irwin, M.R. and Vitiello, M.V. (2019) Implications of Sleep Disturbance and Inflammation for Alzheimer’s Disease Dementia. The Lancet Neurology, 18, 296-306.
https://doi.org/10.1016/s1474-4422(18)30450-2
[32] Heneka, M.T., Carson, M.J., Khoury, J.E., Landreth, G.E., Brosseron, F., Feinstein, D.L., et al. (2015) Neuroinflammation in Alzheimer’s Disease. The Lancet Neurology, 14, 388-405.
https://doi.org/10.1016/s1474-4422(15)70016-5
[33] Zhang, T., Gao, G., Kwok, L. and Sun, Z. (2023) Gut Microbiome-Targeted Therapies for Alzheimer’s Disease. Gut Microbes, 15, Article 2271613.
https://doi.org/10.1080/19490976.2023.2271613
[34] Avgerinos, K.I., Ferrucci, L. and Kapogiannis, D. (2021) Effects of Monoclonal Antibodies against Amyloid-β on Clinical and Biomarker Outcomes and Adverse Event Risks: A Systematic Review and Meta-Analysis of Phase III RCTs in Alzheimer’s Disease. Ageing Research Reviews, 68, Article 101339.
https://doi.org/10.1016/j.arr.2021.101339
[35] Hoy, S.M. (2023) Lecanemab: First Approval. Drugs, 83, 359-365.
https://doi.org/10.1007/s40265-023-01851-2
[36] Larkin, H.D. (2023) Lecanemab Gains FDA Approval for Early Alzheimer Disease. Journal of the American Medical Association, 329, 363.
https://doi.org/10.1001/jama.2022.24490
[37] McDade, E., Cummings, J.L., Dhadda, S., Swanson, C.J., Reyderman, L., Kanekiyo, M., et al. (2022) Lecanemab in Patients with Early Alzheimer’s Disease: Detailed Results on Biomarker, Cognitive, and Clinical Effects from the Randomized and Open-Label Extension of the Phase 2 Proof-of-Concept Study. Alzheimer’s Research & Therapy, 14, Article No. 191.
https://doi.org/10.1186/s13195-022-01124-2
[38] Honig, L.S., Sabbagh, M.N., van Dyck, C.H., Sperling, R.A., Hersch, S., Matta, A., et al. (2024) Updated Safety Results from Phase 3 Lecanemab Study in Early Alzheimer’s Disease. Alzheimer’s Research & Therapy, 16, Article No. 105.
https://doi.org/10.1186/s13195-024-01441-8
[39] Andrews, J.S., Desai, U., Kirson, N.Y., Zichlin, M.L., Ball, D.E. and Matthews, B.R. (2019) Disease Severity and Minimal Clinically Important Differences in Clinical Outcome Assessments for Alzheimer’s Disease Clinical Trials. Alzheimer’s & Dementia: Translational Research & Clinical Interventions, 5, 354-363.
https://doi.org/10.1016/j.trci.2019.06.005
[40] Liu, K.Y., Schneider, L.S. and Howard, R. (2021) The Need to Show Minimum Clinically Important Differences in Alzheimer’s Disease Trials. The Lancet Psychiatry, 8, 1013-1016.
https://doi.org/10.1016/s2215-0366(21)00197-8
[41] The Lancet (2022) Lecanemab for Alzheimer’s Disease: Tempering Hype and Hope. The Lancet, 400, 1899.
https://doi.org/10.1016/s0140-6736(22)02480-1
[42] Burke, J.F., Kerber, K.A., Langa, K.M., Albin, R.L. and Kotagal, V. (2023) Lecanemab. Neurology, 101, 661-665.
https://doi.org/10.1212/wnl.0000000000207505
[43] Freitas, C., Perez, J.M., Knobel, M., Tormos, J.M., Oberman, L., Eldaief, M., et al. (2011) Changes in Cortical Plasticity across the Lifespan. Frontiers in Aging Neuroscience, 3, Article 5.
https://doi.org/10.3389/fnagi.2011.00005
[44] Trebbastoni, A., Pichiorri, F., D’Antonio, F., Campanelli, A., Onesti, E., Ceccanti, M., et al. (2016) Altered Cortical Synaptic Plasticity in Response to 5-Hz Repetitive Transcranial Magnetic Stimulation as a New Electrophysiological Finding in Amnestic Mild Cognitive Impairment Converting to Alzheimer’s Disease: Results from a 4-Year Prospective Cohort Study. Frontiers in Aging Neuroscience, 7, Article 253.
https://doi.org/10.3389/fnagi.2015.00253
[45] Medeiros, L.F., de Souza, I.C.C., Vidor, L.P., de Souza, A., Deitos, A., Volz, M.S., et al. (2012) Neurobiological Effects of Transcranial Direct Current Stimulation: A Review. Frontiers in Psychiatry, 3, Article 110.
https://doi.org/10.3389/fpsyt.2012.00110
[46] Fröhlich, F. and McCormick, D.A. (2010) Endogenous Electric Fields May Guide Neocortical Network Activity. Neuron, 67, 129-143.
https://doi.org/10.1016/j.neuron.2010.06.005
[47] Yang, T., Liu, W., He, J., Gui, C., Meng, L., Xu, L., et al. (2024) The Cognitive Effect of Non-Invasive Brain Stimulation Combined with Cognitive Training in Alzheimer’s Disease and Mild Cognitive Impairment: A Systematic Review and Meta-Analysis. Alzheimer’s Research & Therapy, 16, Article No. 140.
https://doi.org/10.1186/s13195-024-01505-9
[48] Begemann, M.J., Brand, B.A., Ćurčić-Blake, B., Aleman, A. and Sommer, I.E. (2020) Efficacy of Non-Invasive Brain Stimulation on Cognitive Functioning in Brain Disorders: A Meta-Analysis. Psychological Medicine, 50, 2465-2486.
https://doi.org/10.1017/s0033291720003670
[49] 曹甜甜, 王亚飞, 张文龙, 等. 经颅交流电刺激对阿尔兹海默病小鼠双侧海马有效连接的干预研究[J]. 西安交通大学学报, 2023, 57(4): 80-87.
[50] Petrovskaya, A., Tverskoi, A., Medvedeva, A. and Nazarova, M. (2023) Is Blood-Brain Barrier a Probable Mediator of Non-Invasive Brain Stimulation Effects on Alzheimer’s Disease? Communications Biology, 6, Article No. 416.
https://doi.org/10.1038/s42003-023-04717-1