阿尔茨海默病的诊治进展

doi:10.3969/j.issn.1003-9198.2025.02.004

摘要/Abstract

摘要： AD是发生于老年期和老年前期的神经系统退行性疾病,其起病隐匿,病程呈进行性发展,预后不良。AD的临床表现以获得性认知功能损害为核心症状,涉及记忆、学习、定向、理解、判断、计算、语言和视空间等认知域,不同程度地影响病人日常生活能力及社会职业功能,最终进展为全面性痴呆。本文综述了AD诊断标准的发展历程、诊断相关生物标志物以及治疗方面的进展,旨在帮助提高AD早期诊断的准确性及治疗的精准化。

关键词: 阿尔茨海默病, 诊断标准, 生物标志物, 早期诊断, 修饰治疗

Abstract: Alzheimer's disease(AD) is a neurodegenerative disease that occurs in late adulthood and early old age, characterized by an insidious onset and a progressive course, with a poor prognosis. Its central syndrome is acquired cognitive impairment, affecting various cognitive domains including memory, learning, orientation, understanding, judgment, calculation, language and visuospatial skills. These impairments can significantly impact daily living abilities and social occupational functions, ultimately progressing to complete dementia. This article reviews the evolution of diagnostic criteria for AD, relevant diagnostic biomarkers, and advances in treatment, aiming to enhance the accuracy of early diagnosis and the precision of treatment for AD.

Key words: Alzheimer's disease, diagnostic criteria, biomarker, early diagnosis, modifying treatment

中图分类号:

R 749.16

辛梦凡, 冯美江. 阿尔茨海默病的诊治进展[J]. 实用老年医学, 2025, 39(2): 121-126.

XIN Mengfan, FENG Meijiang. Advance in the diagnosis and treatment of Alzheimer's disease[J]. Practical Geriatrics, 2025, 39(2): 121-126.

参考文献

[1] Alzheimer's Association. 2023 Alzheimer's disease facts and figures[J]. Alzheimers Dement, 2023, 19(4): 1598-1695.
[2] MCKHANN G, DRACHMAN D, FOLSTEIN M, et al. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA work group under the auspices of department of health and human services task force on Alzheimer's disease[J]. Neurology, 1984, 34(7): 939-944.
[3] DUBOIS B, FELDMAN H H, JACOVA C, et al. Research criteria for the diagnosis of Alzheimer's disease: revising the NINCDS-ADRDA criteria[J]. Lancet Neurol, 2007, 6(8): 734-746.
[4] MCKHANN G M, KNOPMAN D S, CHERTKOW H, et al. The diagnosis of dementia due to Alzheimer's disease: recommendations from the national institute on aging-alzheimer's association workgroups on diagnostic guidelines for Alzheimer's disease[J]. Alzheimers Dement, 2011, 7(3): 263-269.
[5] DUBOIS B, FELDMAN H H, JACOVA C, et al. Advancing research diagnostic criteria for Alzheimer's disease: the IWG-2 criteria[J]. Lancet Neurol, 2014, 13(6): 614-629.
[6] JACK C R Jr, BENNETT D A, BLENNOW K, et al. NIA-AA research framework: toward a biological definition of Alzheimer's disease[J]. Alzheimers Dement, 2018, 14(4): 535-562.
[7] HAMPEL H, CUMMINGS J, BLENNOW K, et al. Developing the ATX(N) classification for use across the Alzheimer disease continuum[J]. Nat Rev Neurol, 2021, 17(9): 580-589.
[8] JACK C R Jr , ANDREWS J S, BEACH T G, et al. Revised criteria for diagnosis and staging of Alzheimer's disease: Alzheimer's association workgroup[J]. Alzheimers Dement, 2024, 20(8): 5143-5169.
[9] JIA J, NING Y, CHEN M, et al. Biomarker changes during 20 years preceding Alzheimer's disease[J]. N Engl J Med, 2024, 390(8): 712-722.
[10] LI Y, SCHINDLER S E, BOLLINGER J G, et al. Validation of plasma amyloid-β 42/40 for detecting Alzheimer disease amyloid plaques[J]. Neurology, 2022, 98(7):e688-e699.
[11] JANELIDZE S, BARTHÉLEMY N R, SALVADÓ G, et al. Plasma phosphorylated tau 217 and Aβ42/40 to predict early brain Aβ accumulation in people without cognitive impairment[J]. JAMA Neurol, 2024, 81(9): 947-957.
[12] CANO A, CAPDEVILA M, PUERTA R, et al. Clinical value of plasma pTau181 to predict Alzheimer's disease pathology in a large real-world cohort of a memory clinic[J]. EBioMedicine, 2024, 108: 105345.
[13] JANELIDZE S, BERRON D, SMITH R, et al. Associations of plasma phospho-Tau217 levels with tau positron emission tomography in early Alzheimer disease[J]. JAMA Neurol, 2021, 78(2): 149-156.
[14] PALMQVIST S, JANELIDZE S, QUIROZ Y T, et al. Discriminative accuracy of plasma phospho-tau217 for Alzheimer disease vs other neurodegenerative disorders[J]. JAMA, 2020, 324(8): 772-781.
[15] SCHINDLER S E, PETERSEN K K, SAEF B, et al. Head-to-head comparison of leading blood tests for Alzheimer's disease pathology[J]. medRxiv, 2024: 2024.06.12.24308839.
[16] FEIZPOUR A, DOECKE J D, DORÉ V, et al. Detection and staging of Alzheimer's disease by plasma pTau217 on a high throughput immunoassay platform[J]. EBioMedicine, 2024, 109: 105405.
[17] ASHTON N J, PASCOAL T A, KARIKARI T K, et al. Plasma p-tau231: a new biomarker for incipient Alzheimer's disease pathology[J]. Acta Neuropathol, 2021, 141(5): 709-724.
[18] MILÀ-ALOMÀ M, ASHTON N J, SHEKARI M, et al. Plasma p-tau231 and p-tau217 as state markers of amyloid-β pathology in preclinical Alzheimer's disease[J]. Nat Med, 2022, 28(9): 1797-1801.
[19] GONZALEZ-ORTIZ F, TURTON M, KAC P R, et al. Brain-derived tau: a novel blood-based biomarker for Alzheimer's disease-type neurodegeneration[J]. Brain, 2023, 146(3): 1152-1165.
[20] GAETANI L, BLENNOW K, CALABRESI P, et al. Neurofilament light chain as a biomarker in neurological disorders[J]. J Neurol Neurosurg Psychiatry, 2019, 90(8): 870-881.
[21] HOFMANN A, HÄSLER L M, LAMBERT M, et al. Comparative neurofilament light chain trajectories in CSF and plasma in autosomal dominant Alzheimer's disease[J]. Nat Commun, 2024, 15(1): 9982.
[22] GUO Y, SHEN X N, WANG H F, et al. The dynamics of plasma biomarkers across the Alzheimer's continuum[J]. Alzheimers Res Ther, 2023, 15(1): 31.
[23] HOLPER S, LOVELAND P, CHURILOV L, et al. Blood astrocyte biomarkers in Alzheimer disease: a systematic review and meta-analysis[J]. Neurology, 2024, 103(3): e209537.
[24] GUO Y, YOU J, ZHANG Y, et al. Plasma proteomic profiles predict future dementia in healthy adults[J]. Nat Aging, 2024, 4(2): 247-260.
[25] SHIM K H, KANG M J, YOUN Y C, et al. Alpha-synuclein: a pathological factor with Aβ and tau and biomarker in Alzheimer's disease[J]. Alzheimers Res Ther, 2022, 14(1): 201.
[26] GAITSCH H, FRANKLIN R J M, REICH D S. Cell-free DNA-based liquid biopsies in neurology[J]. Brain, 2023, 146(5): 1758-1774.
[27] CHEN L, SHEN Q, XU S, et al. 5-hydroxymethylcytosine signatures in circulating cell-free DNA as diagnostic biomarkers for late-onset Alzheimer's disease[J]. J Alzheimers Dis, 2022, 85(2): 573-585.
[28] DING B, ZHANG X, WAN Z, et al. Characterization of mitochondrial DNA methylation of Alzheimer's disease in plasma cell-free DNA[J]. Diagnostics: Basel, 2023, 13(14): 2351.
[29] MORETA M P, BURGOS-ALONSO N, TORRECILLA M, et al. Efficacy of acetylcholinesterase inhibitors on cognitive function in Alzheimer's disease. Review of reviews[J]. Biomedicines, 2021, 9(11): 1689.
[30] YU T W, LANE H Y, LIN C H. Novel therapeutic approaches for Alzheimer's disease: an updated review[J]. Int J Mol Sci, 2021, 22(15): 8208.
[31] HAEBERLEIN S B, AISEN P S, BARKHOF F, et al. Two randomized phase 3 studies of aducanumab in early Alzheimer's disease[J]. J Prev Alzheimers Dis, 2022, 9(2): 197-210.
[32] VAN DYCK C H, SWANSON C J, AISEN P, et al. Lecanemab in early Alzheimer's disease[J]. N Engl J Med, 2023, 388(1): 9-21.
[33] KANG C. Donanemab: first approval[J]. Drugs, 2024, 84(10): 1313-1318.
[34] SIMS J R, ZIMMER J A, EVANS C D, et al. Donanemab in early symptomatic Alzheimer disease: the TRAILBLAZER-ALZ 2 randomized clinical trial[J]. JAMA, 2023, 330(6): 512-527.
[35] 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.
[36] 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.
[37] JACKSON R J, KEISER M S, MELTZER J C, et al. APOE2 gene therapy reduces amyloid deposition and improves markers of neuroinflammation and neurodegeneration in a mouse model of Alzheimer disease[J]. Mol Ther, 2024, 32(5): 1373-1386.
[38] ZHUANG Z, YANG R, WANG W, et al. Associations between gut microbiota and Alzheimer's disease, major depressive disorder, and schizophrenia[J]. J Neuroinflammation, 2020, 17(1): 288.
[39] HAZAN S. Rapid improvement in Alzheimer's disease symptoms following fecal microbiota transplantation: a case report[J]. J Int Med Res, 2020, 48(6): 300060520925930.
[40] ELANGOVAN S, BORODY T J, HOLSINGER R M D. Fecal microbiota transplantation reduces pathology and improves cognition in a mouse model of Alzheimer's disease[J]. Cells, 2022, 12(1): 119.
[41] YOO Y, NEUMAYER G, SHIBUYA Y, et al. A cell therapy approach to restore microglial Trem2 function in a mouse model of Alzheimer's disease[J]. Cell Stem Cell, 2023, 30(10): 1392.
[42] VAN LENGERICH B, ZHAN L, XIA D, et al. A TREM2-activating antibody with a blood-brain barrier transport vehicle enhances microglial metabolism in Alzheimer's disease models[J]. Nat Neurosci, 2023, 26(3): 416-429.
[43] HUANG P, LIN L, ZHANG J, et al. Efficacy analysis of three brain stimulation techniques for Alzheimer's disease: a meta-analysis of repeated transcranial magnetic stimulation, transcranial direct current stimulation, and deep brain stimulation[J]. Expert Rev Neurother, 2024, 24(1): 117-127.
[44] ZOU C, MEI X, LI X, et al. Effect of light therapy on delirium in older patients with Alzheimer's disease-related dementia[J]. J Psychiatr Res, 2022, 149: 124-127.
[45] SUN L, WANG Q, AI J. The underlying roles and neurobiological mechanisms of music-based intervention in Alzheimer's disease: a comprehensive review[J]. Ageing Res Rev, 2024, 96: 102265.
[46] YANG C, LIU G, ZENG X, et al. Therapeutic effects of long-term HBOT on Alzheimer's disease neuropathologies and cognitive impairment in APP^swe/PS1^dE9 mice[J]. Redox Biol, 2024, 70: 103006.
[47] WU L, DONG Y, ZHU C, et al. Effect and mechanism of acupuncture on Alzheimer's disease: a review[J]. Front Aging Neurosci, 2023, 15: 1035376.