Share：
Share this content in WeChat
X
[Chinese] [PDF] 32 1
• Clinical Article •
Dynamic modulation of cognition, brain structure and covariance networks in AD patients by donepezil: A longitudinal study based on structural MRI
CHEN Yingxin  CHEN Jiu  XU Xinru  CHEN Qian  LU Jiaming  ZHANG Xin  ZHAO Hui  ZHANG Bing 

Cite this article as CHEN Y X, CHEN J, XU X R, et al. Dynamic modulation of cognition, brain structure and covariance networks in AD patients by donepezil: A longitudinal study based on structural MRI[J]. Chin J Magn Reson Imaging, 2026, 17(6): 1-10, 27. DOI:10.12015/issn.1674-8034.2026.06.001.


[Abstract] Objective To investigate the long-term effects of donepezil on the progression of Alzheimer's disease (AD), this study examined the dynamic changes in cognitive function, brain morphology, and structural covariance network properties in AD patients treated with donepezil over a 24-month follow-up period.Materials and Methods This study comprises two parts: a cross-sectional study and a longitudinal study of drug therapy. The cross-sectional study included 30 normal controls (NC) and 42 AD patients, evaluating differences in cognition, brain morphology, and global properties and node metrics of structural covariance networks between the two groups. The longitudinal study of drug therapy retrospectively enrolled 26 AD patients receiving donepezil treatment and 26 AD patients who did not receive any AD medication as non-treatment group. Clinical and MRI data were collected from both groups over the 24-month follow-up period. Linear mixed-effects models were employed to analyze changes in cognitive scale scores, volumes of characteristic brain regions, and structural covariance network metrics.Results AD patients exhibited significant atrophy in the right hippocampus, left amygdala, left cuneus, and right thalamus (P < 0.05, FWE corrected), accompanied by extensive damage to structural covariance networks. The results of the linear mixed-effects model showed significant time × group interaction effects for the MMSE scores, right hippocampus volume, and left amygdala volume (P < 0.05). The rate of decline in MMSE scores was significantly slower in the donepezil treatment group than in the non-treatment group, and the atrophy rates of the right hippocampus and left amygdala were significantly decelerated. No significant interaction effects were observed for global metrics of the structural covariance network.Conclusions The therapeutic effect of donepezil on AD is a multi-level process. Following intervention, global network properties show a transient improvement trend, which may subsequently activates network metrics in brain regions critical for cognition, and thereby delays cognitive decline and atrophy in disease-affected brain regions. However, its long-term influence on the topology of the whole-brain structural covariance network is limited. This study provides multi-level longitudinal evidence for understanding the neuroimaging mechanisms underlying the modulation of AD progression by donepezil.
[Keywords] donepezil；Alzheimer's disease；structural covariance network；magnetic resonance imaging；graph theory analysis

CHEN Yingxin1   CHEN Jiu2   XU Xinru3   CHEN Qian2   LU Jiaming2   ZHANG Xin2   ZHAO Hui4   ZHANG Bing1, 2, 3*  

1 Department of Radiology, Nanjing Drum Tower Hospital, Clinical College of Nanjing University of Chinese Medicine, Nanjing 210008, China

2 Department of Radiology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China

3 Department of Radiology, Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, Nanjing 210008, China

4 Department of Neurology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China

Corresponding author: ZHANG B, E-mail: zhangbing_nanjing@nju.edu.cn

Conflicts of interest   None.

Received  2026-02-11
Accepted  2026-06-01
DOI: 10.12015/issn.1674-8034.2026.06.001
Cite this article as CHEN Y X, CHEN J, XU X R, et al. Dynamic modulation of cognition, brain structure and covariance networks in AD patients by donepezil: A longitudinal study based on structural MRI[J]. Chin J Magn Reson Imaging, 2026, 17(6): 1-10, 27. DOI:10.12015/issn.1674-8034.2026.06.001.

[1]
BAVISKAR P S, MAHAJAN H S. Unveiling Alzheimer's disease (1901-2025): insightsHistorical, burdenglobal, mechanismsbiological, diagnostics, and therapeutic strategies[J/OL]. Ageing Res Rev, 2026, 114: 102990 [2026-02-10]. https://pubmed.ncbi.nlm.nih.gov/41386339/. DOI: 10.1016/j.arr.2025.102990.
[2]
FOX N C, BELDER C, BALLARD C, et al. Treatment for Alzheimer's disease[J]. Lancet, 2025, 406(10510): 1408-1423. DOI: 10.1016/S0140-6736(25)01329-7.
[3]
BIRKS J S, HARVEY R J. Donepezil for dementia due to Alzheimer's disease[J/OL]. Cochrane Database Syst Rev, 2018, 2018(6) [2026-02-10]. https://pubmed.ncbi.nlm.nih.gov/29923184/. DOI: 10.1002/14651858.cd001190.pub3.
[4]
WINBLAD B, KILANDER L, ERIKSSON S, et al. Donepezil in patients with severe Alzheimer's disease: double-blind, parallel-group, placebo-controlled study[J]. Lancet, 2006, 367(9516): 1057-1065. DOI: 10.1016/S0140-6736(06)68350-5.
[5]
HOWARD R, MCSHANE R, LINDESAY J, et al. Donepezil and memantine for moderate-to-severe Alzheimer's disease[J]. N Engl J Med, 2012, 366(10): 893-903. DOI: 10.1056/nejmoa1106668.
[6]
DU X Y, DUAN L H, YAN P, et al. Changes and therapeutic effects of Ginkgo biloba extract, Donepezil and combination therapy on gray matter volume and cortical morphology in patients with cognitive dysfunction[J]. J Clin Neurol, 2025, 38(4): 268-275. DOI: 10.3969/j.issn.1004-1648.2025.04.010.
[7]
GUO H, GRAJAUSKAS L, HABASH B, et al. Functional MRI technologies in the study of medication treatment effect on Alzheimer's disease[J]. Aging Med (Milton), 2018, 1(1): 75-95. DOI: 10.1002/agm2.12017.
[8]
CAVEDO E, GROTHE M J, COLLIOT O, et al. Reduced basal forebrain atrophy progression in a randomized Donepezil trial in prodromal Alzheimer's disease[J/OL]. Sci Rep, 2017, 7(1): 11706 [2026-02-10]. https://pubmed.ncbi.nlm.nih.gov/28916821/. DOI: 10.1038/s41598-017-09780-3.
[9]
JIN Y, LI Y, LEI X W. Clinical trial of donepezil in the treatment of patients with AD induced mild cognitive impairment[J]. Chin J Clin Pharmacol, 2024, 40(18): 2616-2620. DOI: 10.13699/j.cnki.1001-6821.2024.18.002.
[10]
DUBOIS B, CHUPIN M, HAMPEL H, et al. Donepezil decreases annual rate of hippocampal atrophy in suspected prodromal Alzheimer's disease[J]. Alzheimers Dement, 2015, 11(9): 1041-1049. DOI: 10.1016/j.jalz.2014.10.003.
[11]
KRISHNAN K R, CHARLES H C, DORAISWAMY P M, et al. Randomized, placebo-controlled trial of the effects of donepezil on neuronal markers and hippocampal volumes in Alzheimer's disease[J]. Am J Psychiatry, 2003, 160(11): 2003-2011. DOI: 10.1176/appi.ajp.160.11.2003.
[12]
PINI L, PIEVANI M, BOCCHETTA M, et al. Brain atrophy in Alzheimer's disease and aging[J/OL]. Ageing Res Rev, 2016, 30: 25-48 [2026-02-10]. https://pubmed.ncbi.nlm.nih.gov/26827786/. DOI: 10.1016/j.arr.2016.01.002.
[13]
FENG F, HUANG W J, MENG Q Q, et al. Altered volume and structural connectivity of the hippocampus in Alzheimer's disease and amnestic mild cognitive impairment[J/OL]. Front Aging Neurosci, 2021, 13: 705030 [2026-02-10]. https://pubmed.ncbi.nlm.nih.gov/34675796/. DOI: 10.3389/fnagi.2021.705030.
[14]
SULTANA O F, BANDARU M, ISLAM M A, et al. Unraveling the complexity of human brain: Structure, function in healthy and disease states[J/OL]. Ageing Res Rev, 2024, 100: 102414 [2026-02-10]. https://pubmed.ncbi.nlm.nih.gov/39002647/. DOI: 10.1016/j.arr.2024.102414.
[15]
MONGAY-OCHOA N, GONZALEZ-ESCAMILLA G, et al. Structural covariance analysis for neurodegenerative and neuroinflammatory brain disorders[J]. Brain, 2025, 148(9): 3072-3084. DOI: 10.1093/brain/awaf151.
[16]
FAN L H, WEI W, CHEN Y Y, et al. Graph theory analysis of Alzheimer's disease patients based on gray matter structural covariance network[J]. Chin J Magn Reson Imaging, 2025, 16(6): 27-33. DOI: 10.12015/issn.1674-8034.2025.06.004.
[17]
WANG Y, ZHAO K, ZHU Z L, et al. Altered brain morphometry and structural covariant networks based on cortical thickness in Alzheimer's disease[J]. Chin J Magn Reson Imaging, 2024, 15(8): 52-58. DOI: 10.12015/issn.1674-8034.2024.08.008.
[18]
DICKS E, VERMUNT L, VAN DER FLIER W M, et al. Grey matter network trajectories across the Alzheimer's disease continuum and relation to cognition[J/OL]. Brain Commun, 2020, 2(2): fcaa177 [2026-02-10]. https://pubmed.ncbi.nlm.nih.gov/33376987/. DOI: 10.1093/braincomms/fcaa177.
[19]
JACK C R, 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. DOI: 10.1002/alz.13859.
[20]
FORTIN J P, CULLEN N, SHELINE Y I, et al. Harmonization of cortical thickness measurements across scanners and sites[J/OL]. NeuroImage, 2018, 167: 104-120 [2026-02-10]. https://pubmed.ncbi.nlm.nih.gov/29155184/. DOI: 10.1016/j.neuroimage.2017.11.024.
[21]
LIU Z W, PALANIYAPPAN L, WU X R, et al. Resolving heterogeneity in schizophrenia through a novel systems approach to brain structure: individualized structural covariance network analysis[J]. Mol Psychiatry, 2021, 26(12): 7719-7731. DOI: 10.1038/s41380-021-01229-4.
[22]
ZHENG C C, ZHAO W, YANG Z Y, et al. Resolving heterogeneity in Alzheimer's disease based on individualized structural covariance network[J/OL]. Prog Neuro Psychopharmacol Biol Psychiatry, 2024, 129: 110873 [2026-02-10]. https://pubmed.ncbi.nlm.nih.gov/37827426/. DOI: 10.1016/j.pnpbp.2023.110873.
[23]
WEI X T, XIONG R L, XU P, et al. Revealing heterogeneity in mild cognitive impairment based on individualized structural covariance network[J/OL]. Alzheimers Res Ther, 2025, 17(1): 106 [2026-02-10]. https://pubmed.ncbi.nlm.nih.gov/40375286/. DOI: 10.1186/s13195-025-01752-4.
[24]
WANG J H, WANG X D, XIA M R, et al. GRETNA: a graph theoretical network analysis toolbox for imaging connectomics[J/OL]. Front Hum Neurosci, 2015, 9: 386 [2026-02-10]. https://pubmed.ncbi.nlm.nih.gov/26175682/. DOI: 10.3389/fnhum.2015.00386.
[25]
CHANDRA A, DERVENOULAS G, POLITIS M, et al. Magnetic resonance imaging in Alzheimer's disease and mild cognitive impairment[J]. J Neurol, 2019, 266(6): 1293-1302. DOI: 10.1007/s00415-018-9016-3.
[26]
BRAAK H, ALAFUZOFF I, ARZBERGER T, et al. Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry[J]. Acta Neuropathol, 2006, 112(4): 389-404. DOI: 10.1007/s00401-006-0127-z.
[27]
DE BOURBON-TELES J, BENTLEY P, KOSHINO S, et al. Thalamic control of human attention driven by memory and learning[J]. Curr Biol, 2014, 24(9): 993-999. DOI: 10.1016/j.cub.2014.03.024.
[28]
BERNSTEIN A S, RAPCSAK S Z, HORNBERGER M, et al. Structural changes in thalamic nuclei across prodromal and clinical Alzheimer's disease[J]. J Alzheimers Dis, 2021, 82(1): 361-371. DOI: 10.3233/JAD-201583.
[29]
DICKS E, VAN DER FLIER W M, SCHELTENS P, et al. Single-subject gray matter networks predict future cortical atrophy in preclinical Alzheimer's disease[J/OL]. Neurobiol Aging, 2020, 94: 71-80 [2026-02-10]. https://pubmed.ncbi.nlm.nih.gov/32585492/. DOI: 10.1016/j.neurobiolaging.2020.05.008.
[30]
TIJMS B M, KATE M TEN, GOUW A A, et al. Gray matter networks and clinical progression in subjects with predementia Alzheimer's disease[J/OL]. Neurobiol Aging, 2018, 61: 75-81 [2026-02-10]. https://pubmed.ncbi.nlm.nih.gov/29040871/. DOI: 10.1016/j.neurobiolaging.2017.09.011.
[31]
XIAO Y Q, GAO L, HU Y B. Disrupted single-subject gray matter networks are associated with cognitive decline and cortical atrophy in Alzheimer's disease[J/OL]. Front Neurosci, 2024, 18: 1366761 [2026-02-10]. https://pubmed.ncbi.nlm.nih.gov/39165340/. DOI: 10.3389/fnins.2024.1366761.
[32]
BEHFAR Q, BEHFAR S K, VON REUTERN B, et al. Graph theory analysis reveals resting-state compensatory mechanisms in healthy aging and prodromal Alzheimer's disease[J/OL]. Front Aging Neurosci, 2020, 12: 576627 [2026-02-10]. https://pubmed.ncbi.nlm.nih.gov/33192468/. DOI: 10.3389/fnagi.2020.576627.
[33]
SKOURAS S, FALCON C, TUCHOLKA A, et al. Mechanisms of functional compensation, delineated by eigenvector centrality mapping, across the pathophysiological continuum of Alzheimer's disease[J/OL]. Neuroimage Clin, 2019, 22: 101777 [2026-02-10]. https://pubmed.ncbi.nlm.nih.gov/30913531/. DOI: 10.1016/j.nicl.2019.101777.
[34]
CHEN Q Y, ABRIGO J, DENG M, et al. Structural network topology reveals higher brain resilience in individuals with preclinical Alzheimer's disease[J]. Brain Connect, 2023, 13(9): 553-562. DOI: 10.1089/brain.2023.0013.
[35]
ZHAO C, HUANG W J, FENG F, et al. Abnormal characterization of dynamic functional connectivity in Alzheimer's disease[J]. Neural Regen Res, 2022, 17(9): 2014-2021. DOI: 10.4103/1673-5374.332161.
[36]
YU M C, SPORNS O, SAYKIN A J. The human connectome in Alzheimer disease: relationship to biomarkers and genetics[J/OL]. Nat Rev Neurol, 2021, 17: 545-563 [2026-02-10]. https://pubmed.ncbi.nlm.nih.gov/34285392/. DOI: 10.1038/s41582-021-00529-1.
[37]
MA Y X, JI J M, LI G, et al. Effects of donepezil on cognitive functions and the expression level of β-amyloid in peripheral blood of patients with Alzheimer's disease[J]. Exp Ther Med, 2018, 15(2): 1875-1878. DOI: 10.3892/etm.2017.5613.
[38]
WINBLAD B, WIMO A, ENGEDAL K, et al. 3-year study of donepezil therapy in Alzheimer's disease: effects of early and continuous therapy[J]. Dement Geriatr Cogn Disord, 2006, 21(5/6): 353-363. DOI: 10.1159/000091790.
[39]
ZULIANI G, ZUIN M, ROMAGNOLI T, et al. Acetyl-cholinesterase-inhibitors reconsidered. A narrative review of post-marketing studies on Alzheimer's disease[J/OL]. Aging Clin Exp Res, 2024, 36: 23 [2026-02-10]. https://pubmed.ncbi.nlm.nih.gov/38321321/. DOI: 10.1007/s40520-023-02675-6.
[40]
ANDREWS J S, DESAI U, KIRSON N Y, et al. Disease severity and minimal clinically important differences in clinical outcome assessments for Alzheimer's disease clinical trials[J/OL]. Alzheimers Dement Transl Res Clin Interv, 2019, 5: 354-363 [2026-02-10]. https://pubmed.ncbi.nlm.nih.gov/31417957/. DOI: 10.1016/j.trci.2019.06.005.
[41]
LIU W Y, LI Y, QIN W, et al. The impact of cholinesterase inhibitors on cognitive trajectories in mild cognitive impairment patients based on amyloid beta status[J/OL]. Alzheimers Dement, 2025, 21(5): e70193 [2026-02-10]. https://pubmed.ncbi.nlm.nih.gov/41568736/. DOI: 10.1002/alz.70193.
[42]
SHEIKH M, AMMAR M. Efficacy of 5 and 10 mg donepezil in improving cognitive function in patients with dementia: a systematic review and meta-analysis[J/OL]. Front Neurosci, 2024, 18: 1398952 [2026-02-10]. https://pubmed.ncbi.nlm.nih.gov/39104606/. DOI: 10.3389/fnins.2024.1398952.
[43]
GOVEAS J S, XIE C M, WARD B D, et al. Recovery of hippocampal network connectivity correlates with cognitive improvement in mild Alzheimer's disease patients treated with donepezil assessed by resting-state fMRI[J]. J Magn Reson Imaging, 2011, 34(4): 764-773. DOI: 10.1002/jmri.22662.
[44]
KIM S H, KANDIAH N, HSU J L, et al. Beyond symptomatic effects: potential of donepezil as a neuroprotective agent and disease modifier in Alzheimer's disease[J]. Br J Pharmacol, 2017, 174(23): 4224-4232. DOI: 10.1111/bph.14030.
[45]
YANG W Q, SHI Y L, ZHANG Y W, et al. Intranasal carrier-free nanomodulator addresses both symptomatology and etiology of Alzheimer's disease by restoring neuron plasticity and reprogramming lesion microenvironment[J]. ACS Nano, 2024, 18(43): 29779-29793. DOI: 10.1021/acsnano.4c09449.
[46]
YANG T, WEI F Q, GUO Y F, et al. The increased effective connectivity from left middle occipital gyrus to right medial septum/diagonal bands in AD patients after donepezil intervention[J/OL]. Front Aging Neurosci, 2024, 16: 1362790 [2026-02-10]. https://pubmed.ncbi.nlm.nih.gov/38659702/. DOI: 10.3389/fnagi.2024.1362790.
[47]
SOLÉ-PADULLÉS C, BARTRÉS-FAZ D, LLADÓ A, et al. Donepezil treatment stabilizes functional connectivity during resting state and brain activity during memory encoding in Alzheimer's disease[J]. J Clin Psychopharmacol, 2013, 33(2): 199-205. DOI: 10.1097/JCP.0b013e3182825bfd.
[48]
WAN Q, DENG Y Y, HAO J W, et al. Effect of repetitive transcranial magnetic stimulation combined with cholinesterase inhibitor on cognitive impairment of Alzheimer's disease and its mechanism[J]. Chin J Gerontol, 2023, 43(18): 4440-4443. DOI: 10.3969/j.issn.1005-9202.2023.18.027.
[49]
DEVITA M, MASINA F, MAPELLI D, et al. Acetylcholinesterase inhibitors and cognitive stimulation, combined and alone, in treating individuals with mild Alzheimer's disease[J]. Aging Clin Exp Res, 2021, 33(11): 3039-3045. DOI: 10.1007/s40520-021-01837-8.
[50]
LIU Y H, BU A, MA X, et al. Guidelines for drug treatment of Alzheimer's disease[J]. Chin J Alzheimers Dis Relat Disord, 2025, 8(1): 8-16. DOI: 10.3969/j.issn.2096-5516.2025.01.002.
[51]
GUO J X, WANG Z Y, LIU R S, et al. Memantine, donepezil, or combination therapy-what is the best therapy for Alzheimer's disease a network meta-analysis[J/OL]. Brain Behav, 2020, 10(11): e01831 [2026-02-10]. https://pubmed.ncbi.nlm.nih.gov/32914577/. DOI: 10.1002/brb3.1831.
[52]
GAUTHIER S, MOLINUEVO J L. Benefits of combined cholinesterase inhibitor and memantine treatment in moderate-severe Alzheimer's disease[J]. Alzheimers Dement, 2013, 9(3): 326-331. DOI: 10.1016/j.jalz.2011.11.005.
[53]
AREVALO-RODRIGUEZ I, SMAILAGIC N, ROQUÉ-FIGULS M, et al. Mini-Mental State Examination (MMSE) for the early detection of dementia in people with mild cognitive impairment (MCI)[J/OL]. Cochrane Database Syst Rev, 2021, 2021(7) [2026-02-10]. https://pubmed.ncbi.nlm.nih.gov/34313331/. DOI: 10.1002/14651858.cd010783.pub3.

PREV Advances in the application of artificial intelligence and mri in the diagnosis of triangular fibrocartilage complex injuries
NEXT Correlation between brain functional network alterations and cognitive function in patients with type 1 diabetes mellitus
  


LINK


Tel & Fax: +8610-67113815    E-mail: editor@cjmri.cn