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• Clinical Article •
Identification of brain structural alterations and key molecular pathways in Alzheimer's disease using voxel-based morphometry and the Allen Human Brain Atlas
FAN Lihua  WEI Wei  TIAN Xin  CHEN Yuanyuan  YANG Yichao  WANG Yuan  ZHOU Feng  ZHENG Yunsong 

Cite this article as: FAN L H, WEI W, TIAN X, et al. Identification of brain structural alterations and key molecular pathways in Alzheimer's disease using voxel-based morphometry and the Allen Human Brain Atlas[J]. Chin J Magn Reson Imaging, 2026, 17(10): 11-20. DOI:10.12015/issn.1674-8034.2026.10.002.


[Abstract] Objective To investigate the alteration patterns of gray matter volume (GMV) in patients with Alzheimer's disease (AD) using voxel-based morphometry (VBM), and to identify key genes and biological pathways associated with these structural brain changes.Materials and Methods A total of 63 subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database were enrolled and divided into an Alzheimer's disease (AD) group (n = 32) and a healthy control (HC) group (n = 31). The whole brain GMV of the two groups of subjects was calculated by the VBM method, and a stepwise double-correction strategy was adopted. First, perform multiple comparison correction of the voxel level family wise error (FWE) (P < 0.05 after correction) to initially screen the differential voxels, and then set the minimum mass threshold k > 100 voxels. Then, a secondary correction of the false discovery rate (FDR) at the cluster-level was carried out on the continuous voxel clusters obtained through the initial screening. Only the continuous voxel clusters that simultaneously meet the conditions of significant voxel FWE and significant cluster-FDR are defined as brain regions with statistically significant GMV differences. GMV values from identified brain regions were extracted using CAT12 software, and t-values for inter-group differences were obtained via independent samples t-tests. These t-values were then correlated with the Allen Human Brain Atlas using partial least squares (PLS) regression analysis. A total of 15 633 genes were ranked based on their PLS weights. The top 500 positively weighted and top 500 negatively weighted genes were selected for subsequent gene enrichment analysis (FDR correction, P < 0.05), and the top 20 pathways with the highest enrichment significance were further analyzed.Results The AD group exhibited smaller total GMV compared to the HC group (t = 2.405, P < 0.05). Specifically, GMV was reduced in the bilateral hippocampi, right inferior temporal gyrus, and right middle temporal gyrus in the AD group compared to the HC group (peak t value = 5.415 to 8.222, P < 0.05). The first PLS component (PLS1) accounted for 37% of the image-gene association variations and showed positive correlation with the t-values of GMV differences between the two groups (r = 0.61, P = 0.03). The top 20 positively weighted genes from PLS1 were enriched in pathways related to synaptic transmission, neurodevelopment, and neuronal projection. Conversely, the top 20 negatively weighted genes were enriched in pathways related to immune inflammation, Rho GTPase signaling, endocytosis, and apoptosis. The two types of weighting genes were respectively enriched in the biological pathways related to neural structure maintenance and neurodegenerative injury.Conclusions The characteristic gray matter atrophy in AD is closely associated with pathways governing synaptic function, neurodevelopment, immune regulation, and cell death. This integrative approach provides insights into the imaging-genetics mechanisms underlying AD, offering candidate evidence for mechanistic research.
[Keywords] Alzheimer's disease；gray matter volume；magnetic resonance imaging；voxel-based morphometry；partial least squares analysis；Allen Human Brain Atlas；gene enrichment；imaging-transcriptomics

FAN Lihua1   WEI Wei1   TIAN Xin1   CHEN Yuanyuan1   YANG Yichao1   WANG Yuan2   ZHOU Feng3*   ZHENG Yunsong1, 4*  

1 Department of Medical Imaging, Affiliated Hospital of Shaanxi University of Traditional Chinese Medicine, Xianyang 712000, China

2 School of Acupuncture-Moxibustion and Tuina, Shaanxi University of Traditional Chinese Medicine, Xianyang 712046, China

3 Department of Scientific Research, Affiliated Hospital of Shaanxi University of Traditional Chinese Medicine, Xianyang 712000, China

4 School of Medical Technology, Shaanxi University of Traditional Chinese Medicine, Xianyang 712046, China

Corresponding author: ZHOU F, E-mail: 362811715@qq.com ZHENG Y S, E-mail: 576753017@qq.com

Conflicts of interest   None.

Received  2026-05-18
Accepted  2026-09-18
DOI: 10.12015/issn.1674-8034.2026.10.002
Cite this article as: FAN L H, WEI W, TIAN X, et al. Identification of brain structural alterations and key molecular pathways in Alzheimer's disease using voxel-based morphometry and the Allen Human Brain Atlas[J]. Chin J Magn Reson Imaging, 2026, 17(10): 11-20. DOI:10.12015/issn.1674-8034.2026.10.002.

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