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Publications

Journal Article Epublish

PubMed: 42744775 DOI: 10.1038/s41398-026-04292-z

Regional juxtacortical microstructural changes and gene expression provide insights into neurodegeneration in Alzheimer's disease.

Transl Psychiatry 16(1)

Authors: Junfang Zhang, Lipeng Sun, Xinyuan Yang, Lin Kang, Yingting Zheng, Qi Huang, Wei Xu, Yihui Guan, Jun Liu, Yulei Deng, Fang Xie, Xiaomeng Xu, Binyin Li

Affiliations

  • Department of Neurology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. Department of Neurology & Institute of Neurology, Ruijin Hospital affiliated with Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • Department of Neurology & Institute of Neurology, Ruijin Hospital affiliated with Shanghai Jiao Tong University School of Medicine, Shanghai, China. Clinical Neuroscience Center, Ruijin Hospital LuWan Branch, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • Department of Neurology & Institute of Neurology, Ruijin Hospital affiliated with Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • Department of Nuclear Medicine & PET Center, Huashan Hospital, Fudan University, Shanghai, China.
  • Department of Neurology & Institute of Neurology, Ruijin Hospital affiliated with Shanghai Jiao Tong University School of Medicine, Shanghai, China. Clinical Neuroscience Center, Ruijin Hospital LuWan Branch, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • Neurology, Taicang Loujiang New City Hospital (Ruijin Hospital, Taicang), Taicang, China, Shanghai, China.

Abstract

White matter microstructural changes play a crucial role in cognitive decline in aging and neurodegenerative disorders including Alzheimer's disease (AD). However, the processes underlying white matter microstructural changes and the molecular pathways leading to these changes in AD remain largely unknown. AD involves cortical and juxtacortical microstructural changes, with free water fraction (FWF) as a potential imaging marker. We measured FWF using diffusion magnetic resonance imaging in 68 juxtacortical regions of 153 cognitively normal controls and 194 patients with AD as evidenced by elevated amyloid PET. We estimated the expression of 15,633 genes in the same regions using transcriptomic data from the Allen Human Brain Atlas. The biological processes and cell types associated with the linked genes were evaluated. Mediation analysis was used to examine whether FWF mediates the association between APOE ε4 status and cognitive performance. Gene ontological analyses revealed that these genes were enriched for biological processes relating to lipid metabolic process, ensheathment of neurons, and synaptic signaling and were predominantly expressed in oligodendrocytes, GABAergic neurons, and pyramidal neurons from the hippocampus CA region. These ontological enrichment results were replicated in two additional datasets. Furthermore, mediation analyses revealed a domain-specific role of FWF in the association between APOE ε4 status and cognitive performance. Our findings provide mechanistic insights into regional juxtacortical microstructural changes in AD, particularly the processes involving lipid metabolism, offering potential therapeutic targets.

MeSH

Genes, Neurons, Alzheimer Disease, Aging, Mediation Analysis, Psychiatry, Gene Expression