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<p>Lewy body dementia (LBD), encompassing dementia with Lewy bodies and Parkinson’s disease dementia, is neuropathologically defined by neuronal accumulation of α-synuclein encoded by the <i>SNCA</i> gene. Genetic risk factors strongly influence LBD susceptibility, including <i>SNCA</i> multiplication, particularly triplication, and the apolipoprotein E ε4 allele (<i>APOE4</i>), the strongest common genetic risk factor for LBD. While <i>SNCA</i> is predominantly expressed in neurons and <i>APOE</i> primarily in glial cells, how these genetic factors converge to impact neuronal vulnerability and regional pathology in the human brain remains poorly understood. Here, we applied spatial transcriptomics to postmortem temporal cortex tissue from LBD cases with <i>SNCA</i> triplication or different <i>APOE</i> genotypes, alongside age- and sex-matched controls, to map gene expression within intact cortical architecture. We identified layer 5 of the gray matter as a particularly vulnerable region, characterized by elevated <i>SNCA</i> expression, pronounced synaptic and metabolic dysregulation, and exacerbation of these alterations in <i>APOE4</i> carriers. Reelin signaling emerged as a core Lewy body-associated pathway disrupted across cortical layers, validated in independent postmortem cohorts and human-induced pluripotent stem cell (iPSC)-derived cortical organoids. In contrast, white matter exhibited distinct molecular alterations, including disrupted myelination pathways, with <i>APOE4</i> carriers showing increased myelin debris and glial responses compared with non-carriers. Cell-type deconvolution informed by single-nucleus RNA sequencing further revealed <i>APOE4</i>-associated impairments in neuronal vulnerability and intercellular communication. Together, these findings define spatially and cell-type-specific mechanisms through which <i>SNCA</i> dosage and <i>APOE4</i> genotype impact LBD pathology, providing insight into regionally distinct disease processes and potential targets for genetically stratified therapeutic interventions.</p>

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Spatially resolved molecular signatures of Lewy body dementia

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年1月26日

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  • Yunjung Jin,
  • Kai Chen,
  • Alexander Q. Wixom,
  • Zonghua Li,
  • Shunsuke Koga,
  • Hiroaki Sekiya,
  • Gisela Xhafkollari,
  • Monica Castanedes-Casey,
  • Hannah Santhakumar,
  • Axel D. Meneses,
  • Abigail J. Neff,
  • Guojun Bu,
  • Michael G. Heckman,
  • Yuanhang Liu,
  • Owen A. Ross,
  • Dennis W. Dickson,
  • Na Zhao

摘要

Lewy body dementia (LBD), encompassing dementia with Lewy bodies and Parkinson’s disease dementia, is neuropathologically defined by neuronal accumulation of α-synuclein encoded by the SNCA gene. Genetic risk factors strongly influence LBD susceptibility, including SNCA multiplication, particularly triplication, and the apolipoprotein E ε4 allele (APOE4), the strongest common genetic risk factor for LBD. While SNCA is predominantly expressed in neurons and APOE primarily in glial cells, how these genetic factors converge to impact neuronal vulnerability and regional pathology in the human brain remains poorly understood. Here, we applied spatial transcriptomics to postmortem temporal cortex tissue from LBD cases with SNCA triplication or different APOE genotypes, alongside age- and sex-matched controls, to map gene expression within intact cortical architecture. We identified layer 5 of the gray matter as a particularly vulnerable region, characterized by elevated SNCA expression, pronounced synaptic and metabolic dysregulation, and exacerbation of these alterations in APOE4 carriers. Reelin signaling emerged as a core Lewy body-associated pathway disrupted across cortical layers, validated in independent postmortem cohorts and human-induced pluripotent stem cell (iPSC)-derived cortical organoids. In contrast, white matter exhibited distinct molecular alterations, including disrupted myelination pathways, with APOE4 carriers showing increased myelin debris and glial responses compared with non-carriers. Cell-type deconvolution informed by single-nucleus RNA sequencing further revealed APOE4-associated impairments in neuronal vulnerability and intercellular communication. Together, these findings define spatially and cell-type-specific mechanisms through which SNCA dosage and APOE4 genotype impact LBD pathology, providing insight into regionally distinct disease processes and potential targets for genetically stratified therapeutic interventions.