Spatially resolved molecular signatures of Lewy body dementia

TL;DR

This study uses spatial transcriptomics to uncover how genetic factors like SNCA triplication and APOE4 influence brain regions and cell types in Lewy body dementia.

Contribution

The study reveals spatially and cell-type-specific mechanisms of LBD pathology linked to SNCA and APOE4.

Findings

Layer 5 of the gray matter shows elevated SNCA expression and synaptic/metabolic dysregulation in LBD.

APOE4 carriers exhibit worsened alterations and increased myelin debris in white matter.

Reelin signaling is a core disrupted pathway in LBD, validated in multiple models.

Abstract

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.

The online version contains supplementary material available at 10.1007/s00401-026-02981-z.

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