Distinct single-nucleus RNA-seq changes among non-neuronal cells in ADNC, LATE-NC, and mixed pathologies.

introductionLimbic-predominant age-related transactive response DNA binding protein 43 kDa encephalopathy neuropathological change (LATE-NC) frequently co-occurs with Alzheimer's disease neuropathologic change (ADNC), complicating classification. Cell type-specific molecular features distinguishing LATE-NC-dominant, ADNC-dominant, and mixed LATE-NC and ADNC pathology remain incompletely characterized.

methodsWe analyzed single-nucleus RNA sequencing data from the Seattle Alzheimer's Disease Brain Cell Atlas consortium, focusing on non-neuronal cells in the middle temporal gyrus (MTG). Donors were stratified into LATE-NC dominant, ADNC dominant, and mixed LATE-NC and ADNC. Differential expression and gene set enrichment analyses were performed across glial and vascular cell supertypes.

resultsDistinct transcriptional patterns differentiated pathologies. Astrocytes, microglia, and oligodendrocytes exhibited differential expression between LATE-NC- and ADNC-dominant cases. Representative genes and pathways highlighted these distinctions, with LATE-NC dominant showing enrichment in signaling and RNA regulation, ADNC dominant in mitochondrial dysfunction, and mixed pathology in translational dysregulation and lipid remodeling, suggesting a distinct biological state. DISCUSSION: Findings highlight biological heterogeneity and non-neuronal molecular features relevant to disease classification and future research. CLINICAL TRIAL REGISTRATION INFORMATION: Not applicable. This study is a secondary analysis of publicly available Seattle Alzheimer's Disease Brain Cell Atlas (SEA-AD) data.