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

Introduction: Limbic-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.

Methods: We 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.

Results: Distinct 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.