{
  "abstract": "Oligodendrocyte (OL) dysfunction and white-matter (WM) vulnerability are increasingly recognized as important aspects of aging and Alzheimer's Disease (AD), yet human WM-focused, cellular-resolution transcriptomic data remain limited. Here, we profiled prefrontal WM from 48 brain donors spanning young adulthood and late-life with low versus high AD Neuropathologic Change (ADNC) using single-nucleus RNA sequencing followed by spatial transcriptomics (CosMx) in a subset of matched donors. We integrated aged WM OLs with a reference dorsolateral prefrontal cortex grey-matter (GM) OL dataset (SEA-AD) to define region- and pathology-associated OL programs. Across modalities, GM OLs exhibited a robust synapse/neurotransmitter-associated transcriptional signature relative to WM OLs, whereas this program was reduced with aging and attenuated in high ADNC GM. In contrast, WM OLs showed stronger immune-associated programs with aging and further enhancement in high ADNC, including cytokine/chemokine signaling and antigen presentation-related pathways. High ADNC WM OLs also displayed amplified proteostasis and stress-adaptation signatures, including selective upregulation of chaperone/heat shock genes and ferritin subunits, consistent with increased protein-folding demand and altered iron handling. To resolve OL state organization beyond static differential expression, we annotated OL sub-states using marker panels and inferred pseudotime-guided directional state-to-state flows within each tissue/condition stratum. This analysis identified a conserved newly formed differentiating (NFOL)/differentiating [->] lipid remodeling (APOE/ABCA1/LPL+) [->] Stress/ISR-reactive architecture, with a pronounced expansion of the Stress/ISR-reactive compartment and altered transition-associated pathway enrichment in high ADNC WM. Together, these data define WM-specific OL programs linked to aging and ADNC and nominate a stress/immune-enriched OL state landscape consistent with a putative senescence-like phenotype in diseased WM.",
  "abstract_shown": true,
  "affiliations": [
    "University of California San Diego Department of Pathology, University of Washington Department of Laboratory Medicine and Pathology"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 17,
  "authors": [
    {
      "name": "J. P. Voth"
    },
    {
      "name": "J. A. Ramos Benitez"
    },
    {
      "name": "A. M. Wilson"
    },
    {
      "name": "S. R. Kennedy"
    },
    {
      "name": "M. Damodarasamy"
    },
    {
      "name": "A. Kirkland"
    },
    {
      "name": "J. A. Miller"
    },
    {
      "name": "C. S. Latimer"
    },
    {
      "name": "E. Ragaglia"
    },
    {
      "name": "A. Nolan"
    },
    {
      "name": "D. D. Child"
    },
    {
      "affs": [
        0
      ],
      "name": "L. Keene"
    },
    {
      "name": "C. L. Reichel"
    },
    {
      "name": "B. F. Kohrn"
    },
    {
      "name": "L. S. Sherman"
    },
    {
      "name": "S. A. Back"
    },
    {
      "affs": [
        0
      ],
      "name": "C. D. Keene"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/1zv4t6fhmfczy.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.08.29.747923",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.08.29.747923v1.full",
  "id": "1zv4t6fhmfczy",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.08.29.747923v1",
  "language": null,
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "neuroscience"
    ],
    [
      "openalex",
      "1312|Single-cell and spatial transcriptomics"
    ]
  ],
  "openalex": "W7207699828",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.08.29.747923v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-08-29",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/1zv4t6fhmfczy.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:18:46Z",
      "native_id": "10.64898/2026.08.29.747923",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.08.29.747923v1"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "biorxiv:neuroscience",
      "subfield": "neuroscience"
    }
  ],
  "title": "Single nucleus RNA sequencing and spatial transcriptomics reveal unique functionalities of gray matter versus white matter oligodendrocytes in aging and Alzheimer's Disease",
  "title_text": "Single nucleus RNA sequencing and spatial transcriptomics reveal unique functionalities of gray matter versus white matter oligodendrocytes in aging and Alzheimer's Disease",
  "type": "preprint",
  "updated_at": "2026-10-30T12:18:46Z",
  "url": "https://research.draconitic.com/paper/1zv4t6fhmfczy",
  "venue": "bioRxiv",
  "versions": []
}