{
  "abstract": "TAR DNA-binding protein 43 (TDP-43) pathology is a major contributor to cognitive decline in Alzheimer’s disease (AD), yet the cellular substrates and circuit-level consequences of its limbic accumulation remain poorly defined. Here, we combined multiplex immunofluorescence with 3D Artificial Intelligence (AI)-based object detection and quantitative colocalization to map phosphorylated TDP-43 (pTDP-43) across neuronal subtypes in the amygdala, hippocampal subfields, and entorhinal cortex (ERC) in human AD, AD with Lewy body disease (AD-LBD), and primary age-related tauopathy (PART). Across 15 deeply phenotyped cases, pTDP-43 showed preferential accumulation in neuromodulatory noradrenergic neurons, with more limited involvement of glutamatergic terminals and cholinergic populations. Noradrenergic neurons marked by dopamine β-hydroxylase (DβH) demonstrated extensive colocalization with pTDP-43 across regions, correlating with APOE genotype, amyloid burden, and tau staging in this cross-sectional cohort, suggesting that neuromodulatory circuits might represent a major convergence point for AD-related molecular stressors. Dopaminergic (tyrosine hydroxylase (TH)) and cholinergic (choline acetyltransferase (ChAT)) neurons showed more restricted but pathology-dependent involvement, with LBD consistently showing lower pTDP-43 burden across multiple transmitter systems. Glutamatergic vesicular glutamate transporter-1 (VGLUT1)-positive neurons and terminals exhibited minimal colocalization except in PART. Principal component (PCA) and hierarchical clustering analyses (HCA) integrating pTDP-43 colocalization with neuropathologic staging metrics (A, B, C, Thal, Braak, LBD) reliably separated PART, AD-TDP, and AD-TDP-LBD groups, with LBD emerging as a dominant modifier of cellular vulnerability. Together, these findings point out that TDP-43 pathology in AD preferentially targets neuromodulatory circuits, is strongly shaped by coexisting synucleinopathy, and provides a cell-type-resolved framework for understanding how TDP-43 contributes to limbic network dysfunction in neurodegeneration.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA",
    "Department of Radiology, Mayo Clinic, Rochester, MN 55905, USA",
    "Department of Neuropsychiatry (Neuropsychology), Mayo Clinic, Rochester, MN 55905, USA",
    "Department of Laboratory Medicine and Pathology (Neuropathology), Mayo Clinic, Rochester, MN 55905, USA",
    "Department of Neurology, Behavioral Neurology, and Movement Disorders, Mayo Clinic, College of Medicine, and Science, 200 1st Street Southwest, Rochester, MN 55905, USA"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 11,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Gokhan Uruk"
    },
    {
      "affs": [
        0
      ],
      "name": "Hossam Youssef",
      "orcid": "0009-0000-8876-8038"
    },
    {
      "affs": [
        0
      ],
      "name": "Rodolfo G. Gatto",
      "orcid": "0000-0003-2170-6662"
    },
    {
      "affs": [
        0
      ],
      "name": "Nadia Hossain",
      "orcid": "0000-0001-9202-1172"
    },
    {
      "affs": [
        0
      ],
      "name": "Jerusha Bhaskaran",
      "orcid": "0009-0008-4509-5425"
    },
    {
      "affs": [
        1
      ],
      "name": "Yuqi Tian"
    },
    {
      "affs": [
        2
      ],
      "name": "Mary M. Machulda",
      "orcid": "0000-0003-4834-5967"
    },
    {
      "affs": [
        0
      ],
      "name": "Ronald C. Petersen"
    },
    {
      "affs": [
        1
      ],
      "name": "Jennifer L. Whitwell",
      "orcid": "0000-0001-6914-1563"
    },
    {
      "affs": [
        3
      ],
      "name": "Robert Ross Reichard"
    },
    {
      "affs": [
        0,
        4
      ],
      "name": "Keith A. Josephs",
      "orcid": "0000-0003-2930-8634"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/7sxemgrmwgzq6.bib",
  "cited_by": 0,
  "doi": "10.3390/cells15201850",
  "fulltext_url": "https://europepmc.org/articles/PMC13703715",
  "id": "7sxemgrmwgzq6",
  "issns": [
    "2073-4409"
  ],
  "landing_url": "https://www.mdpi.com/2073-4409/15/20/1850",
  "language": "eng",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2737|Alzheimer's disease research and treatments"
    ]
  ],
  "openalex": "W7221510456",
  "pdf_url": "https://europepmc.org/articles/PMC13703715?pdf=render",
  "pmcid": "PMC13703715",
  "pmid": "42929824",
  "published": "2026-10-12",
  "publisher": "MDPI AG",
  "ris": "https://research.draconitic.com/paper/7sxemgrmwgzq6.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:19:02Z",
      "native_id": "10.3390/cells15201850",
      "source": "crossref",
      "url": "https://www.mdpi.com/2073-4409/15/20/1850"
    },
    {
      "first_seen": "2026-10-30T12:22:01Z",
      "native_id": "MED:42929824",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42929824"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2737|Alzheimer's disease research and treatments",
      "subfield": "physiology"
    }
  ],
  "title": "TDP-43 Coincides with Noradrenergic Neurons in Alzheimer’s Disease (AD) and Primary Age-Related Tauopathy (PART)",
  "title_text": "TDP-43 Coincides with Noradrenergic Neurons in Alzheimer’s Disease (AD) and Primary Age-Related Tauopathy (PART)",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:22:01Z",
  "url": "https://research.draconitic.com/paper/7sxemgrmwgzq6",
  "venue": "Cells",
  "versions": []
}