{
  "abstract": "OBJECTIVE: Tau is widely studied in neurodegeneration, yet most work has focused on canonical brain tau isoforms. A longer isoform, \"big tau,\" produced by inclusion of exon 4a, is expressed in the peripheral nervous system (PNS) and central nervous system (CNS) regions. We sought to characterize big tau composition, anatomic distribution, and disease relevance. METHODS: Mass spectrometry (MS) was used to sequence big tau and map its distribution across the human nervous system. Postmortem samples included brain tissue from Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and controls; spinal cord and peripheral nerves. Big and canonical (\"small\") tau isoforms were also quantified in cerebrospinal fluid (CSF) from controls and participants stratified by amyloid status and cognitive impairment. RESULTS: Human big tau results from insertion of either 355 or 251 amino acids encoded by exon 4a-long and exon 4a-short, respectively. Alternative splicing of exons 2, 3, and 10 generates multiple big tau isoforms. Total tau levels were approximately 1,000-fold higher in the brain than in the PNS; however, the relative abundance of big tau increased from the CNS to the PNS, comprising 50% of the total tau in the periphery and approximately 1% in the brain, primarily localized to the cerebellum. In CSF, big tau levels were unchanged by amyloid abnormalities or cognitive impairment, whereas canonical tau increased with AD pathology. INTERPRETATION: Big tau represents a distinct tau population enriched in the PNS and uncoupled from disease-associated changes in brain-derived tau, suggesting that distinguishing big tau from canonical tau may improve interpretation of tau biomarkers and help differentiate CNS neurodegeneration from peripheral nerve pathology. ANN NEUROL 2026;100:709-736.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Psychiatry Washington University School of Medicine St. Louis MO USA",
    "The Tracy Family Stable Isotope Labeling Quantitation (SILQ) Center Washington University School of Medicine St. Louis MO USA",
    "Department of Neurology Washington University School of Medicine St. Louis MO USA",
    "Departments of Pathology and Immunology Washington University School of Medicine St. Louis MO USA",
    "Charles F. and Joanne Knight Alzheimer Disease Research Center Washington University School of Medicine St. Louis MO USA",
    "Hope Center for Neurological Disorders Washington University St. Louis MO USA",
    "Departments of Genetics and Genomic Sciences Icahn School of Medicine at Mount Sinai New York NY USA",
    "Neuroscience sperimentali, IRCCS Azienda Ospedaliera Metropolitana, Policlinico San Martino Genoa Italy",
    "Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai New York NY USA",
    "Nash Family Department of Neuroscience Icahn School of Medicine at Mount Sinai New York NY USA"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 18,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Rama K. Koppisetti",
      "orcid": "0000-0002-7539-4572"
    },
    {
      "affs": [
        2,
        1
      ],
      "name": "Nicolas R. Barthélemy",
      "orcid": "0000-0003-4937-2860"
    },
    {
      "affs": [
        2,
        1
      ],
      "name": "Kanta Horie",
      "orcid": "0000-0001-7736-2614"
    },
    {
      "affs": [
        2
      ],
      "name": "Cindy V. Ly",
      "orcid": "0000-0002-7063-5170"
    },
    {
      "affs": [
        3
      ],
      "name": "Kaleigh F. Roberts",
      "orcid": "0000-0001-6483-9153"
    },
    {
      "affs": [
        3
      ],
      "name": "Srinivas Koutarapu",
      "orcid": "0000-0002-4355-6733"
    },
    {
      "affs": [
        4,
        2,
        3,
        5
      ],
      "name": "Richard J. Perrin",
      "orcid": "0000-0002-3443-7716"
    },
    {
      "affs": [
        4,
        3
      ],
      "name": "Erin E. Franklin",
      "orcid": "0000-0002-6614-4109"
    },
    {
      "affs": [
        6,
        7,
        8
      ],
      "name": "Chiara Pedicone",
      "orcid": "0000-0002-9486-1746"
    },
    {
      "affs": [
        6,
        8
      ],
      "name": "Joshua Orrick",
      "orcid": "0009-0009-4083-6172"
    },
    {
      "affs": [
        2,
        1
      ],
      "name": "Justin Melendez"
    },
    {
      "affs": [
        2,
        5
      ],
      "name": "Timothy M. Miller",
      "orcid": "0000-0002-3424-5511"
    },
    {
      "affs": [
        2,
        1
      ],
      "name": "Chihiro Sato",
      "orcid": "0000-0002-7639-8727"
    },
    {
      "affs": [
        2,
        0
      ],
      "name": "Nupur Ghoshal",
      "orcid": "0000-0002-6680-6731"
    },
    {
      "affs": [
        6,
        9,
        8
      ],
      "name": "Alison Goate",
      "orcid": "0000-0002-0576-2472"
    },
    {
      "affs": [
        4,
        0
      ],
      "name": "Celeste M M. Karch",
      "orcid": "0000-0002-6854-5547"
    },
    {
      "affs": [
        2,
        1
      ],
      "name": "Randall John Bateman",
      "orcid": "0000-0002-7729-1702"
    },
    {
      "affs": [
        2,
        1
      ],
      "name": "Soumya Mukherjee",
      "orcid": "0000-0001-5326-4008"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/cxvzfkmaq1bmn.bib",
  "cited_by": 8,
  "doi": "10.1002/ana.78300",
  "fulltext_url": null,
  "id": "cxvzfkmaq1bmn",
  "issns": [
    "0364-5134",
    "1531-8249"
  ],
  "landing_url": "https://doi.org/10.1002/ana.78300",
  "language": "en",
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
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      "openalex",
      "2804|Alzheimer's disease research and treatments"
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  "openalex": "W7169729491",
  "pdf_url": null,
  "pmcid": "PMC12458324",
  "pmid": "41000752",
  "published": "2026-07-19",
  "publisher": "Wiley",
  "ris": "https://research.draconitic.com/paper/cxvzfkmaq1bmn.ris",
  "sources": [
    {
      "first_seen": "2026-11-06T13:20:36Z",
      "native_id": "W7169729491",
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      "url": "https://doi.org/10.1002/ana.78300"
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  "subjects": [
    {
      "field": "biology",
      "origin": "openalex:2804|Alzheimer's disease research and treatments",
      "subfield": "neuroscience"
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  ],
  "title": "Distribution of Big Tau Isoforms in the Human Central and Peripheral Nervous System",
  "title_text": "Distribution of Big Tau Isoforms in the Human Central and Peripheral Nervous System",
  "type": "peer-reviewed",
  "updated_at": "2026-11-13T13:21:08Z",
  "url": "https://research.draconitic.com/paper/cxvzfkmaq1bmn",
  "venue": "Annals of Neurology",
  "versions": []
}