{
  "abstract": "The human extracellular-matrix-related FREM3 gene is strongly age-dependent, enriched in age-sensitive excitatory long-range-projecting neurons, and implicated in neurodegenerative diseases. To establish the first translationally relevant causal evidence for the role of FREM3 in brain structure and cognition, we developed an excitatory-neuron-specific Frem3 conditional knockout mouse model (Frem3-cKO) and computed genetically regulated expression of FREM3 (FREM3-GReX) in humans, enabling convergent neurostructural and cognitive characterizations. Frem3-cKO mice showed widespread lower global and regional brain volume in middle age vs young adulthood, consistent with drastic age-dependent volume loss absent in wildtype mice. These effects were strongest in cognitively relevant cortical regions and paralleled by lower cognitive performance. In humans, lower FREM3-GReX was associated with lower total surface area, which further mediated an indirect link to lower cognitive performance across multiple age-sensitive domains. We provide the first translationally relevant cross-species evidence supporting a key role for FREM3/Frem3 in maintaining brain and cognitive health across aging.",
  "abstract_shown": true,
  "affiliations": [
    "Centre for Addiction and Mental Health"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 15,
  "authors": [
    {
      "name": "K. P. Clifford"
    },
    {
      "name": "T. D. Prevot"
    },
    {
      "name": "A. Sumitomo"
    },
    {
      "name": "Y. Bansal"
    },
    {
      "name": "S. Das"
    },
    {
      "name": "M. Marcotte"
    },
    {
      "name": "R. Zhou"
    },
    {
      "name": "J. Yeung"
    },
    {
      "name": "M. Ding"
    },
    {
      "name": "D. Felsky"
    },
    {
      "name": "B. Nieman"
    },
    {
      "name": "M. Banasr"
    },
    {
      "name": "E. Sibille"
    },
    {
      "name": "T. Tomoda"
    },
    {
      "affs": [
        0
      ],
      "name": "Y. Nikolova"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/4qj6t3z5xzpdq.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.10.27.762265",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.10.27.762265v1.full",
  "id": "4qj6t3z5xzpdq",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.10.27.762265v1",
  "language": null,
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "neuroscience"
    ],
    [
      "openalex",
      "1302|Genetics, Aging, and Longevity in Model Organisms"
    ]
  ],
  "openalex": "W7224102596",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.10.27.762265v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-27",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/4qj6t3z5xzpdq.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:30:02Z",
      "native_id": "10.64898/2026.10.27.762265",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.10.27.762265v1"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "biorxiv:neuroscience",
      "subfield": "neuroscience"
    }
  ],
  "title": "The Aging Brain Matrix: Cross-Species Evidence Linking FREM3 to Brain and Cognitive Aging",
  "title_text": "The Aging Brain Matrix: Cross-Species Evidence Linking FREM3 to Brain and Cognitive Aging",
  "type": "preprint",
  "updated_at": "2026-10-30T12:30:02Z",
  "url": "https://research.draconitic.com/paper/4qj6t3z5xzpdq",
  "venue": "bioRxiv",
  "versions": []
}