{
  "abstract": "Microglia are central mediators of Alzheimers disease (AD) pathogenesis, yet the mechanisms driving disease-associated microglial states and their therapeutic modulation remain poorly understood. Here, we integrated single-nucleus transcriptomic datasets across the AD spectrum and identified disease- and lipid-associated microglia (DLaM) as a major AD-enriched population linked to genetic risk, neuropathology and cognitive decline. To model this state experimentally, we screened AD-relevant perturbations in human induced pluripotent stem cell (hiPSC)-derived microglia and found that ferric ammonium citrate (FAC) reproducibly induced a DLaM-like state characterized by lipid accumulation, lysosomal dysfunction and impaired A{beta} phagocytosis. Using a transcriptomics-based state-reversion screen, we identified LY2090314 as a potent modulator that restored microglial function and induced a distinct lysosomal-metabolic state. These findings establish a framework for transcriptomic disease-state-guided therapeutic discovery in AD.",
  "abstract_shown": true,
  "affiliations": [
    "Evotec SE"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 17,
  "authors": [
    {
      "name": "G. Garcia-Diaz Barriga"
    },
    {
      "name": "D. Rosebrock"
    },
    {
      "name": "H. Renner"
    },
    {
      "name": "I. Meyer"
    },
    {
      "name": "G. Penalosa-Ruiz"
    },
    {
      "name": "M. M. Firulyova"
    },
    {
      "name": "M. Simon"
    },
    {
      "name": "T. Yang"
    },
    {
      "name": "G. M. Serratto"
    },
    {
      "name": "F. Zoppetti"
    },
    {
      "name": "W. Müller"
    },
    {
      "name": "A. Illarionova"
    },
    {
      "name": "K. Heise"
    },
    {
      "name": "R. Kuhn"
    },
    {
      "name": "H. von der Kammer"
    },
    {
      "name": "B. Zimmer"
    },
    {
      "affs": [
        0
      ],
      "name": "D. Gruber-Schoffnegger"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/6tswgk58krc20.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.08.26.747247",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.08.26.747247v1.full",
  "id": "6tswgk58krc20",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.08.26.747247v1",
  "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",
      "2808|Neuroinflammation and Neurodegeneration Mechanisms"
    ]
  ],
  "openalex": "W7204666668",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.08.26.747247v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-08-26",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/6tswgk58krc20.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:43Z",
      "native_id": "10.64898/2026.08.26.747247",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.08.26.747247v1"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "biorxiv:neuroscience",
      "subfield": "neuroscience"
    }
  ],
  "title": "Characterization and pharmacological modulation of Alzheimers disease-associated human microglial states",
  "title_text": "Characterization and pharmacological modulation of Alzheimers disease-associated human microglial states",
  "type": "preprint",
  "updated_at": "2026-10-30T12:17:43Z",
  "url": "https://research.draconitic.com/paper/6tswgk58krc20",
  "venue": "bioRxiv",
  "versions": []
}