{
  "abstract": "Familial Alzheimer's disease (fAD) is an early-onset form of AD caused by autosomal-dominant variants in APP, PSEN1, or PSEN2, with PSEN1 accounting for most genetically defined cases [1]. The hippocampus is among the earliest and most severely affected brain regions in AD [2,3]. Human induced pluripotent stem cell (iPSC)-derived brain organoids recapitulate key features of early human brain development and provide a tractable model for studying how fAD mutations perturb neurodevelopmental processes [4]. However, their interpretation is complicated by heterogeneous regional identity, variable maturation state, and cell-type composition across protocols [5,6]. Existing single-cell studies of human hippocampus cover prenatal [7] and postnatal [8-10] stages but do not provide a continuous developmental reference. By elevating the atlas approach in utilizing single-cell RNA-sequencing data, we obtain standardized information on the organoid cell class and type composition and maturation states. Here, we constructed the Human Developing Hippocampus Atlas (HuDeHA), an integrated single-cell reference comprising 658,059 cells spanning post-conceptional week 3 to 15.3 years, and used it to benchmark iPSC-derived brain organoids carrying PSEN1 E280A which is associated with fAD in a large Colombian population. Reference-based mapping revealed altered cellular composition in PSEN1 E280A organoids, including reduced radial glia and increased neural crest-derived neurons. These changes were accompanied by cross-lineage transcriptional alterations, including broad upregulation of the ventral patterning factor MEIS2 and reduced expression of the {beta}-binding protein transthyretin (TTR) in choroid-plexus and ependymal-associated populations. Reconstructed neuronal-lineage trajectories showed a shift toward mature states in PSEN1 E280A organoids. Together, these findings establish HuDeHA as a resource for developmental benchmarking of hippocampus-relevant organoid systems and describe cell-lineage-specific developmental changes in PSEN1 E280A organoids that may inform interpretation of early cellular alterations in fAD.",
  "abstract_shown": true,
  "affiliations": [
    "University of Pittsburgh"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 4,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "E. Ivleva"
    },
    {
      "name": "E. Kruikov"
    },
    {
      "name": "J. F. Arboleda-Velasquez"
    },
    {
      "name": "P. Baranov"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/7rfhhcjz13f20.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.09.18.752796",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.09.18.752796v1.full",
  "id": "7rfhhcjz13f20",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.09.18.752796v1",
  "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",
      "2737|Alzheimer's disease research and treatments"
    ]
  ],
  "openalex": "W7213752600",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.09.18.752796v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-18",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/7rfhhcjz13f20.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:23:24Z",
      "native_id": "10.64898/2026.09.18.752796",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.09.18.752796v1"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "biorxiv:neuroscience",
      "subfield": "neuroscience"
    }
  ],
  "title": "A lifespan single-cell atlas of the human developing hippocampus benchmarks familial Alzheimer's disease brain organoids.",
  "title_text": "A lifespan single-cell atlas of the human developing hippocampus benchmarks familial Alzheimer's disease brain organoids.",
  "type": "preprint",
  "updated_at": "2026-10-30T12:23:24Z",
  "url": "https://research.draconitic.com/paper/7rfhhcjz13f20",
  "venue": "bioRxiv",
  "versions": []
}