---
title: "Single-cell atlas of the developing human hippocampus benchmarks PSEN1 E280A familial Alzheimer’s"
id: "biorxiv-21-a-lifespan-single-cell-atlas-of-the-human-developing-hippocampus-benchmarks"
canonical_url: "https://medichelpline.com/clinical-feed/biorxiv-21-a-lifespan-single-cell-atlas-of-the-human-developing-hippocampus-benchmarks"
content_type: "clinical_feed_article"
specialty: "Neurology"
source_name: "bioRxiv (Biomedical Preprints)"
source_url: "https://www.biorxiv.org/content/10.64898/2026.09.18.752796v1?rss=1"
published_at: "2026-09-20T12:00:00.000Z"
evidence_level: "Verified Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Single-cell atlas of the developing human hippocampus benchmarks PSEN1 E280A familial Alzheimer’s
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/biorxiv-21-a-lifespan-single-cell-atlas-of-the-human-developing-hippocampus-benchmarks
- **Specialty:** [Neurology](https://medichelpline.com/clinical-feed/neurology.md)
- **Primary Source:** bioRxiv (Biomedical Preprints)
- **Source URL:** [Original Journal Publication](https://www.biorxiv.org/content/10.64898/2026.09.18.752796v1?rss=1)
- **Published At:** 2026-09-20T12:00:00.000Z
- **Evidence Rating:** Verified Feed
## Executive GIST (TL;DR)
- The study created the Human Developing Hippocampus Atlas (**HuDeHA**), an integrated single-cell RNA-sequencing reference consisting of **658,059 cells** spanning from post-conceptional week 3 to 15.3 years, to provide a continuous developmental map of the human hippocampus. - HuDeHA is intended to standardize interpretation of iPSC-derived brain organoids by providing reference cell-class, cell-type composition, and maturation-state information across hippocampus development. - Familial Alzheimer’s disease (fAD) is caused by autosomal-dominant variants in **APP**, **PSEN1**, or **PSEN2**, with **PSEN1** accounting for most genetically defined cases; the hippocampus is an early and severely affected region in Alzheimer disease. - The authors benchmarked iPSC-derived brain organoids carrying the **PSEN1 E280A** mutation (a pathogenic variant associated with fAD) against HuDeHA to evaluate developmental and cell composition differences. - Reference-based mapping of PSEN1 E280A organoids revealed altered cellular composition: **reduced radial glia** populations and **increased neural crest–derived neurons** compared with the developmental hippocampal reference. - PSEN1 E280A organoids showed cross-lineage transcriptional changes, including broad upregulation of the ventral patterning factor **MEIS2** and decreased expression of the αβ-binding protein **transthyretin (TTR)** in choroid-plexus and ependymal-associated populations. - Reconstructed neuronal-lineage trajectories indicated a shift toward more mature neuronal states in PSEN1 E280A organoids relative to the developmental reference. - The study positions HuDeHA as a resource for developmental benchmarking of hippocampus-relevant organoid systems and highlights lineage-specific developmental perturbations in PSEN1 E280A organoids that may inform interpretation of early cellular alterations in fAD. - Competing interests reported: one author is coinventor on patents and cofounder of a biotech company working on Alzheimer’s therapies. Funding sources were declared but specific experimental protocols and additional quantitative metrics beyond those reported in the abstract were not detailed in the source text.
## Clinical Analysis & Structured Key Points
A lifespan single-cell atlas of the human developing hippocampus benchmarks familial Alzheimer's disease brain organoids. | bioRxiv Skip to main content New Results A lifespan single-cell atlas of the human developing hippocampus benchmarks familial Alzheimer's disease brain organoids. Ekaterina Ivleva , Emil Kruikov , Joseph F. Arboleda-Velasquez , Petr Baranov doi: https://doi.org/10.64898/2026.09.18.752796 Ekaterina Ivleva 1 University of Pittsburgh; Find this author on Google Scholar Find this author on PubMed Search for this author on this site For correspondence: eki7{at}pitt.edu Emil Kruikov 1 University of Pittsburgh; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Joseph F. Arboleda-Velasquez 2 Schepens Eye Research Institute of Massachusetts Eye and Ear; Harvard Medical School Find this author on Google Scholar Find this author on PubMed Search for this author on this site Petr Baranov 1 University of Pittsburgh; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Abstract Info/History Metrics Supplementary material Preview PDF 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 αβ-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. Competing Interest Statement Joseph Arboleda-Velasquez is a co-inventor in issued patents for the use of APOE Christchurch-inspired therapeutics and a co-founder of Epoch Biotech, a company advancing therapies for Alzheimer's disease. Funder Information Declared Gilbert Family Foundation (PB) MGB GCTI (PB) National Institutes of Health , RM1NS132996-01 Copyright The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license . Back to top Previous Next Posted September 20, 2026. Download PDF Supplementary Material Email Thank you for your interest in spreading the word about bioRxiv. NOTE: Your email address is requested solely to identify you as the sender of this article. Your Email * Your Name * Send To * Enter multiple addresses on separate lines or separate them with commas. You are going to email the following A lifespan single-cell atlas of the human developing hippocampus benchmarks familial Alzheimer's disease brain organoids. Message Subject (Your Name) has forwarded a page to you from bioRxiv Message Body (Your Name) thought you would like to see this page from the bioRxiv website. Your Personal Message CAPTCHA This question is for testing whether or not you are a human visitor and to prevent automated spam submissions. Share A lifespan single-cell atlas of the human developing hippocampus benchmarks familial Alzheimer's disease brain organoids. Ekaterina Ivleva , Emil Kruikov , Joseph F. Arboleda-Velasquez , Petr Baranov bioRxiv 2026.09.18.752796; doi: https://doi.org/10.64898/2026.09.18.752796 Share This Article: Copy Citation Tools A lifespan single-cell atlas of the human developing hippocampus benchmarks familial Alzheimer's disease brain organoids. Ekaterina Ivleva , Emil Kruikov , Joseph F. 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