Summary
A bioRxiv preprint presents a 658,059-cell reference atlas of human hippocampus development and uses it to study brain organoids carrying the familial Alzheimer’s disease-associated PSEN1 E280A variant. The organoids showed altered cell composition, gene expression and inferred neuronal maturation.
Researchers have assembled a single-cell reference of the developing human hippocampus and used it to examine brain organoids carrying a familial Alzheimer’s disease-associated mutation. The bioRxiv preprint, posted on September 20, 2026, reports differences in cell composition, gene activity and inferred maturation in organoids carrying the PSEN1 E280A variant.
The resource, named the Human Developing Hippocampus Atlas (HuDeHA), integrates data from 658,059 cells spanning post-conceptional week 3 to 15.3 years. Its purpose is to provide a continuous developmental reference for interpreting induced pluripotent stem cell (iPSC)-derived brain organoids, which are laboratory-grown three-dimensional cell models used to study aspects of human brain development.
A continuous reference for hippocampus development
Single-cell RNA sequencing measures gene activity in individual cells, allowing researchers to distinguish cell types and developmental states within a tissue. By combining such data across developmental stages, an atlas can show how cell populations emerge, change and mature over time.
The hippocampus is one of the brain regions affected early and severely in Alzheimer’s disease. Familial Alzheimer’s disease is an early-onset form caused by autosomal-dominant variants in genes including APP, PSEN1 and PSEN2. PSEN1 accounts for most genetically defined familial cases, according to the preprint.
Previous single-cell studies of the human hippocampus covered either prenatal or postnatal stages. HuDeHA is intended to connect those stages in one reference. That makes it possible to compare organoid cells with human developmental states rather than evaluating an organoid only against the protocol used to produce it.
Developmental changes in PSEN1 E280A organoids
The researchers mapped cells from iPSC-derived brain organoids carrying PSEN1 E280A against the atlas. The variant is associated with familial Alzheimer’s disease in a large Colombian population.
The reference-based analysis found fewer radial glia and more neural crest-derived neurons in the PSEN1 E280A organoids. Radial glia are neural progenitor cells that generate and organise other neural cell populations during development, so changes in their abundance can alter the cellular composition of a developing neural model.
The researchers also identified transcriptional changes across cell lineages. The ventral patterning factor MEIS2 was broadly upregulated, while expression of transthyretin, or TTR, was reduced in choroid-plexus and ependymal-associated populations. These populations are relevant to specialised structures that support the developing brain and its fluid environment.
Reconstructed neuronal-lineage trajectories showed a shift towards more mature states in the PSEN1 E280A organoids. Such trajectories are computational reconstructions of likely developmental relationships among cells rather than direct observations of the same cells maturing over time.
Together, the findings establish HuDeHA as a developmental benchmarking resource and identify cell-lineage-specific changes in a familial Alzheimer’s disease organoid model. The atlas may help researchers separate differences caused by an organoid’s developmental state or cellular composition from changes associated with a disease-linked mutation.
The work is a preprint and uses iPSC-derived organoids, whose regional identity, maturation and cell-type composition can vary between protocols. The authors also disclose that Joseph Arboleda-Velasquez is a co-inventor on issued patents related to Alzheimer’s therapeutics and a co-founder of Epoch Biotech.