The authors assembled the Human Developing Hippocampus Atlas (HuDeHA), an integrated single-cell RNA-sequencing reference composed of 658,059 cells. The reference spans a continuous developmental window from post-conceptional week 3 to 15.3 years. By elevating an atlas-type approach, the study provides standardized information on cell-class and cell-type composition as well as maturation states across hippocampal development.
Familial Alzheimer’s disease (fAD) is an early-onset form of Alzheimer disease caused by autosomal-dominant variants in APP, PSEN1, or PSEN2, with PSEN1 accounting for most genetically defined cases. The hippocampus is among the earliest and most severely affected brain regions in AD, motivating construction of a developmental hippocampal reference relevant to disease modeling.
Human induced pluripotent stem cell (iPSC)-derived brain organoids recapitulate many features of early human brain development and are a tractable model for studying how fAD mutations perturb neurodevelopment. Interpretation of organoid experiments is complicated by heterogeneous regional identity, variable maturation, and differing cell-type composition across protocols. A continuous, single-cell developmental reference aims to reduce ambiguity when assigning cell identity and maturation state to organoid-derived cells.
HuDeHA integrates single-cell transcriptional data covering a lifespan window from early post-conception to adolescence. The atlas comprises 658,059 cells sampled from developmental stages ranging from post-conceptional week 3 through 15.3 years, enabling mapping of prenatal and postnatal trajectories within a single reference framework.
Using reference-based mapping, the authors benchmarked iPSC-derived brain organoids that carry the pathogenic PSEN1 E280A variant, a mutation associated with familial Alzheimer’s disease in a large Colombian population. Mapping revealed altered cellular composition in PSEN1 E280A organoids compared with the HuDeHA reference. Notable changes included a reduction in radial glia populations and an increase in neural crest–derived neurons. These composition differences indicate lineage-specific perturbations in organoid models bearing the PSEN1 E280A mutation.
Beyond changes in cell-type proportions, PSEN1 E280A organoids displayed cross-lineage transcriptional alterations. The study reports a broad upregulation of the ventral patterning factor MEIS2 across affected populations. Additionally, there was reduced expression of the αβ-binding protein transthyretin (TTR) in choroid-plexus and ependymal-associated populations. These transcriptional shifts suggest that the PSEN1 E280A variant affects both patterning-related programs and secreted/transport proteins in specific non-neuronal lineages.
Reconstruction of neuronal-lineage trajectories showed a shift toward more mature states in PSEN1 E280A organoids relative to the developmental reference. This trajectory-level change indicates an altered maturation dynamic within the neuronal lineage that may reflect accelerated or dysregulated differentiation associated with the fAD-associated mutation.
HuDeHA serves as a resource for developmental benchmarking of hippocampus-relevant organoid systems by providing a continuous reference for cell classes, types, and maturation states. Application of this atlas to PSEN1 E280A organoids identified lineage-specific developmental changes—reduced radial glia, increased neural crest–derived neurons, upregulation of MEIS2, decreased TTR, and a shift toward mature neuronal states—that may inform interpretation of early cellular alterations in familial Alzheimer’s disease. The findings demonstrate how a lifespan single-cell reference can clarify organoid composition and transcriptional state in disease modeling.
The source reports a competing interest: one author is a coinventor on issued patents for therapeutics inspired by APOE Christchurch and is a cofounder of a company developing Alzheimer’s therapies. Funding sources were declared in the source text. The abstract does not detail experimental protocols, analytic pipelines, or additional quantitative metrics beyond those summarized above; those details are not reported in the provided source excerpt.