A lifespan single-cell atlas of the human developing hippocampus benchmarks familial Alzheimer's disease brain organoids.

Familial Alzheimer's disease (fAD) is an early-onset form of Alzheimer's disease caused by autosomal-dominant variants in APP, PSEN1, or PSEN2, with PSEN1 accounting for most genetically defined cases. The hippocampus is one of the earliest and most severely affected brain regions in AD, and human iPSC-derived brain organoids can model early brain development and how fAD mutations perturb neurodevelopmental processes. However, organoid interpretation is complicated by heterogeneous regional identity, variable maturation state, and cell-type composition across protocols, and existing single-cell studies of human hippocampus cover prenatal or postnatal stages but lack a continuous developmental reference.

To address this, the authors built the Human Developing Hippocampus Atlas (HuDeHA), an integrated single-cell RNA-sequencing reference of 658,059 cells spanning post-conceptional week 3 to 15.3 years. They used this atlas to obtain standardized information on organoid cell class and type composition and maturation states, and to benchmark iPSC-derived brain organoids carrying the PSEN1 E280A variant 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 the PSEN1 E280A organoids.

Together, these findings establish HuDeHA as a resource for developmental benchmarking of hippocampus-relevant organoid systems. They also describe cell-lineage-specific developmental changes in PSEN1 E280A organoids that may inform interpretation of early cellular alterations in fAD.