Integrative Transcriptomic Analyses of Hippocampal–Entorhinal System Subfields Identify Key Regulators in Alzheimer's Disease

The hippocampal–entorhinal system supports cognitive function and is selectively vulnerable to Alzheimer's disease (AD). Little is known about global transcriptomic changes in the hippocampal–entorhinal subfields during AD. Herein, large‐scale transcriptomic analysis is performed in five hippocampal–entorhinal subfields of postmortem brain tissues (262 unique samples). Differentially expressed genes are assessed across subfields and disease states, and integrated genotype data from an AD genome‐wide association study. An integrative gene network analysis of bulk and single‐nucleus RNA sequencing (snRNA‐Seq) data identifies genes with causative roles in AD progression. Using a system‐biology approach, pathology‐specific expression patterns for cell types are demonstrated, notably upregulation of the A1‐reactive astrocyte signature in the entorhinal cortex (EC) during AD. SnRNA‐Seq data show that PSAP signaling is involved in alterations of cell– communications in the EC during AD. Further experiments validate the key role of PSAP in inducing astrogliosis and an A1‐like reactive astrocyte phenotype. In summary, this study reveals subfield‐, cell type‐, and AD pathology‐specific changes and demonstrates PSAP as a potential therapeutic target in AD.