BioProject

The heterogeneous etiology of Alzheimer’s disease (AD) challenges therapeutic development. More...

The heterogeneous etiology of Alzheimer’s disease (AD) challenges therapeutic development. Understanding cell type specificity and local spatial contributions to different AD etiologies is instrumental to optimize therapeutic strategies for precision medicine. In this study, we compared cell-specific transcriptomes from the frontal cortex of carriers with the autosomal dominant mutation, PSEN1-E280A, sporadic AD and controls. Among the pathways that distinguished the autosomal dominant AD mutation disease from sporadic AD was increased autophagy and proteostasis pathways in astrocytes and oligodendrocytes in the former. Synaptic genes associated with neurofibrillary tangles in excitatory neurons were increased in both sporadic AD and mutation carriers. Spatial transcriptomics in samples from frontal cortex and CA1 hippocampus in PSEN1-E280A cases compared to non-diseased control individuals further validated the activation of chaperone-mediated autophagy genes and NFT-associated genes in E280A cases compared to controls. In conclusion, although autosomal dominant Alzheimer’s disease (ADAD) and sporadic AD share many features, the uniqueness of the cellular responses in each condition must be taken into consideration when designing clinical studies and therapeutics. Overall design: We performed comparative gene expression profiling analysis using spatial transcriptomics data obtained from two different brain regions (frontal cortex and hippocampus) of post mortem brains of two patient carriers of the autosomal dominant PSEN-1E280A mutation and one healthy older control. Less...