Transcriptomic analysis to identify genes associated with selective hippocampal vulnerability in Alzheimer's disease

Selective vulnerability of different brain regions is seen in many neurodegenerative disorders. The hippocampus and cortex are selectively vulnerable in Alzheimer's disease (AD), however the degree of involvement of the different brain regions differs among patients. We classified corticolimbic patterns of neurofibrillary tangles in postmortem tissue to capture extreme and representative phenotypes. We combined bulk RNA sequencing with digital pathology to examine hippocampal vulnerability in AD. We identified hippocampal gene expression changes associated with hippocampal vulnerability and used machine learning to identify genes that were associated with AD neuropathology, including SERPINA5, RYBP, SLC38A2, FEM1B, and PYDC1. Further histologic and biochemical analyses suggested SERPINA5 expression is associated with tau expression in the brain. Our study highlights the importance of embracing heterogeneity of the human brain in disease to identify disease-relevant gene expression.

Automated summary

Selective vulnerability of different brain regions is observed in many neurodegenerative disorders, with the hippocampus and cortex being particularly affected in Alzheimer's disease (AD). By studying postmortem tissue, researchers were able to identify gene expression changes associated with hippocampal vulnerability in AD, as well as genes related to AD neuropathology through machine learning. Further analysis suggested a relationship between SERPINA5 expression and tau expression in the brain.