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

Angela M. Crist, Kelly M. Hinkle, Xue Wang, Christina M. Moloney, Billie J. Matchett, Sydney A. Labuzan, Isabelle Frankenhauser, Nkem O. Azu, Amanda M. Liesinger, Elizabeth R. Lesser, Daniel J. Serie, Zachary S. Quicksall, Tulsi A. Patel, Troy P. Carnwath, Michael DeTure, Xiaojia Tang, Ronald C. Petersen, Ranjan Duara, Neill R. Graff-Radford, Mariet AllenMinerva M. Carrasquillo, Hu Li, Owen A. Ross, Nilüfer Ertekin-Taner, Dennis W. Dickson, Yan W. Asmann, Rickey E. Carter, Melissa E. Murray

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Article number2311
JournalNature communications
Volume12
Issue number1
DOIs
StatePublished - Dec 2021

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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