An immune response characterizes early Alzheimer’s disease pathology and subjective cognitive impairment in hydrocephalus biopsies

Wenrui Huang, Anne Marie Bartosch, Harrison Xiao, Suvrajit Maji, Elliot H.H. Youth, Xena Flowers, Sandra Leskinen, Zeljko Tomljanovic, Gail Iodice, Deborah Boyett, Eleonora Spinazzi, Vilas Menon, Robert A. McGovern, Guy M. McKhann, Andrew F. Teich

Research output: Contribution to journalArticlepeer-review

Abstract

Early Alzheimer’s disease (AD) pathology can be found in cortical biopsies taken during shunt placement for Normal Pressure Hydrocephalus. This represents an opportunity to study early AD pathology in living patients. Here we report RNA-seq data on 106 cortical biopsies from this patient population. A restricted set of genes correlate with AD pathology in these biopsies, and co-expression network analysis demonstrates an evolution from microglial homeostasis to a disease-associated microglial phenotype in conjunction with increasing AD pathologic burden, along with a subset of additional astrocytic and neuronal genes that accompany these changes. Further analysis demonstrates that these correlations are driven by patients that report mild cognitive symptoms, despite similar levels of biopsy β-amyloid and tau pathology in comparison to patients who report no cognitive symptoms. Taken together, these findings highlight a restricted set of microglial and non-microglial genes that correlate with early AD pathology in the setting of subjective cognitive decline.

Original languageEnglish (US)
Article number5659
JournalNature communications
Volume12
Issue number1
DOIs
StatePublished - Dec 2021

Bibliographical note

Funding Information:
This work was supported by NIH grants K08-AG049938 (to A.F.T.) and K76-AG054868 (to A.F.T.) and with support from the Thompson Family Foundation. We would also like to acknowledge Richard Hickman for assistance with developing the tau grading system.

Publisher Copyright:
© 2021, The Author(s).

Keywords

  • Age of Onset
  • Aged
  • Aged, 80 and over
  • Alzheimer Disease/complications
  • Astrocytes/immunology
  • Biopsy
  • Cerebral Cortex/cytology
  • Cognitive Dysfunction/diagnosis
  • Female
  • Gene Regulatory Networks/immunology
  • Humans
  • Hydrocephalus, Normal Pressure/genetics
  • Male
  • Microglia/immunology
  • Neuropsychological Tests
  • RNA-Seq
  • Retrospective Studies

PubMed: MeSH publication types

  • Research Support, Non-U.S. Gov't
  • Journal Article
  • Research Support, N.I.H., Extramural

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