An immune response characterizes early Alzheimer\u2019s disease pathology and subjective cognitive impairment in hydrocephalus biopsies

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

doi:10.1038/s41467-021-25902-y

Anne Marie Bartosch, Gail Iodice + Show 13 more

Open Access

https://doi.org/10.1038/s41467-021-25902-y

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Journal: Nature Communications	Publication Date: Sep 27, 2021
Citations: 5	License type: open-access

Affiliation: Columbia University, University of Minnesota

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.

Highlights

Alzheimer’s disease (AD) pathology can be found in cortical biopsies taken during shunt placement for Normal Pressure Hydrocephalus
We identify a gene expression module enriched for murine disease-associated genes that positively correlates with AD pathology and a module enriched for murine homeostatic genes that negatively correlates with AD pathology, and in aggregate, this is more consistent with the existing mouse literature than other publicly available AD autopsy datasets[1,2,4,19,21,22]
In this study, we examine changes in gene expression that accompany early AD pathology in cortical biopsies that were removed in the course of shunt placement for normal pressure hydrocephalus (NPH) and compare the results with AD pathology on histology and contemporaneously gathered cognitive data

Summary

Introduction

Alzheimer’s disease (AD) pathology can be found in cortical biopsies taken during shunt placement for Normal Pressure Hydrocephalus. Cortical biopsies taken from elderly NPH patients at shunt placement have been shown to have a relatively high frequency of β-amyloid plaque pathology, ranging from 42 to 67%8,12, perhaps due to the fact that earlystage AD in many cases may be causing some of the symptoms attributed to NPH/chronic hydrocephalus. We report RNA-seq data from 106 NPH cortical biopsies and correlate changes in gene expression with co-morbid AD pathology in this patient population Analysis of these biopsies shows a restricted set of microglial and non-microglial genes that correlate with histological measurements of β-amyloid and tau pathology primarily in patients who report subjective cognitive impairment. These data suggest that an initial microglial response to AD pathology is associated with accumulating pathology, non-microglial cell responses, and patientreported cognitive status

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