Longitudinal basal forebrain degeneration interacts with TREM2/C3 biomarkers of inflammation in presymptomatic Alzheimer’s disease

Authors

Taylor W. Schmitz, The University of Western Ontario
Hermona Soreq, Hebrew University of Jerusalem
X. Judes Poirier, Institut Universitaire en Santé Mentale Douglas
X. R. Nathan Spreng, Institut Universitaire en Santé Mentale Douglas

Document Type

Article

Publication Date

2-26-2020

Journal

Journal of Neuroscience

Volume

40

Issue

9

First Page

1931

Last Page

1942

URL with Digital Object Identifier

10.1523/JNEUROSCI.1184-19.2019

Abstract

Copyright © 2020 the authors Cholinergic inputs originating from the peripheral nervous system regulate the inflammatory immune responses of macrophages during clearance of blood-based pathogens. Because microglia are involved in clearing amyloid and tau pathology from the central nervous system, we hypothesized that cholinergic input originating from the basal forebrain might similarly regulate inflammatory immune responses to these pathologies in the aging brain. To explore this hypothesis, we leveraged the Alzheimer’s Disease Neuroimaging Initiative dataset. Cognitively normal older male and female human adults were differentiated according to the relative concentration of phosphorylated tau and amyloid in their cerebrospinal fluid, yielding neurotypical and preclinical, cognitively healthy, subgroups. We then tracked these two groups longitudinally with structural MRI and biomarkers of inflammation, including soluble sTREM2 levels in the CSF and complement C3 expression in the blood transcriptome. Longitudinal loss of basal forebrain volume was larger in the preclinical compared with the neurotypical subgroup. Across preclinical adults, loss of basal forebrain volume was associated with greater longitudinal accumulation of sTREM2 and higher peripheral blood C3 expression. None of these relationships were attributable to degeneration in the whole-brain gray matter volume. Preclinical APOE e4 carriers exhibited the largest loss of basal forebrain volume and highest C3 expression. Consistent with the known anti-inflammatory influence of the peripheral cholinergic pathways on macrophages, our findings indicate that a loss of central cholinergic input originating from the basal forebrain might remove a key check on microglial inflammation induced by amyloid and tau accumulation.

Notes

Longitudinal Basal Forebrain Degeneration Interacts with TREM2/C3 Biomarkers of Inflammation in Presymptomatic Alzheimer's Disease