Markers of neuroinflammation associated with Alzheimer’s disease pathology in older adults

Highlights

• Distinct serum and CSF inflammation signatures are associated with AD pathology.

• Serum and CSF inflammation markers improve the classification accuracy for AD.

• Six CSF inflammation markers were associated with tau pathology and neuronal injury.

Abstract

Background

In vitro and animal studies have linked neuroinflammation to Alzheimer’s disease (AD) pathology. Studies on markers of inflammation in subjects with mild cognitive impairment or AD dementia provided inconsistent results. We hypothesized that distinct blood and cerebrospinal fluid (CSF) inflammatory markers are associated with biomarkers of amyloid and tau pathology in older adults without cognitive impairment or with beginning cognitive decline.

Objective

To identify blood-based and CSF neuroinflammation marker signatures associated with AD pathology (i.e. an AD CSF biomarker profile) and to investigate associations of inflammation markers with CSF biomarkers of amyloid, tau pathology, and neuronal injury.

Design/methods

Cross-sectional analysis was performed on data from 120 older community-dwelling adults with normal cognition (n = 48) or with cognitive impairment (n = 72). CSF Aβ1–42, tau and p-tau181, and a panel of 37 neuroinflammatory markers in both CSF and serum were quantified. Least absolute shrinkage and selection operator (LASSO) regression was applied to determine a reference model that best predicts an AD CSF biomarker profile defined a priori as p-tau181/Aβ1–42 ratio >0.0779. It was then compared to a second model that included the inflammatory markers from either serum or CSF. In addition, the correlations between inflammatory markers and CSF Aβ1–42, tau and p-tau181 levels were assessed.

Results

Forty-two subjects met criteria for having an AD CSF biomarker profile. The best predictive models included 8 serum or 3 CSF neuroinflammatory markers related to cytokine mediated inflammation, vascular injury, and angiogenesis. Both models improved the accuracy to predict an AD biomarker profile when compared to the reference model. In analyses separately performed in the subgroup of participants with cognitive impairment, adding the serum or the CSF neuroinflammation markers also improved the accuracy of the diagnosis of AD pathology.

None of the inflammatory markers correlated with the CSF Aβ1–42 levels. Six CSF markers (IL-15, MCP-1, VEGFR-1, sICAM1, sVCAM-1, and VEGF-D) correlated with the CSF tau and p-tau181 levels, and these associations remained significant after controlling for age, sex, cognitive impairment, and APOEε4 status.

Conclusions

The identified serum and CSF neuroinflammation biomarker signatures improve the accuracy of classification for AD pathology in older adults. Our results suggest that inflammation, vascular injury, and angiogenesis as reflected by CSF markers are closely related to cerebral tau pathology.

Introduction

Neuroinflammation has long been known as an accompanying pathology of Alzheimer’s disease (AD). It is now well-established that localized low-level inflammation occurs early in the AD brain. In vitro and animal studies demonstrated the activation of different inflammatory pathways in association with amyloid pathology and tau-related neurodegeneration during the course of the disease. (Calsolaro and Edison, 2016, Heppner et al., 2015) In humans, genetic studies identified associations between polymorphisms in genes related to the immune system and the risk of AD (Calsolaro and Edison, 2016, Heneka et al., 2015), while histopathological studies suggested that glial activation is an important mediator of neurotoxicity and altered cognition in the presence of amyloid and tau pathology (Perez-Nievas et al., 2013). The inflammatory process driven by activated and proliferating glial cells, but also astrocytes, other myeloid cells, epithelium and other reactive elements leads to increased production and release of proinflammatory cytokines, chemokines and other mediators of inflammation. These factors may exacerbate amyloid production and toxicity, and contribute to tau hyperphosphorylation and neuronal injury. Vascular injury and endothelial dysfunction in relation to inflammation are also common in AD. They lead to the accumulation of several vasculotoxic and neurotoxic molecules within brain parenchyma, thus likely contributing to a noxious milieu finally promoting neuronal dysfunction and death (Grammas, 2011, Zlokovic, 2011). Several studies in subjects with mid cognitive impairment (MCI) and AD dementia revealed increased inflammatory activity in both the CNS and the circulating blood. However, reports on cytokines and other markers of inflammation in MCI or AD were controversial or inconsistent so far (Brosseron et al., 2014, Delaby et al., 2015, Hesse et al., 2016).

The development of AD pathology starts many years before the onset of the first clinical signs. Older subjects with normal cognition may already have cerebral AD pathology and may be seen as being at the preclinical stage of the disease (Sperling et al., 2011). On the other hand, subjects with cognitive deficits may have cognitive impairment not primarily or only in part related to AD pathology. New research criteria consider AD as a biological continuum across the clinical spectrum from asymptomatic stage to advanced dementia, and emphasize the utility of biomarkers of AD pathology for an accurate diagnosis, in particular at the preclinical and prodromal disease stages (Albert et al., 2011, Dubois et al., 2014, Sperling et al., 2011).

In this study, we aimed at identifying blood and cerebrospinal fluid (CSF) inflammation marker profiles related to the presence of cerebral AD pathology in older adults without cognitive impairment and with beginning cognitive decline. Furthermore, we hypothesized that blood and CSF inflammatory markers of cytokine mediated inflammation, vascular injury, and angiogenesis are associated with CSF biomarkers of amyloid and tau pathology.