An Investigation of Inflammatory and Metabolic Blood-Based Biomarkers of Cognitive Decline

Abstract

Alzheimer’s disease (AD) and other dementias a re the main cause of cognitive impairment in older adults. AD is fast becoming a global epidemic, yet the development of a disease - modifying therapy remains elusive. The identification of earlier preclinical stages of disease offers the best possibility of slowing down disease progression, and the use of blood - based biomarkers for this purpose is crucial. However, studies so far have shown poor reproducibility and few studies have exami ned asymptomatic individuals before significant cognitive deficits arise . Inflammation is a key feature of AD pathogenesis, and recently a close link between inflammation and metabolism has been demonstrated. The aim of this study was to investigate inflammatory and metabolic blood - based biomarkers that could be indicative of cognitive decline. This was accomplished through examining markers in monocytes incubat ed with plasma from cohorts with cognitiv e dysfunction, and by assess ing markers in pro - inflammatory stimulated monocyte - derived macrophages (MDMs) and peripheral blood mononuclear cells (PBMCs) from a group of healthy older adults described as having a subtle cognitive deficit based on their performance on a story recall test relative to their estimated IQ (IQ - discrepant) . The age - related inflammatory phenotype of C57/BL 6 mice was initially assessed and CXCL1 mRNA was identified in plasma - treated monocytes as a potential peripheral marker of neuroinflammation . Expression of IL - 8, the human homolog of CXCL1, was revealed to be upregulated in monocytes incubated with plasma from IQ - discrepant participants and mild cognitive impairment and AD patients compared with their respective controls. In addition, monocytes treated with plasma from AD patients exhibited an increase in glycolysis. The data suggest that IL - 8 mRNA , and pe rhaps glycolysis , in plasma - treated monocytes could be useful as a potential biomarker assay for cognitive dysfunction. MDMs from IQ - discrepant, compared with IQ - consistent, participants displayed an exacerbated increase in TNFα mRNA and protein expression of TLR2 and CD206 following stimulation with amyloid - beta (Aβ) , as well as a n exaggerated response to Aβ + lipopolysaccharide (LPS) as demonstrated by the increase in TNFα mRNA and secretion and shift towards glycolysis. Th e effect of Aβ +LPS stimulation was also greater i n PBMCs from IQ - discrepant participants , as shown by an increase in TNFα, IL - 6 and IL - 8 production, increased glycolysis and upregulation of PFKFB3 mRNA , an enzyme which drives glycolysis . The data suggest t hat cells from IQ - discrepant participants have a heightened response to pro - inflammatory stimulation. Overall, the findings from this study show that IL - 8 mRNA in plasma - treated monocytes and inflammatory and metabolic markers in MDMs and PBMCs from subje cts with an IQ - discrepant memory may be useful indicators of cognitive decline