Serum IL-6, sAXL, and YKL-40 as systemic correlates of reduced brain structure and function in Alzheimer’s disease: results from the DELCODE study

Abstract

Background Neuroinflammation constitutes a pathological hallmark of Alzheimer’s disease (AD). Still, it remains unresolved if peripheral inflammatory markers can be utilized for research purposes similar to blood-based beta-amyloid and neurodegeneration measures. We investigated experimental inflammation markers in serum and analyzed interrelations towards AD pathology features in a cohort with a focus on at-risk stages of AD. Methods Data of 74 healthy controls (HC), 99 subjective cognitive decline (SCD), 75 mild cognitive impairment (MCI), 23 AD relatives, and 38 AD subjects were obtained from the DELCODE cohort. A panel of 20 serum biomarkers was determined using immunoassays. Analyses were adjusted for age, sex, APOE status, and body mass index and included correlations between serum and CSF marker levels and AD biomarker levels. Group-wise comparisons were based on screening diagnosis and routine AD biomarker-based schematics. Structural imaging data were combined into composite scores representing Braak stage regions and related to serum biomarker levels. The Preclinical Alzheimer’s Cognitive Composite (PACC5) score was used to test for associations between the biomarkers and cognitive performance. Results Each experimental marker displayed an individual profile of interrelations to AD biomarkers, imaging, or cognition features. Serum-soluble AXL (sAXL), IL-6, and YKL-40 showed the most striking associations. Soluble AXL was significantly elevated in AD subjects with pathological CSF beta-amyloid/tau profile and negatively related to structural imaging and cognitive function. Serum IL-6 was negatively correlated to structural measures of Braak regions, without associations to corresponding IL-6 CSF levels or other AD features. Serum YKL-40 correlated most consistently to CSF AD biomarker profiles and showed the strongest negative relations to structure, but none to cognitive outcomes. Conclusions Serum sAXL, IL-6, and YKL-40 relate to different AD features, including the degree of neuropathology and cognitive functioning. This may suggest that peripheral blood signatures correspond to specific stages of the disease. As serum markers did not reflect the corresponding CSF protein levels, our data highlight the need to interpret serum inflammatory markers depending on the respective protein’s specific biology and cellular origin. These marker-specific differences will have to be considered to further define and interpret blood-based inflammatory profiles for AD research.

Dynamic changes in immune cell populations by AXL kinase targeting diminish liver inflammation and fibrosis in experimental MASH

“…In a broader perspective and in concordance with our results, monocyte-derived macrophages have been shown to appear concurrent with the loss of tissue-resident macrophages in several tissues including the liver, brain, lungs, and heart, during events of sustained tissue damage ( 56 , 57 ). Damage in these same tissues (cirrhosis, Alzheimer’s disease, pneumonia, and heart failure) has also been directly linked to increased levels of sAXL ( 53 , 58 – 60 ). This suggests that an elevated sAXL level serves as an indicator of ongoing tissue damage that initially depletes tissue-resident macrophages, leading to their replacement by monocyte-derived macrophages, which regrettably are unable to resolve the sustained tissue damage and resultant inflammation.…”

Clinical Phenotypes of Progressive Supranuclear Palsy—The Differences in Interleukin Patterns

“…Increased levels of IL-6 were also detected in AD [22], and IL-6 trans-signaling was linked with cognitive deterioration in AD [23]. Another study showed a negative correlation between serum IL-6 levels and the volumetric measures within the Braak region, whereas no such correlation was observed between IL-6 levels in the CSF and possible atrophic changes in this region [24]. Interestingly, IL-1 was over-expressed in AD brains [25,26], with the mechanism interpreted as leading to plaque formation and an increase in acetylcholinesterase [25].…”

Neuroplasticity of children in autism spectrum disorder

“…Children with ASD who have gastrointestinal symptoms are often associated with increases in many innate (IL-1α, TNFα, GM-CSF, IFNα) and adaptive cytokines (IL-4, IL-13, IL-12p70) ( 112 ). IL-6 is a neurogenic cytokine that affects neuronal proliferation, synapse formation, differentiation, and migration and acts as a modulator of central neural pathways, which are important for cognitive functioning ( 113 ), and has also been associated with worsening of restricted and repetitive behaviors ( 114 ). TNF-α has homeostatic functions, such as regulating neurogenesis, myelin formation, blood-brain barrier permeability and synaptic plasticity, and mediates changes in excitatory and inhibitory neurotransmission in a concentration-dependent manner ( 115 ).…”