From identification to implementation: state of the art in biomarkers for immune function in CSF and blood

AbstractBackgroundBrain immune activation, i.e. activation of microglia and astrocytes, is one of the earliest pathological features of Alzheimer’s disease (AD) pathology. It is likely a consequence of pathological aggregation of amyloid, and can have both detrimental and beneficial effects on multiple aspects of AD pathogenesis. Moreover, recent results show that peripheral immune activation may affect AD pathology and the progression of clinical symptoms as well. Accordingly, biomarkers of innate and adaptive immune activation, as measured in CSF and in blood, have been associated with pathologic status, cognitive decline, as well as increased risk of developing AD. Modulation of central and peripheral immune function offers a potentially promising therapeutic approach for treating AD. As such therapies continue to be developed, there will be an increasing need to noninvasively monitor the neuro‐immune response. If we want to target the brain immune‐cells, microglia or astrocytes, it is essential that we have biomarkers specifically tracing their activation and the concomitant pharmacological response. Developing blood based biomarkers for monitoring neuro‐immune activation is especially challenging given the abundance of immune proteins in blood which are often be indistinguishable from brain‐derived immune proteins.MethodIn this introductory presentation I will discuss recent developments in research to develop immune‐related fluid biomarkers.ResultsRecent proteomics studies and hypothesis‐driven approaches have detected promising changes in immune‐related biomarkers, reflecting either microglia (e.g. complement factors, sTREM2, sAXL) or astrocyte activation (GFAP, YKL‐40), in the CSF of AD patients, even in the earliest disease stages. For example, GFAP levels are increased in cognitively unimpaired persons with AD pathology and have prognostic value for cognitive decline. Using a proteomics approach, we identified clusters of patients with an increased CSF immune biomarker profile, indicating that these would benefit most from immune‐modulating therapy. In addition, recent RNA‐sequencing studies have shown disease related activation and senescence of microglia in both mice and man. We related these expression patterns to CSF proteomic datasets and revealed several potential biomarkers for disease‐associated microglia.ConclusionThere are several interesting advancements in biomarker development for immune function that will be addressed in this FRS.