Neuroinflammatory Biomarkers in Alzheimer's Disease: From Pathophysiology to Clinical Implications

Abstract

The identification of neuroinflammation as a critical factor in Alzheimer's disease (AD) has expanded the focus of research beyond amyloid-β and tau pathology. The neuroinflammatory fluid biomarkers GFAP, sTREM2, and YKL-40 have gained attention for their potential in early detection and monitoring of disease progression. Plasma GFAP has demonstrated promise in predicting the conversion from mild cognitive impairment to AD dementia, while sTREM2 highlights microglial activation, although there are conflicting results regarding its dynamics in AD pathogenesis. Advanced imaging techniques, such as PET tracers targeting TSPO and MAO-B, have also been developed to visualize glial activation in vivo, offering spatial and temporal insights into neuroinflammatory processes. However, the clinical implementation of these biomarkers faces challenges due to their lack of specificity, as many of them can be elevated in other conditions. Therapeutic strategies targeting neuroinflammation are emerging, with TREM2-targeting therapies and antidiabetic drugs like GLP-1 receptor agonists showing potential in modulating microglial activity. Nevertheless, the complexity of neuroinflammation, which encompasses both protective and harmful responses, necessitates further research to fully unravel its role and optimize therapeutic approaches for AD.

Keywords: Alzheimer’s disease; biomarkers; neurobiological diseases; neuroinflammation; neuropathogenesis.

Figure 1

Aβ fibrils and plaques can trigger an immune response through microglial receptors. This activates microglia and astrocytes, which attempt to clear the plaques. However, chronic inflammation occurs when clearance fails, leading to the release of pro-inflammatory cytokines like IL-1β, TNF-α, and IL-6, which contribute to neuronal damage. Concurrently, pro-inflammatory cytokines promote the activity of kinases involved in the hyperphosphorylation of tau. Tau proteins become hyperphosphorylated, forming toxic aggregates that spread and worsen neurodegeneration, with molecules released from dying neurons that further amplify neuroinflammation. The interaction between Aβ and tau in an inflammatory environment drives AD progression, creating a vicious cycle of damage. Created in Biorender.com. Roveta, F. (2024) https://BioRender.com/t93c382.