Neuroinflammation in Alzheimer's disease: From glial cell states and molecular networks to biomarkers and precision therapeutics.

Alzheimer's disease (AD) is now recognized as a biologically heterogeneous syndrome in which amyloid-β pathology, Tau-related alterations, and neuroinflammation are key interconnected processes. Microglia, astrocytes, oligodendrocytes, complement, inflammasomes, neurovascular cells, and peripheral immunity are implicated as both adaptive and disease-promoting contributors to the pathophysiology of AD. Here, we highlight mechanisms by which innate immunity and peripheral immune cells influence amyloid β-peptide metabolism, Tau pathophysiology, excitatory synaptic function, oxidative stress response, blood-brain barrier integrity, and systemic inflammation in the context of Alzheimer's disease. A particular focus is made on the role of TREM2-related microglial function and the NLRP3 inflammasome, complement-mediated synaptic pruning, astrocyte crosstalk, and the limitations of the M1/M2 and A1/A2 concepts. A distinction is made between biomarkers of core AD pathophysiology and those specific to neuroinflammation and neurodegeneration. An emphasis is placed on the clinical utility of plasma p-tau217 in combination with Aβ42/Aβ40, GFAP, NfL, sTREM2, YKL-40, and neuroinflammation imaging. With respect to therapeutics, an effort is made to focus on the need to harness desirable inflammatory pathways while specifically targeting deleterious processes rather than adopting an overarching anti-inflammatory approach. Single-cell, spatial, multi-omics, and biomarker-driven approaches may enable patient stratification based on underlying pathophysiology, allowing for stage-specific combination therapeutic strategies. Overall, studies presented in this review highlight a precision-neuroimmunology concept in which neuroinflammatory processes are both triggers and effectors of disease pathology and can be selectively modulated for clinical benefit.