Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by abnormalities in protein metabolism leading to the accumulation of extracellular amyloid-beta (Aβ) plaques and intracellular neurofibrillary tangles (hyperphosphorylated tau protein). While these pathological constructs have held significant attention for decades, emerging evidence highlights the understanding of neuroinflammation (notably involving microglia, and cytokine signaling) as a critical initial event with respect to the inception and progression of AD. This review discusses the dynamic and dualistic effects of immune response in AD based on the relationship between neuroinflammatory processes and classical neuropathological characteristics. Microglia are ubiquitous immune cells in the central nervous system responsible for maintaining homeostasis as the brain's "housekeepers" by removing cellular debris, pruning synapses, and monitoring cell interactions. However, microglia in AD function produce a chronically activated phenotype that elicits neurotoxicity, impairs synaptic functioning, and is are protracted source of neuroinflammation. The appearance of disease-associated microglia (DAM) may illustrate complexities of TREM2 signaling for the anabolism of Aβ clearance and the modulation of inflammatory systems. Cytokine imbalance - higher expression of pro-inflammatory (e.g., IL-1β, TNF-α) and lower expression of antiinflammatory (e.g., IL-10, TGF-β) - adds to a self-perpetuating inflammatory loop that exacerbates Aβ and tau pathology, brain-blood barrier permeability, and peripheral-CNS immune communications. The mechanisms of an inflammatory event may drive brain tau hyperphosphorylation, tau propagation, along with other pathophysiological neurodegenerative features of traumatic brain injury and Alzheimer's disease. While examples of therapies targeting microglia and their cytokine activity are actively being explored, clinical efforts have been mixed. Neuroimaging development (e.g., TSPO-PET), cytokine collection and compositional approaches, and application of single-cell transcriptomics are providing new ways of thinking about complex neuroimmunology. Exploring, informing, and defining the timing, context, and variations of neuroinflammatory responses will be ultimately needed to create effective, targeted therapies for Alzheimer's disease (AD).
