Chemokines in Alzheimer's Disease: Early Defence, Late Damage and the Impact of Sex and Infection

Abstract

Chemokines constitute a versatile signalling network maintaining homeostasis and glia–neuron communication in the healthy brain but become progressively dysregulated during aging and Alzheimer's disease (AD). This review examines how chemokine systems transition from tightly regulated homeostatic signals to drivers of chronic neuroinflammation in AD. We describe the major chemokine families (CC, CXC, CX3C) and their dominant central nervous system (CNS) receptors (CCR2, CXCR3, CX3CR1), which activate canonical inflammatory pathways including NF-κB, JAK/STAT and PI3K-AKT. In AD, chemokine dysregulation occurs in a coordinated manner across multiple functional modules, including recruitment-associated (CCL2, CXCL1), interferon-inducible (CXCL10), loss-of-restraint (CX3CL1) and vascular-associated chemokines. These alterations shift the network from regulated immune communication to self-sustaining inflammatory circuits perpetuating chronic neuroinflammation. These networks reprogram microglia and astrocytes into disease-associated phenotypes, amplify peripheral immune cell infiltration and destabilise synaptic function. Biological sex profoundly influences neuroinflammatory trajectories, with females exhibiting enhanced microglial senescence and interferon signalling, while males show accelerated complement activation. Viral pathogens, particularly neurotropic viruses (HSV-1, HHV-6, VZV) and SARS-CoV-2, actively reprogram chemokine networks, linking infection to amyloid-β accumulation, tau pathology and neurodegeneration. Therapeutically, chemokine axes represent precision targets requiring stage-matched, sex-stratified interventions rather than broad anti-inflammatory approaches. Understanding chemokine network dynamics offers mechanistic insights into AD pathogenesis and could provide pointers for therapeutic strategies.