Understanding why some brains succumb to Alzheimer's disease while others remain resilient despite similar amyloid burden is one of neuroscience's most pressing puzzles. A sophisticated signalling network — chemokines — may hold part of the answer, and new mechanistic analysis suggests the same molecules that protect the brain early in life become architects of its destruction in aging and disease.
This review, published in Basic & Clinical Pharmacology & Toxicology, maps how three major chemokine families — CC, CXC, and CX3C — and their principal CNS receptors (CCR2, CXCR3, CX3CR1) orchestrate brain immune activity through canonical pathways including NF-κB, JAK/STAT, and PI3K-AKT. In Alzheimer's disease, the analysis identifies four functionally distinct dysregulation modules: recruitment-associated chemokines (CCL2, CXCL1), interferon-inducible signals (CXCL10), loss-of-restraint signals (CX3CL1), and vascular-associated chemokines. Together, these shift microglia and astrocytes into disease-associated phenotypes and generate self-sustaining inflammatory loops that amplify peripheral immune cell infiltration and destabilise synaptic function. Crucially, neurotropic viruses — HSV-1, HHV-6, VZV, and SARS-CoV-2 — can actively reprogram these same chemokine networks, offering a plausible biological bridge between infection history and amyloid-β accumulation.
The sex-biology findings are particularly significant and underappreciated in clinical contexts. Females appear to exhibit amplified microglial senescence and heightened interferon-axis signalling, while males show accelerated complement cascade activation — divergent immunological trajectories that could explain differential Alzheimer's risk and progression rates between sexes. These sex-specific patterns align with growing epidemiological evidence that women represent roughly two-thirds of Alzheimer's patients, yet the mechanistic underpinning has remained elusive. As a comprehensive review rather than original trial data, causal claims remain limited; however, the synthesis of infection, sex biology, and glial reprogramming into a unified chemokine framework is conceptually valuable. For researchers and clinicians, it prioritises CX3CL1 signalling loss and interferon-inducible chemokines as tractable therapeutic targets worth pursuing in sex-stratified clinical trials.
