Neuroinflammation as a driver of Down syndrome-associated Alzheimer’s disease

• Neuroinflammation is a central, targetable hub in DS-associated AD. • Microglial activation amplifies and interacts with amyloid and tau pathology. • Lifelong immune dysregulation and redox stress accelerate neurodegeneration. • DS models demonstrate partial reversal of deficits with microglial/redox therapy. • Translational roadmap integrates DS-specific biomarkers and precision therapies. Individuals with Down syndrome (DS) face the highest lifetime risk of early-onset Alzheimer’s disease (DS-AD). While largely driven by APP triplication, the dementing process is heavily influenced by additional mechanisms as a consequence of both environmental and genetic modifiers. While virtually all adults with DS develop amyloid pathology by mid-life, only a subset progress to symptomatic dementia, implicating modifiers beyond amyloidosis. Increasing evidence identifies chronic neuroinflammation as a central driver of disease trajectory. Neuropathological, multi-omics, and cellular studies demonstrate that immune dysregulation begins prenatally, persists across the lifespan, and converges with oxidative stress, tauopathy, and vascular dysfunction to accelerate neurodegeneration. Peripheral immune abnormalities, including interferon-driven “interferonopathy” and comorbidities such as sleep apnea, endocrine disorders and thyroid disease, further amplify central inflammation. Preclinical DS models confirm that microglial activation and redox imbalance precede synaptic dysfunction and cognitive decline, and demonstrate reversibility with microglial or redox-targeted interventions. These findings reframe DS-AD as an inflammation-driven disorder in which amyloid and tau act as cofactors within a chronic immune cascade. This review addresses emerging therapeutic strategies targeting inflammation, oxidative stress, and vascular dysfunction. A translational pipeline integrating DS-specific biomarkers and preclinical models now offers a rational path toward precision interventions for this high-risk population.