Peripheral inflammation impairs glymphatic function, contributing to neurodegeneration in Alzheimer's disease

Alzheimer's disease (AD) is associated with systemic immune alterations and glymphatic dysfunction, both of which are linked to brain structural and network changes that contribute to cognitive decline. In 570 participants with AD, mild cognitive impairment, or normal cognition, we combined peripheral immune profiling with multimodal magnetic resonance imaging (MRI) to evaluate glymphatic function, brain structure, and network organization. AD was characterized by reduced analysis along the perivascular space index, enlarged choroid plexus (CP) volume, increased white matter free water, reduced lymphocyte count, and elevated neutrophil-to-lymphocyte ratio (NLR). Immune indices, including NLR, platelet-to-lymphocyte ratio, systemic immune-inflammation index, and lymphocyte count, were associated with cognition and glymphatic-related MRI measures. Mediation analyses indicated that NLR influenced cognition indirectly through CP volume and downstream brain structural and network features. These findings link peripheral immune imbalance to cognitive decline through glymphatic and brain network alterations, supporting biomarker development and mechanism-guided therapeutic strategies.