Blood-brain barrier biomarkers modulate the associations of peripheral immunity with Alzheimer's disease

The association between peripheral immunity and Alzheimer's disease (AD) has been increasingly recognized, but the underlying mechanisms are still unclear. We used multiple linear regression models to explore the association between peripheral immune biomarkers / blood-brain barrier (BBB)-related biomarkers and AD biomarkers. And we used causal mediation analysis with 10,000 bootstrapped iterations to investigate the functions of BBB-related biomarkers in mediating the associations between peripheral immune biomarkers and AD pathology, cerebral atrophy degree, as well as cognitive function. A total of 543 participants (38.7% female, mean age of 74.8 years) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were involved. Neutrophils percent (NEU%), lymphocytes percent (LYM%), neutrophils / lymphocytes (NLR), and chemotactic factor-3 (CCL26) were significantly associated with cerebrospinal fluid (CSF) β-amyloid-42 (Aβ-42), phosphorylated-tau (P-tau), total tau (T-tau)/Aβ-42 and P-tau/Aβ-42, the associations of NEU% with AD pathology were mediated by CCL26 (proportion: 18-24%; p < 0.05). NEU%, LYM%, NLR, CCL26, CD40 and matrix metalloproteinase-10 (MMP10) were significantly associated with whole brain, hippocampal volume, middle temporal lobe (MTL) volume, and entorhinal cortex (EC) thickness, the associations of peripheral immune biomarkers with cerebral atrophy degree were mediated by BBB-related biomarkers (proportion: 7-17%; p < 0.05). NEU%, LYM%, NLR, CCL26, CD40 and MMP10 were significantly associated with global cognition, executive function, memory function, immediate recall, and delayed recall, the associations of peripheral immune biomarkers with cognitive function were mediated by BBB-related biomarkers (proportion: 9-24%; p < 0.05). This study suggests that peripheral immunity may influence AD through influencing BBB function, providing a more robust and comprehensive evidence chain for the potential role of inflammation in AD.