Abstract
Background
The association between peripheral immunity and Alzheimer's disease (AD) has been increasingly recognized, but the underlying mechanisms are still unclear. This study aims to investigate whether peripheral immunity affects AD by influencing blood-brain barrier (BBB) function.
Methods
Multiple linear regression models were employed to explore the association between peripheral immune biomarkers [neutrophils percent (NEU%), lymphocytes percent (LYM%), and neutrophils / lymphocytes (NLR)] and AD biomarkers (including AD pathology, cerebral atrophy degree, and cognitive function). Subsequently, multiple linear regression models were performed to investigate the association between BBB-related biomarkers [chemotactic factor-3 (CCL26), CD40 and matrix metalloproteinase-10 (MMP10)] and AD biomarkers. Finally, causal mediation analysis with 10,000 bootstrapped iterations was conducted to investigate the functions of BBB-related biomarkers in mediating the associations peripheral immune biomarkers with AD pathology, cerebral atrophy degree, as well as cognitive function.
Results
A total of 543 participants (38.7% female, mean age of 74.8 years) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) were involved. NEU%, LYM%, NLR, and 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 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).
Conclusions
This study suggests that both peripheral immune and BBB-related biomarkers are associated with AD pathology deposition, cerebral atrophy degree and cognitive function, and 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.