Cerebrospinal fluid β2-microglobulin promotes the tau pathology through microglia-astrocyte communication in Alzheimer's disease

Cerebrospinal fluid (CSF) β2-microglobulin (β2M) has been demonstrated as an important factor in β-amyloid (Aβ) neurotoxicity and a potential target for Alzheimer's disease (AD). However, more investigation is required to ascertain the relationship between β2M and glial activities in AD pathogenesis. In this study, 211 participants from the Alzheimer's disease Neuroimaging Initiative (ADNI) with CSF and Plasma β2M, CSF glial fibrillary acidic protein (GFAP), soluble triggering receptor expressed on myeloid cells 2 (sTREM2), Aβ , phosphorylated-tau (P-tau) and total tau (T-tau) were divided into four groups, stage 0, 1, 2, and suspected non-AD pathology (SNAP) based on the National Institute on Aging- Alzheimer's Association (NIA-AA) criteria. Multiple linear regression, linear mixed effects models, and causal mediation analyses bootstrapped 10,000 iterations were used to investigate the underlying associations among β2M and CSF biomarkers at baseline and during a longitudinal visit. CSF β2M concentration decreased with amyloid in stage 1 compared with stage 0 and increased with tau pathology and neurodegeneration in stage 2 and SNAP compared with stage 1. Moreover, CSF β2M level was positively correlated with the Aβ (β = 0.230), P-tau (β = 0.564), T-tau (β = 0.603), GFAP (β = 0.552), and sTREM2 (β = 0.641) (all P