Plasma β₂‐microglobulin and cerebrospinal fluid biomarkers of Alzheimer's disease pathology in cognitively intact older adults: the CABLE study

Abstract Background Previous studies have suggested a correlation between elevated levels of β 2 ‐microglobulin (B2M) and cognitive impairment. However, the existing evidence is insufficient to establish a conclusive relationship. This study aims to analyse the link of plasma B2M to cerebrospinal fluid (CSF) Alzheimer's Disease (AD) biomarkers, and cognition. Method To track the dynamics of plasma B2M in preclinical AD, 846 cognitively healthy individuals in the Chinese Alzheimer's Biomarker and LifestylE (CABLE) cohort were divided into four groups (suspected non‐AD pathology [SNAP], 2, 1, 0) according to NIA‐AA criteria. Multiple linear regression models were employed to examine plasma B2M’s relationship with cognitive and CSF AD biomarkers. Causal mediation analysis was conducted through 10,000 bootstrapped iterations to explore the mediating effect of AD pathology on cognition. Result We found that the levels of plasma B2M were increased in stages 1 (P=0.0007) and 2 (P< 0.0001), in contrast to stage 0. In total participants, higher levels of B2M were associated with worse cognitive performance (P = 0.006 for MMSE; P= 0.012 for MoCA). Moreover, a higher level of B2M was associated with decreases in Aβ 1‐42 (P<0.001) and Aβ 1‐42 /Aβ 1‐40 (P=0.015) as well as increases in T‐tau/Aβ 1‐42 (P<0.001) and P‐tau/Aβ 1‐42 (P<0.001). Subgroup analysis found B2M correlated with Aβ 1‐42 in non‐APOE ε4 individuals (P<0.001) but not in APOE ε4 carriers. Additionally, the link between B2M and cognition was partially mediated by Aβ pathology (percentage: 8.6% to 19.3%), whereas tau pathology did not mediate this effect. Conclusion This study consolidated demonstrated the association of plasma B2M with CSF AD biomarkers as well as a possible important role of Aβ pathology in the association between B2M and cognitive impairment, particularly in cognitively normal individuals, particularly in cognitively normal individuals. The results indicated that B2M could be a potential biomarker for preclinical AD and might have varied functions throughout various stages of preclinical AD progression.