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 β₂-microglobulin (B2M) and cognitive impairment. However, the existing evidence is insufficient to establish a conclusive relationship. This study aims to analyze the link of plasma B2M to cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarkers and cognition.

Methods: 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 the NIA-AA criteria. Multiple linear regression models were employed to examine the 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.

Results: 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). The 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.

Conclusions: This study 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. 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.

Keywords: Alzheimer’s disease; Biomarkers; Neurodegeneration; β2-Microglobulin.

Fig. 1

Plasma B2M in the biomarker classification. The cutoff values to define abnormal CSF AD biomarkers were < 205.82 pg/ml for Aβ_1–42 (A +), > 48.73 pg/ml for P-tau (T +), or > 221.84 pg/ml for T-tau (T +). One-way ANOVA followed by Bonferroni post hoc analyses with adjustment for age was applied to examine the differences in plasma B2M across biomarker profiles in a biomarker framework. Abbreviations: B2M, β₂-microglobulin; SNAP, suspected non-AD pathology

Fig. 2

Associations of B2M and cognitive performance. Multiple linear regression models were used to examine the associations between the plasma B2M with MMSE (A) and MoCA (B), adjusting for age, sex, education level, and APOE ɛ4 carrier statuses. Abbreviations: B2M, β₂-microglobulin; MMSE, Mini-Mental State Examination; MoCA, Montreal Cognitive Assessment; APOE, apolipoprotein E

Fig. 3

Associations between B2M and CSF AD biomarkers. Multiple linear regression models were used to examine the associations between the plasma B2M with cerebrospinal fluid (CSF) Aβ_1–42 (A), T-tau (B), P-tau (C), Aβ_1–42/Aβ_1–40 (D) T-tau/Aβ_1–42 (E), and P-tau/Aβ_1–42 (F), adjusting for age, sex, education level, APOE ɛ4 carrier statuses, and MMSE. Abbreviations: B2M, β₂-microglobulin; APOE, apolipoprotein E

Fig. 4

Heatmap for subgroup analyses of the association between B2M and CSF AD biomarkers. Multiple linear regression models were employed with adjustment for age, sex, years of education, APOE ε4 status, and MMSE. In stratified analyses, stronger correlations were observed between B2M and biomarkers in middle-aged individuals and individuals without the APOE ε4 allele. Abbreviations: CVF, cardiovascular factors; APOE, apolipoprotein E. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001

Fig. 5

Mediation analyses of AD biomarkers between B2M and cognition. Mediation analyses with 10,000 bootstrapped iterations were used to examine the mediation effects of Aβ pathologies on cognition. Aβ_1–42, Aβ_1–42/Aβ_1–40, and P-tau/Aβ_1–42 mediated the relationship between B2M and MMSE (A–C). Aβ_1–42, P-tau/Aβ_1–42, and T-tau/Aβ_1–42 mediated the relationship between B2M and MoCA (D–F). Each model path was adjusted for age, sex, years of education, APOE ε4 status, and MMSE. a is the effect of the independent variable on mediators; b is the effect of mediators on dependent variables after controlling the influence of independent variables; c is the total effect of independent variables on dependent variables; c′ is the direct effect. Abbreviations: B2M, β₂-microglobulin; P-tau, phosphorylated tau protein; T-tau, total tau protein; Aβ, amyloid β; APOE, apolipoprotein E