Dynamic changes of CSF clusterin levels across the Alzheimer's disease continuum

Abstract

Background: Clusterin is a multifunctional protein, which is associated with the pathogenesis and the development of Alzheimer's disease (AD). Compared with normal controls, inconsistent results have yielded in previous studies for concentration of cerebrospinal fluid (CSF) clusterin in AD patients. We explored CSF clusterin levels in different pathological processes of AD.

Methods: Following the National Institute on Aging-Alzheimer's Association (NIA-AA) criteria, we employed on the levels of CSF Aβ₄₂(A), phosphorylated-Tau (T), and total-tau (N). Based on previously published cutoffs and the close correlation between CSF p-tau and t-tau, 276 participants from the publicly available ADNI database with CSF biomarkers were divided into four groups: A-(TN)- (normal Aβ₄₂ and normal p-tau and t-tau; n = 50), A+(TN)- (abnormal Aβ₄₂ and normal p-tau and t-tau; n = 39), A+(TN) + (abnormal Aβ₄₂ and abnormal p-tau or t-tau; n = 147), A-(TN) + (normal Aβ₄₂ and abnormal p-tau or t-tau; n = 40). To assess CSF clusterin levels in AD continuum, intergroup differences in four groups were compared. Pairwise comparisons were conducted as appropriate followed by Bonferroni post hoc analyses. To further study the relationships between CSF clusterin levels and AD core pathological biomarkers, we employed multiple linear regression method in subgroups.

Results: Compared with the A-(TN)- group, CSF clusterin levels were decreased in A+ (TN)- group (P = 0.002 after Bonferroni correction), but increased in the A+(TN) + group and the A-(TN) + group (both P < 0.001 after Bonferroni correction). Moreover, we found CSF clusterin levels are positively associated with CSF Aβ₄₂ (β = 0.040, P < 0. 001), CSF p-tau (β = 0.325, P < 0.001) and CSF t-tau (β = 0.346, P < 0.001).

Conclusions: Our results indicated that there are differences levels of CSF clusterin in different stages of AD pathology. The CSF clusterin level decreased at the early stage are related to abnormal Aβ pathology; and the increased levels are associated with tau pathology and neurodegeneration.

Keywords: Alzheimer’s disease; Aβ; CSF; Clusterin; Neurodegeneration; Tau.

Fig. 1

CSF clusterin in the ATN classification. The levels of CSF clusterin in the four biomarker profiles were described by scatter plots. The difference in four groups employed an analysis of covariance (ANCOVA) followed by Bonferroni post hoc analyses. The significant P-values were marked after Bonferroni correction

Fig. 2

Associations of CSF clusterin levels with AD core pathological biomarkers. Scatter plots depict the associations of CSF clusterin with core pathological biomarkers: Aβ₄₂, p-tau and t-tau in whole cohort (a, d, g), biomarker normal (b, e, h) and Alzheimer’s continuum (c, f, i). The multiple linear regression was applied to compute the standardized regression coefficients (β) and the P-values, containing age, diagnosis, gender, education, and APOE ε4 status as covariates