Association of Plasma Clusterin Concentration With Severity, Pathology, and Progression in Alzheimer Disease

Abstract

Context Blood-based analytes as indicators of pathological processes in Alzheimer's disease (AD). Objective Combined proteomic and neuroimaging approach to identify plasma proteins associated with AD pathology. Design Discovery-phase proteomic experiments to identify plasma proteins associated with correlates of AD pathology including evidence of atrophy using neuroimaging and more rapid clinical progression, followed by replication using quantitative immunoassay. Extension studies in older non-demented humans using 11C-PiB amyloid imaging and transgenic mice with amyloid pathology. Setting Multi-center European study, AddNeuroMed, and the Baltimore Longitudinal Study of Aging (BLSA) in United States. Participants AD patients, mild cognitive impairment (MCI) subjects and healthy controls with standardized clinical assessments and structural neuroimaging. Plasma samples from non-demented older BLSA participants with brain amyloid imaging by PET. Main outcome measures Association of plasma proteins with brain atrophy, disease severity and rate of clinical progression. Extension studies in man and transgenic mice tested association between plasma proteins and brain amyloid. Results Clusterin/apolipoprotein-J was associated with atrophy of the entorhinal cortex, baseline disease severity and rapid clinical progression in AD. Increased plasma concentration of clusterin was predictive of greater beta amyloid (Aβ) burden in the medial temporal lobe. Subjects with AD had increased clusterin mRNA in blood but there was no effect of SNPs in the gene encoding clusterin (CLU) with gene or protein expression. Finally, APP/PS1 transgenic mice showed increased plasma clusterin, age-dependent increase in brain clusterin and amyloid and clusterin co-localisation in plaques. Conclusions Clusterin/apolipoprotein-J is a known amyloid chaperone associated with Alzheimer's disease severity, pathology and progression. Increased plasma concentration of clusterin is also associated with greater burden of fibrillar Aβ in the brain. These results demonstrate an important role of clusterin in the pathogenesis of AD and suggest that alterations in amyloid chaperone proteins may be a biologically relevant peripheral signature of Alzheimer's disease.

Proteins that mediate protein aggregation and cytotoxicity distinguish Alzheimer's hippocampus from normal controls

“…Carbonyl reductase is elevated in hippocampi of 3xTg‐AD mice, which have markedly elevated levels of protein carbonylation (Shen et al ., 2015). Clusterin (ApoJ) polymorphism is associated with AD (Lambert et al ., 2009), and its circulating levels predict AD progression (Thambisetty et al ., 2010). Other apolipoproteins are also strongly linked to AD risk: ApoD catalyzes reduction of peroxidized lipids and its levels increase with age and AD, while ApoE has allele‐specific effects on Aβ levels and AD risk (Tai et al ., 2013; Dassati et al ., 2014).…”

Inflammation in Alzheimer’s Disease and Molecular Genetics: Recent Update

“…Moreover, CLU was reported to be present in amyloid plaques (Giannakopoulos et al 1998). In addition, recent studies have revealed that the concentration of CLU in the CSF and plasma of AD patients is significantly elevated (Sihlbom et al 2008;Thambisetty et al 2010). Interestingly, as a chaperone protein, CLU has been proven to interact with Ab peptides and this interaction plays an important role in Ab aggregation, toxicity and clearance (Baig et al 2012;DeMattos et al 2002;Narayan et al 2012;Yerbury et al 2007).…”

Prediction of Mild Cognitive Impairment that Evolves into Alzheimer's Disease Dementia within Two Years using a Gene Expression Signature in Blood: A Pilot Study

“…Later, a systematic review and meta-analysis in 2012 by Koyama et al [31] concluded that plasma A␤ 42 :A␤ 40 ratio may predict development of AD, however, significant heterogeneity in the meta-analysis underlines the need for substantial further investigation of plasma A␤ levels as a preclinical biomarker. Thambisetty et al have identified plasma clusterin as a potential biomarker for AD [32] and present data that suggests that plasma clusterin is associated with rate of atrophy in MCI [33].…”