title: Association of plasma clusterin concentration with severity, pathology, and progression in Alzheimer disease.
abstract: BACKGROUND
  Blood-based analytes may be indicators of pathological processes in Alzheimer disease (AD).
  
  
  OBJECTIVE
  To identify plasma proteins associated with AD pathology using a combined proteomic and neuroimaging approach.
  
  
  METHODS
  Discovery-phase proteomics to identify plasma proteins associated with correlates of AD pathology. Confirmation and validation using immunodetection in a replication set and an animal model.
  
  
  METHODS
  A multicenter European study (AddNeuroMed) and the Baltimore Longitudinal Study of Aging.
  
  
  METHODS
  Patients with AD, subjects with mild cognitive impairment, and healthy controls with standardized clinical assessments and structural neuroimaging.
  
  
  METHODS
  Association of plasma proteins with brain atrophy, disease severity, and rate of clinical progression. Extension studies in humans and transgenic mice tested the 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 fibrillar amyloid-beta burden in the medial temporal lobe. Subjects with AD had increased clusterin messenger RNA in blood, but there was no effect of single-nucleotide polymorphisms in the gene encoding clusterin with gene or protein expression. APP/PS1 transgenic mice showed increased plasma clusterin, age-dependent increase in brain clusterin, as well as amyloid and clusterin colocalization in plaques.
  
  
  CONCLUSIONS
  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 AD.
authors.affiliation: King's College London, Institute of Psychiatry, De Crespigny Park, London SE5 8AF, England.
authors.forename: Madhav
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authors.lastname: Thambisetty
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authors.lastname: Simmons
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authors.lastname: Soininen
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authors.lastname: Tsolaki
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authors.lastname: Vellas
authors.forename: Angela
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authors.lastname: Hodges
authors.forename: Declan G M
authors.initials: DG
authors.lastname: Murphy
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authors.lastname: Parkins
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authors.lastname: Ferrucci
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authors.lastname: Wong
authors.forename: Yun
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authors.lastname: Zhou
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authors.lastname: Muehlboeck
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mesh_terms: D000368:Aged; D000375:Aging / Q000473:pathology; D000544:Alzheimer Disease / Q000097:blood* / Q000235:genetics / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000097:blood / Q000235:genetics; D000818:Animals; D001284:Atrophy / Q000473:pathology; D001921:Brain / Q000473:pathology; D051152:Clusterin / Q000097:blood* / Q000235:genetics; D003072:Cognition Disorders / Q000097:blood / Q000235:genetics / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D018728:Entorhinal Cortex / Q000473:pathology; D005260:Female; D015870:Gene Expression; D005838:Genotype; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018832:Molecular Chaperones / Q000097:blood; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D040901:Proteomics / Q000379:methods; D012720:Severity of Illness Index
chemical_list: D016229:Amyloid beta-Peptides; D051152:Clusterin; D018832:Molecular Chaperones