title: The role of clusterin in amyloid-β-associated neurodegeneration.
abstract: OBJECTIVE
  Converging evidence indicates that clusterin, a chaperone glycoprotein, influences Alzheimer disease neurodegeneration. However, the precise role of clusterin in Alzheimer disease pathogenesis is still not well understood.
  
  
  OBJECTIVE
  To elucidate the relationship between clusterin, amyloid-β (Aβ), phosphorylated tau (p-tau), and the rate of brain atrophy over time among nondemented older individuals.
  
  
  METHODS
  This longitudinal cohort included cognitively normal older participants and individuals with mild cognitive impairment assessed with baseline lumbar puncture and longitudinal structural magnetic resonance imaging. We examined 241 nondemented older individuals from research centers across the United States and Canada (91 participants with a Clinical Dementia Rating score of 0 and 150 individuals with a Clinical Dementia Rating score of 0.5).
  
  
  METHODS
  Using linear mixed-effects models, we investigated interactions between cerebrospinal fluid (CSF) clusterin, CSF Aβ1-42, and CSF p-tau at threonine 181 (p-tau181p) on the atrophy rate of the entorhinal cortex and hippocampus.
  
  
  RESULTS
  Across all participants, we found a significant interaction between CSF clusterin and CSF Aβ1-42 on the entorhinal cortex atrophy rate but not on the hippocampal atrophy rate. Cerebrospinal fluid clusterin was associated with the entorhinal cortex atrophy rate among CSF Aβ1-42-positive individuals but not among CSF Aβ1-42-negative individuals. In secondary analyses, we found significant interactions between CSF Aβ1-42 and CSF clusterin, as well as CSF Aβ1-42 and CSF p-tau181p, on the entorhinal cortex atrophy rate. We found similar results in subgroup analyses within the mild cognitive impairment and cognitively normal cohorts.
  
  
  CONCLUSIONS
  In nondemented older individuals, Aβ-associated volume loss occurs in the presence of elevated clusterin. The effect of clusterin on Aβ-associated brain atrophy is not confounded or explained by p-tau. These findings implicate a potentially important role for clusterin in the earliest stages of the Alzheimer disease neurodegenerative process and suggest independent effects of clusterin and p-tau on Aβ-associated volume loss.
authors.affiliation: Department of Radiology, University of California, San Diego, La Jolla.
authors.forename: Rahul S
authors.initials: RS
authors.lastname: Desikan
authors.affiliation: Department of Psychiatry, University of California, San Diego, La Jolla.
authors.forename: Wesley K
authors.initials: WK
authors.lastname: Thompson
authors.affiliation: Department of Neurosciences, University of California, San Diego, La Jolla.
authors.forename: Dominic
authors.initials: D
authors.lastname: Holland
authors.affiliation: Neuroradiology Section, Department of Radiology and Biomedical Imaging, University of California, San Francisco.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Hess
authors.affiliation: Department of Radiology, University of California, San Diego, La Jolla3Department of Neurosciences, University of California, San Diego, La Jolla.
authors.forename: James B
authors.initials: JB
authors.lastname: Brewer
authors.affiliation: Clinical Neurochemistry Laboratory, The Sahlgrenska Academy at Göteburg University, Mölndal, Gotheburg, Sweden6University College London Institute of Neurology, Queen Square, London, England.
authors.forename: Henrik
authors.initials: H
authors.lastname: Zetterberg
authors.affiliation: Clinical Neurochemistry Laboratory, The Sahlgrenska Academy at Göteburg University, Mölndal, Gotheburg, Sweden.
authors.forename: Kaj
authors.initials: K
authors.lastname: Blennow
authors.affiliation: Department of Psychiatry, University of California, San Diego, La Jolla7Institute of Clinical Medicine, University of Oslo and Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
authors.forename: Ole A
authors.initials: OA
authors.lastname: Andreassen
authors.affiliation: Department of Radiology, University of California, San Diego, La Jolla.
authors.forename: Linda K
authors.initials: LK
authors.lastname: McEvoy
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Bradley T
authors.initials: BT
authors.lastname: Hyman
authors.affiliation: Department of Radiology, University of California, San Diego, La Jolla2Department of Psychiatry, University of California, San Diego, La Jolla.
authors.forename: Anders M
authors.initials: AM
authors.lastname: Dale
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000175:diagnosis*; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid*; D015415:Biomarkers / Q000134:cerebrospinal fluid; D051152:Clusterin / Q000134:cerebrospinal fluid / Q000502:physiology*; D015331:Cohort Studies; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D019636:Neurodegenerative Diseases / Q000134:cerebrospinal fluid / Q000175:diagnosis; D010446:Peptide Fragments / Q000134:cerebrospinal fluid*
chemical_list: D016229:Amyloid beta-Peptides; D015415:Biomarkers; D051152:Clusterin; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)