Association of plasma clusterin concentration with severity, pathology, and progression in Alzheimer disease.
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.
Thambisetty
Madhav
M
King's College London, Institute of Psychiatry, De Crespigny Park, London SE5 8AF, England.
Simmons
Andrew
A
Velayudhan
Latha
L
Hye
Abdul
A
Campbell
James
J
Zhang
Yi
Y
Wahlund
Lars-Olof
LO
Westman
Eric
E
Kinsey
Anna
A
Güntert
Andreas
A
Proitsi
Petroula
P
Powell
John
J
Causevic
Mirsada
M
Killick
Richard
R
Lunnon
Katie
K
Lynham
Steven
S
Broadstock
Martin
M
Choudhry
Fahd
F
Howlett
David R
DR
Williams
Robert J
RJ
Sharp
Sally I
SI
Mitchelmore
Cathy
C
Tunnard
Catherine
C
Leung
Rufina
R
Foy
Catherine
C
O'Brien
Darragh
D
Breen
Gerome
G
Furney
Simon J
SJ
Ward
Malcolm
M
Kloszewska
Iwona
I
Mecocci
Patrizia
P
Soininen
Hilkka
H
Tsolaki
Magda
M
Vellas
Bruno
B
Hodges
Angela
A
Murphy
Declan G M
DG
Parkins
Sue
S
Richardson
Jill C
JC
Resnick
Susan M
SM
Ferrucci
Luigi
L
Wong
Dean F
DF
Zhou
Yun
Y
Muehlboeck
Sebastian
S
Evans
Alan
A
Francis
Paul T
PT
Spenger
Christian
C
Lovestone
Simon
S
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
D016229:Amyloid beta-Peptides; D051152:Clusterin; D018832:Molecular Chaperones