Plasma biomarkers of brain atrophy in Alzheimer's disease.
Peripheral biomarkers of Alzheimer's disease (AD) reflecting early neuropathological change are critical to the development of treatments for this condition. The most widely used indicator of AD pathology in life at present is neuroimaging evidence of brain atrophy. We therefore performed a proteomic analysis of plasma to derive biomarkers associated with brain atrophy in AD. Using gel based proteomics we previously identified seven plasma proteins that were significantly associated with hippocampal volume in a combined cohort of subjects with AD (N = 27) and MCI (N = 17). In the current report, we validated this finding in a large independent cohort of AD (N = 79), MCI (N = 88) and control (N = 95) subjects using alternative complementary methods-quantitative immunoassays for protein concentrations and estimation of pathology by whole brain volume. We confirmed that plasma concentrations of five proteins, together with age and sex, explained more than 35% of variance in whole brain volume in AD patients. These proteins are complement components C3 and C3a, complement factor-I, γ-fibrinogen and alpha-1-microglobulin. Our findings suggest that these plasma proteins are strong predictors of in vivo AD pathology. Moreover, these proteins are involved in complement activation and coagulation, providing further evidence for an intrinsic role of these pathways in AD pathogenesis.
Laboratory of Behavioral Neuroscience, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, United States of America. thambisettym@mail.nih.gov
Madhav
M
Thambisetty
Andrew
A
Simmons
Abdul
A
Hye
James
J
Campbell
Eric
E
Westman
Yi
Y
Zhang
Lars-Olof
LO
Wahlund
Anna
A
Kinsey
Mirsada
M
Causevic
Richard
R
Killick
Iwona
I
Kloszewska
Patrizia
P
Mecocci
Hilkka
H
Soininen
Magda
M
Tsolaki
Bruno
B
Vellas
Christian
C
Spenger
Simon
S
Lovestone
D000368:Aged; D000544:Alzheimer Disease / Q000097:blood* / Q000473:pathology*; D001284:Atrophy / Q000097:blood / Q000473:pathology; D015415:Biomarkers / Q000097:blood; D001798:Blood Proteins / Q000378:metabolism*; D001921:Brain / Q000473:pathology*; D005260:Female; D006801:Humans; D016018:Least-Squares Analysis; D008297:Male; D009929:Organ Size; D015203:Reproducibility of Results
D015415:Biomarkers; D001798:Blood Proteins