Cerebrospinal fluid biomarker signature in Alzheimer's disease neuroimaging initiative subjects.
OBJECTIVE
Develop a cerebrospinal fluid biomarker signature for mild Alzheimer's disease (AD) in Alzheimer's Disease Neuroimaging Initiative (ADNI) subjects.


METHODS
Amyloid-beta 1 to 42 peptide (A beta(1-42)), total tau (t-tau), and tau phosphorylated at the threonine 181 were measured in (1) cerebrospinal fluid (CSF) samples obtained during baseline evaluation of 100 mild AD, 196 mild cognitive impairment, and 114 elderly cognitively normal (NC) subjects in ADNI; and (2) independent 56 autopsy-confirmed AD cases and 52 age-matched elderly NCs using a multiplex immunoassay. Detection of an AD CSF profile for t-tau and A beta(1-42) in ADNI subjects was achieved using receiver operating characteristic cut points and logistic regression models derived from the autopsy-confirmed CSF data.


RESULTS
CSF A beta(1-42) was the most sensitive biomarker for AD in the autopsy cohort of CSF samples: receiver operating characteristic area under the curve of 0.913 and sensitivity for AD detection of 96.4%. In the ADNI cohort, a logistic regression model for A beta(1-42), t-tau, and APO epsilon 4 allele count provided the best assessment delineation of mild AD. An AD-like baseline CSF profile for t-tau/A beta(1-42) was detected in 33 of 37 ADNI mild cognitive impairment subjects who converted to probable AD during the first year of the study.


CONCLUSIONS
The CSF biomarker signature of AD defined by A beta(1-42) and t-tau in the autopsy-confirmed AD cohort and confirmed in the cohort followed in ADNI for 12 months detects mild AD in a large, multisite, prospective clinical investigation, and this signature appears to predict conversion from mild cognitive impairment to AD.
Shaw
Leslie M
LM
Department of Pathology and Laboratory Medicine, Institute on Aging, Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. shawlmj@mail.med.upenn.edu
Vanderstichele
Hugo
H
Knapik-Czajka
Malgorzata
M
Clark
Christopher M
CM
Aisen
Paul S
PS
Petersen
Ronald C
RC
Blennow
Kaj
K
Soares
Holly
H
Simon
Adam
A
Lewczuk
Piotr
P
Dean
Robert
R
Siemers
Eric
E
Potter
William
W
Lee
Virginia M-Y
VM
Trojanowski
John Q
JQ
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000235:genetics / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid*; D053327:Apolipoprotein E4 / Q000235:genetics; D019540:Area Under Curve; D015415:Biomarkers / Q000134:cerebrospinal fluid; D003072:Cognition Disorders / Q000134:cerebrospinal fluid / Q000235:genetics / Q000473:pathology; D015331:Cohort Studies; D003952:Diagnostic Imaging; D018450:Disease Progression; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000134:cerebrospinal fluid*; D010766:Phosphorylation; D012372:ROC Curve; D012189:Retrospective Studies; D012680:Sensitivity and Specificity; D018709:Statistics, Nonparametric; D013912:Threonine / Q000378:metabolism; D016875:tau Proteins / Q000134:cerebrospinal fluid* / Q000737:chemistry
D016229:Amyloid beta-Peptides; D053327:Apolipoprotein E4; D015415:Biomarkers; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D016875:tau Proteins; D013912:Threonine