Cerebrospinal fluid biomarker signature in Alzheimer's disease neuroimaging initiative subjects

• Published in: Annals of neurology Vol. 65; no. 4; pp. 403 - 413
• Main Authors: Shaw, Leslie M., Vanderstichele, Hugo, Knapik-Czajka, Malgorzata, Clark, Christopher M., Aisen, Paul S., Petersen, Ronald C., Blennow, Kaj, Soares, Holly, Simon, Adam, Lewczuk, Piotr, Dean, Robert, Siemers, Eric, Potter, William, Lee, Virginia M.-Y., Trojanowski, John Q.
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.04.2009; Wiley-Liss
• Subjects: 80 and over; Aged; Aged, 80 and over; Alzheimer Disease; Alzheimer Disease - cerebrospinal fluid; Alzheimer Disease - genetics; Alzheimer Disease - pathology; Alzheimer's disease; Amyloid beta-Peptides - cerebrospinal fluid; Amyloid beta-Protein; Apolipoprotein E4; Apolipoprotein E4 - genetics; Area Under Curve; Autopsy; Biological and medical sciences; Biological Markers; biomarkers; Biomarkers - cerebrospinal fluid; Cerebrospinal fluid; chemistry; Cognition Disorders; Cognition Disorders - cerebrospinal fluid; Cognition Disorders - genetics; Cognition Disorders - pathology; Cognitive ability; Cohort Studies; Data processing; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Diagnostic Imaging; Disease Progression; Female; genetics; Geriatrics; Humans; Immunoassays; Male; Medical and Health Sciences; Medical sciences; Medicin och hälsovetenskap; metabolism; Middle Aged; Neurodegenerative diseases; Neuroimaging; Neurology; Nonparametric; pathology; Peptide Fragments; Peptide Fragments - cerebrospinal fluid; Phosphorylation; Regression analysis; Retrospective Studies; ROC Curve; Sensitivity and Specificity; Statistics; Statistics, Nonparametric; Tau protein; tau Proteins; tau Proteins - cerebrospinal fluid; tau Proteins - chemistry; Threonine; Threonine - metabolism; Human; Nervous system diseases; Alzheimer disease; Central nervous system disease; Degenerative disease; Cerebrospinal fluid; Cerebral disorder
• ISSN: 0364-5134; 1531-8249; 1531-8249
• DOI: 10.1002/ana.21610

Objective Develop a cerebrospinal fluid biomarker signature for mild Alzheimer's disease (AD) in Alzheimer's Disease Neuroimaging Initiative (ADNI) subjects. Methods Amyloid‐β 1 to 42 peptide (Aβ1–42), 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 Aβ1–42 in ADNI subjects was achieved using receiver operating characteristic cut points and logistic regression models derived from the autopsy‐confirmed CSF data. Results CSF Aβ1–42 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 Aβ1–42, t‐tau, and APOε4 allele count provided the best assessment delineation of mild AD. An AD‐like baseline CSF profile for t‐tau/Aβ1–42 was detected in 33 of 37 ADNI mild cognitive impairment subjects who converted to probable AD during the first year of the study. Interpretation The CSF biomarker signature of AD defined by Aβ1–42 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. Ann Neurol 2009