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

Abstract

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.

Interpretation: 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.

Fig 1

(A) Frequency distribution of cerebrospinal fluid (CSF) amyloid-β 1 to 42 peptide (Aβ_1-42) concentration in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) Alzheimer’s disease (AD), mild cognitive impairment (MCI), and cognitively normal (NC) groups at their baseline visit. Dotted vertical lines within each diagnosis is the Aβ_1-42 cutoff concentration of 192pg/ml determined from the ADNI-independent autopsy-based AD CSF samples. (B) Aβ_1-42 concentrations in CSF, collected at the baseline visit, of 37 ADNI MCI subjects who at their 1-year visit converted to a diagnosis of probable AD. Data points for the MCI→AD converters are presented as a horizontal dot plot with the x-axis scale identical to that of the Aβ_1-42 frequency plot for the entire ADNI MCI group.

Fig 2

Plot of cerebrospinal fluid (CSF) tau concentration versus CSF amyloid-β 1 to 42 peptide (Aβ_1-42) concentration for the autopsy-confirmed Alzheimer’s disease (AD) cases (solid circles) and elderly cognitively normal (NC) subjects (open circles).

Fig 3

Plot of cerebrospinal fluid (CSF) tau concentration versus CSF amyloid-β 1 to 42 peptide (Aβ_1-42) concentration for the Alzheimer’s Disease Neuroimaging Initiative (ADNI) probable Alzheimer’s disease (AD; solid circles), mild cognitive impairment (MCI; squares), and elderly cognitively normal (NC; open circles) subjects.

Fig 4

(A) Receiver operating characteristic curve (ROC) curves for the non–Alzheimer’s Disease Neuroimaging Initiative (ADNI) autopsy-based Alzheimer’s disease (AD) cases versus non-ADNI cognitively normal (NC) subjects. The LR_TAA model, amyloid-β 1 to 42 peptide (Aβ_1-42), and tau/Aβ_1-42 ratio are the independent variables whose ROC curves are shown. (B) ROC curves for ADNI probable AD versus NC subjects. CSF = cerebrospinal fluid.