Longitudinal change in CSF Tau and Aβ biomarkers for up to 48 months in ADNI

Abstract

The dynamics of cerebrospinal fluid (CSF) tau and Aβ biomarkers over time in Alzheimer's disease (AD) patients from prodromal pre-symptomatic to severe stages of dementia have not been clearly defined and recent studies, most of which are cross-sectional, present conflicting findings. To clarify this issue, we analyzed the longitudinal CSF tau and Aβ biomarker data from 142 of the AD Neuroimaging Initiative (ADNI) study subjects [18 AD, 74 mild cognitive impairment (MCI), and 50 cognitively normal subjects (CN)]. Yearly follow-up CSF collections and studies were conducted for up to 48 months (median = 36 months) for CSF Aβ1-42, phosphorylated tau (p-tau181), and total tau (t-tau). An unsupervised analysis of longitudinal measurements revealed that for Aβ1-42 and p-tau181 biomarkers there was a group of subjects with stable longitudinal CSF biomarkers measures and a group of subjects who showed a decrease (Aβ1-42, mean = -9.2 pg/ml/year) or increase (p-tau181, mean = 5.1 pg/ml/year) of these biomarker values. Low baseline Aβ1-42 values were associated with longitudinal increases in p-tau181. Conversely, high baseline p-tau181 values were not associated with changes in Aβ1-42 levels. When the subjects with normal baseline biomarkers and stable concentrations during follow-up were excluded, the expected time to reach abnormal CSF levels and the mean AD values was significantly shortened. Thus, our data demonstrate for the first time that there are distinct populations of ADNI subjects with abnormal longitudinal changes in CSF p-tau181 and Aβ1-42 levels, and our longitudinal results favor the hypothesis that Aβ1-42 changes precede p-tau181 changes.

Fig. 1

Longitudinal group changes with 95 % confidence intervals for Aβ_1–42 (a), t-tau (c) and p-tau₁₈₁ (e). CSF levels are displayed based on clinical diagnosis at baseline [red cognitively normal subjects (CN), green mild cognitive impairment subjects (MCI) subjects, blue Alzheimer’s disease (AD) subjects]. Individual subject longitudinal changes for Aβ_1–42 (b), t-tau (d) and p-tau₁₈₁ (f) CSF levels with colors identifying the baseline clinical category

Fig. 2

Baseline visit Aβ_1–42 (a), t-tau (b) and p-tau₁₈₁ (c) CSF values (x-axis) against their yearly change (y-axis) during a follow-up of 36–48 months for cognitively normal subjects (CN in red), mild cognitive impairment subjects (MCI in green) subjects and Alzheimer’s disease (AD in blue) subjects. Open versus closed circles indicate the absence or presence of an APOE ε4 allele in each diagnostic group

Fig. 3

Finite mixture modeling of of Aβ_1–42 (a), t-tau (b) and p-tau₁₈₁ (c) yearly changes

Fig. 4

Aβ_1–42 (a) and p-tau₁₈₁ (b) yearly changes versus baseline values. The open circles represent subjects with normal baseline values who remain stable during follow-up and the filled circles represent subjects with abnormal baseline values and/or changes during follow-up. The blue line models all the subjects (i.e. filled and closed circles) while the red line only the subjects with abnormal baseline values and/or changes during follow-up (filled circles). Panels c and d illustrate the estimated trajectories of Aβ_1–42 (c) and p-tau₁₈₁ (d) and the estimated time to reach the AD cutpoint threshold for CSF Aβ_1–42 and p-tau₁₈₁ based on the model that includes all subjects (blue) or only those represented by the filled (red) circles with abnormal baseline values or changes during follow-up