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

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 Aβ_1–42, phosphorylated tau (p-tau₁₈₁), and total tau (t-tau). An unsupervised analysis of longitudinal measurements revealed that for Aβ_1–42 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 (Aβ_1–42, mean = −9.2 pg/ml/year) or increase (p-tau₁₈₁, mean = 5.1 pg/ml/year) of these biomarker values. Low baseline Aβ_1–42 values were associated with longitudinal increases in p-tau₁₈₁. Conversely, high baseline p-tau₁₈₁ values were not associated with changes in Aβ_1–42 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 Aβ_1–42 levels, and our longitudinal results favor the hypothesis that Aβ_1–42 changes precede p-tau₁₈₁ changes.