Longitudinal Cerebrospinal Fluid Biomarker Trajectories in Alzheimer Disease

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Total tau and phosphorylated tau follow a different pattern of change in Alzheimer disease.

Total tau (t-tau) and phosphorylated tau (p-tau), which are markers of axonal injury and tau pathology, respectively, follow a different pattern of change in Alzheimer disease (AD) compared with other commonly investigated markers, according to a study published in Alzheimer’s & Dementia.1

AD is characterized by a long preclinical and prodromal phase that precedes the full-blown dementia syndrome, and cerebrospinal fluid (CSF) biomarkers play a major role in the characterization of these different disease stages.1 Although the pattern of change of these biomarkers in AD has been extensively described in many cross-sectional studies,2 the longitudinal trajectories of individual participants are not well defined. Therefore, researchers evaluated the longitudinal pattern of change of CSF biomarkers in 467 subjects with at least 2 serial CSF samples, as part of a large multicenter study.1 The subjects’ diagnoses at baseline were subjective cognitive decline (n=75), mild cognitive impairment (n=128), and AD dementia (n=110), and a control group of cognitively unimpaired subjects (n=154) was also included. The study authors found that CSF levels of t-tau, p-tau, neurofilament light, and YKL-40 were 2% higher per each year of baseline age in control participants (P <.001). In AD, t-tau levels were 1% lower (P <.001), and p-tau levels did not change per each year of baseline age. Longitudinally, only neurofilament light (P <.001) and YKL-40 (P <.02) increased during the study period.

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Limitations of this study, as highlighted by the researchers, included the short interval for the median LP. The researchers also point out that clinical measures could not be used to assess chance over time, as clinical protocols were not harmonized among centers. Further, the lack of common comorbidities, structural imaging, or positron emission tomography measures to correlate the CSF changes may serve as another limitation.

The investigators concluded that, “All four CSF biomarkers increase with age, but this effect deviates in AD for t-tau and p-tau.”1 However, there are still gaps in our knowledge about longitudinal CSF trajectories, and additional studies are needed to determine the value of CSF biomarker change in defining the activity/intensity of diseases.


1. Alberto Lleó, Daniel Alcolea, Pablo Martínez-Lage, et al. Longitudinal cerebrospinal fluid biomarker trajectories along the Alzheimer’s disease continuum in the BIOMARKAPD study [published online April 6, 2019]. Alzheimers Dement. doi:10.1016/j.jalz.2019.01.015.

2. Olsson B, Lautner R, Andreasson U, et al. CSF and blood biomarkers for the diagnosis of Alzheimer’s disease: a systematic review and meta-analysis. Lancet Neurol. 2016;15:673-684.