Associating Alzheimer's disease pathology with its cerebrospinal fluid biomarkers

In an Alzheimer's disease autopsy cohort, Bridel et al. show that associations between neuropathology and CSF P-tau181 and T-tau are stronger and more significant with longer intervals between lumbar puncture and death. CSF biomarkers may not be well suited to monitoring neuropathology at later disease stages. Alzheimer's disease CSF biomarkers 42 amino acid long amyloid-beta peptide (A beta(1-42)), total tau protein (T-tau), and tau protein phosphorylated at threonine 181 (P-tau(181)) are considered surrogate biomarkers of Alzheimer's disease pathology, and significantly improve diagnostic accuracy. Their ability to reflect neuropathological changes later in the disease course is not well characterized. This study aimed to assess the potential of CSF biomarkers measured in mid to late stage Alzheimer's disease to reflect post-mortem neuropathological changes. Individuals were selected from two autopsy cohorts of Alzheimer's disease patients in Antwerp and Amsterdam. Neuropathological diagnosis was performed according to the updated consensus National Institute on Aging-Alzheimer's Association guidelines, which includes quantification of amyloid-beta plaque, neurofibrillary tangle, and neuritic plaque load. CSF samples were analysed for A beta(1-42), T-tau, and P-tau(181) by ELISA. One hundred and fourteen cases of pure definite Alzheimer's disease were included in the study (mean age 74 years, disease duration 6 years at CSF sampling, 50% females). Median interval between CSF sampling and death was 1 year. We found no association between A beta(1-42) and Alzheimer's disease neuropathological change profile. In contrast, an association of P-tau(181) and T-tau with Alzheimer's disease neuropathological change profile was observed. P-tau(181) was associated with all three individual Montine scores, and the associations became stronger and more significant as the interval between lumbar puncture and death increased. T-tau was also associated with all three Montine scores, but in individuals with longer intervals from lumbar puncture to death only. Stratification of the cohort according to APOE epsilon 4 carrier status revealed that the associations applied mostly to APOE epsilon 4 non-carriers. Our data suggest that similar to what has been reported for A beta(1-42), plateau levels of P-tau(181) and T-tau are reached during the disease course, albeit at later disease stages, reducing the potential of tau biomarkers to monitor Alzheimer's disease pathology as the disease progresses. As a consequence, CSF biomarkers, which are performant for clinical diagnosis of early Alzheimer's disease, may not be well suited for staging or monitoring Alzheimer's disease pathology as it progresses through later stages.