Cerebrospinal Fluid and Plasma Biomarkers in Neurodegenerative Diseases

Cerebrospinal fluid (CSF) amyloid-β (Aβ)42 and tau are biomarkers for Alzheimer's disease (AD); however, the effects of other neurodegenerative processes on these biomarkers remain unclear. We measured Aβ40, Aβ42, total tau, phosphorylated-tau, and α-synuclein in CSF and plasma using matched samples from various neurodegenerative diseases to expand our basic knowledge on these biomarkers and their practical applications. A total of 213 CSF and 183 plasma samples were analyzed from cognitively unimpaired subjects, and patients with Alzheimer's disease dementia (ADD), mild cognitive impairment (MCI), non-AD dementias, and other neurological diseases. The CSF/plasma ratios of Aβ40 and Aβ42 were approximately 25:1. Aβ40/42 ratios in CSF and plasma were both 10:1. The CSF total tau/P181tau ratio was 6:1. The CSF/plasma α-synuclein ratio was 1:65. Significantly decreased Aβ42 levels and an increased Aβ40/42 ratio in CSF in ADD/MCI suggested that these relationships were specifically altered in AD. Increased total tau levels in ADD/MCI, encephalopathy, and multiple system atrophy, and increased P181tau in ADD/MCI indicated that these biomarkers corresponded to neurodegeneration and tauopathy, respectively. Although CSF α-synuclein levels were increased in ADD/MCI, there was no merit in measuring α-synuclein in CSF or plasma as a biomarker. The combination of biomarkers by the Aβ40/42 ratio×p181tau reflected specific changes due to the AD pathology in ADD/MCI. Thus, CSF Aβ40, Aβ42, p181tau, and tau were identified as biomarkers for aggregated Aβ associated state (A), aggregated tau associated state (T), and neurodegeneration state (N) pathologies in AD based on the NIA-AA criteria. Overlaps in these biomarkers need to be considered in clinical practice for differential diagnoses of neurodegenerative diseases.