CSF 14-3-3 zeta() isoform is associated with tau pathology and cognitive decline in Alzheimer's disease

14-3-3 is a family of conserved proteins that consist of seven isoforms which are highly expressed in the brain, and 14-3-3 zeta(zeta) is one of the isoforms encoded by the YWHAZ gene. Previous studies demonstrated that 14-3-3 zeta is deposited in the neurofibrillary tangles of Alzheimer's disease (AD) brains, and that 14-3-3 zeta interacts with tau from the purified neurofibrillary tangles of AD brain extract. The present study examined the cerebrospinal fluid (CSF) 14-3-3 zeta levels of 719 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI), including cognitively normal (CN) participants, patients with mild cognitive impairment (MCI) and patients with AD dementia, and aimed to identify whether CSF 14-3-3 zeta is associated with tau pathology. CSF 14-3-3 zeta levels were increased in AD, and particularly elevated among tau pathology positive individuals. CSF 14-3-3 zeta levels were associated with CSF phosphorylated tau 181 (p-tau) (r = 0.741, P < 0.001) and plasma p-tau (r = 0.293, P < 0.001), which are fluid biomarkers of tau pathology, and could predict tau pathology positive status with high accuracy (area under the receiver operating characteristic curve [AUC], 0.891). CSF 14-3-3 zeta levels were also correlated to synaptic biomarker CSF GAP-43 (r = 0.609, P < 0.001) and neuroinflammatory biomarker CSF sTREM-2 (r = 0.507, P < 0.001). High CSF 14-3-3 zeta levels at baseline were associated with progressive decline of cognitive function and neuroimaging findings during follow up. In conclusion, this study suggests that CSF 14-3-3 zeta is a potential biomarker of AD that may be useful in clinical practice.