CSF 14-3-3ζ is associated with tau pathology and elevated across the Alzheimer’s disease continuum

Abstract Background 14-3-3 is a family of conserved proteins that consist of seven isoforms which are highly expressed in the brain, and 14-3-3ζ is one of the isoforms encoded by the YWHAZ gene. Previous studies demonstrated that 14-3-3ζ is deposited in the neurofibrillary tangles of Alzheimer’s disease (AD) brains, and that 14-3-3ζ interacts with tau from the purified neurofibrillary tangles of AD brain extract. Methods The present study examined the cerebrospinal fluid (CSF) 14-3-3ζ 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. Associations between fluid biomarkers of AD (Aβ and tau pathologies, neurodegeneration, synaptic dysfunction and neuroinflammation) with CSF 14-3-3ζ were tested by linear regression models, adjusted by age, sex, years of education and APOE ε4 status. Linear mixed-effect models evaluated how baseline CSF 14-3-3ζ levels predict the changes of cognition scores and neuroimaging findings over time. Cox proportional hazards models assessed how baseline CSF 14-3-3ζ levels influence the relative risk of progression to AD in patients with MCI. Results CSF 14-3-3ζ levels were increased in prodromal AD, and further elevated in AD dementia stage. CSF 14-3-3ζ levels were associated with CSF phosphorylated tau 181(p-tau) and plasma p-tau, which are fluid biomarkers of tau pathology, and could predict tau positive status with high accuracy (area under the receiver operating characteristic curve [AUC], 0.891). CSF 14-3-3ζ levels were also associated with cognitive measurements and neuroimaging findings both at baseline and during follow up, and high CSF 14-3-3ζ levels were associated with subsequent progression to AD dementia in patients with MCI. Conclusions This study suggests that CSF 14-3-3ζ is a potential diagnostic and prognostic biomarker of AD that may be useful in clinical practice.