Early increase of cerebrospinal fluid 14-3-3ζ protein in the alzheimer's disease continuum

Background: The earlier research has shown that the 14-3-3 zeta is increased in neurofibrillary tangles (NFTs) of human Alzheimer's disease (AD) brains and stimulates the tau phosphorylation. Cerebrospinal fluid (CSF) 14-3-3 zeta along the AD continuum remains to be explored. Methods: We analyzed 113 cognitive normal (CN) controls, 372 patients with mild cognitive impairment (MCI), and 225 patients with AD dementia from the Alzheimer's Disease Neuroimaging Initiative database. CSF 14-3-3 zeta protein was measured by Mass Spectrometry. Results: We observed higher CSF 14-3-3 zeta in the MCI group vs. the CN group and in the AD group vs. the MCI or CN group. The 14-3-3 zeta was able to distinguish AD from CN and MCI. High 14-3-3 zeta predicted conversion from MCI to AD. In CSF, phosphorylated tau at threonine 181 and total-tau were associated with 14-3-3 zeta in MCI and AD groups, and beta-amyloid (A beta) 42 correlated with 14-3-3 zeta in the MCI group. Baseline high 14-3-3 zeta was associated with cognitive decline, brain atrophy, glucose hypometabolism, and A beta deposition in MCI and AD at baseline and follow-up. Conclusion: Our findings revealed the potential diagnostic and prognostic utility of CSF 14-3-3 zeta in the AD continuum. The 14-3-3 zeta could be a promising therapeutic target for the intervention of AD.