Blood biomarkers in mild cognitive impairment patients: Relationship between analytes and progression to Alzheimer disease dementia

Background and purpose: Blood-based biomarkers are promising tools for the diagnosis of Alzheimer disease (AD) at prodromal stages (mild cognitive impairment [MCI]) and are hoped to be implemented as screening tools for patients with cognitive complaints. In this work, we evaluated the potential of peripheral neurological biomarkers to predict progression to AD dementia and the relation between blood and cerebrospinal fluid (CSF) AD markers in MCI patients referred from a general neurological department. Methods: A group of 106 MCI patients followed at the Neurology Department of Coimbra University Hospital was included. Data regarding baseline neuropsychological evaluation, CSF levels of amyloid beta 42 (A beta 42), A beta 40, total tau (t-Tau), and phosphorylated tau 181 (p-Tau181) were available for all the patients. A beta 42, A beta 40, t-Tau, p-Tau181, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) levels were determined in baseline stored serum and plasma samples by commercial SiMoA (Single Molecule Array) assays. Progression from MCI to AD dementia was assessed at follow-up (mean = 5.8 +/- 3.4 years). Results: At baseline, blood markers NfL, GFAP, and p-Tau181 were significantly increased in patients who progressed to AD at follow-up (p < 0.001). In contrast, plasma A beta 42/40 ratio and t-Tau showed no significant differences between groups. NfL, GFAP, and p-Tau181 demonstrated good diagnostic accuracy to identify progression to AD dementia (area under the curve [AUC] = 0.81, 0.80, and 0.76, respectively), which improved when combined (AUC = 0.89). GFAP and p-Tau181 were correlated with CSF Ab42. Association of p-Tau181 with NfL was mediated by GFAP, with a significant indirect association of 88% of the total effect. Conclusions Our findings highlight the potential of combining blood-based GFAP, NfL, and p-Tau181 to be applied as a prognostic tool in MCI.