Putative CSF protein biomarker candidates for amnestic mild cognitive impairment

Abstract

The identification of individuals at risk for Alzheimer's disease (AD) is essential for the timely administration of treatment approaches aimed at slowing the onset or progression of the disease. As amnestic forms of mild cognitive impairment (aMCI) may represent preclinical AD, the search for specific diagnostic biomarkers that characterize those with aMCI is a key research objective. Using surface enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDITOF-MS), we screened the cerebrospinal fluid (CSF) of Religious Orders Study participants with a clinical diagnosis of no cognitive impairment (NCI), aMCI, or mild/moderate AD for potential biomarkers. CSF was fractionated on immobilized metal affinity chromatography (IMAC) protein arrays preloaded with either gallium (IMAC-Ga), which binds phosphoproteins, or copper (IMAC-Cu) to isolate copper-binding proteins. SELDI TOF-MS analysis of the IMAC-Ga arrays revealed a phosphopeptide of 2490 Da that was selectively increased ~2-fold in aMCI and AD CSF compared to NCI. SELDI TOF-MS analysis of the IMAC-Cu arrays identified 2 proteins of 11.7 and 13.3 kDa that were both selectively increased ~1.5-1.6-fold in aMCI and AD CSF. Increasing levels of each protein were associated with poorer performance on the Mini Mental State Exam and higher Braak stage. Hence, increased CSF levels of these proteins may be potential biomarkers for preclinical AD and aid in the development of a CSF biomarker panel with high predictive value for identifying people who would most benefit from early therapeutic interventions to modify disease progression.