ASSOCIATION OF AMYLOID-SS SEQUESTER PROTEINS IN SERUM WITH COGNITIVE DECLINE, BRAIN ATROPHY, AND CEREBRAL BLOOD FLOW

Development of blood-based biomarkers for early detection of cognitive impairment is important to potentially reduce the number of patients with dementia. Mild cognitive impairment (MCI) is a syndrome defined as cognitive decline that is greater than expected for an individual's age and is regarded as a risk group for dementia. In healthy individuals, synapse damage by amyloid-ß is prevented by clearance mechanisms via apolipoproteins, complement system, and transthyretin (prealbumin). Recently, we revealed the clinical potential of apolipoprotein A1 (apoA1), complement C3, and transthyretin in the assessment of cognitive decline by longitudinal and cross-sectional studies using independent cohorts (Alzheimer & Dement DADM 1: 270-280, 2015). In this study, we developed conventional immune-assay for these blood-based biomarkers and tested their clinical potential for assessment of cognitive decline. The inactive form of C3 was proteolytically cleaved during activation, and the immunoassay specifically detected an inactive form of C3 but not the activated fragment. The least absolute shrinkage and selection operator (LASSO) modeling using glmnet package (ver. 1.9-5) for R (ver. 3.1.0) was used to evaluate the combination of multiple biomarkers. We categorized individuals according to MMSE score into four groups [score 27–30 (n = 71), 24–27 (n = 34), 20–23 (n = 17), and <20 (n = 20)] that were age-matched and compared levels of these three sequester proteins. Multivariable analysis revealed that a combination apoA1, transthyretin and complement C3 achieved an area under the curve of 0.86 (sensitivity: 80% and specificity: 80%) in MCI vs. non-demented healthy controls. We also analyzed blood sugar, total cholesterol, and high-density lipoprotein with these proteins. Decreased levels of apoA1, high-density lipoprotein and total cholesterol were associated with cerebral blood flow and brain atrophy. The current results are consistent with the hypothesis that individuals with decreased levels or impaired function of sequester proteins are susceptible to cognitive impairment. Thus, a set of sequester proteins could be blood-based biomarkers for assessment of early stages of cognitive decline.