Impaired Lipoprotein Receptor-Mediated Peripheral Binding of Plasma Amyloid-β is an Early Biomarker for Mild Cognitive Impairment Preceding Alzheimer's Disease

Abstract

Soluble circulating low density lipoprotein receptor-related protein-1 (sLRP) provides key plasma binding activity for Alzheimer's disease (AD) amyloid-β peptide (Aβ). sLRP normally binds 70–90% of plasma Aβ preventing free Aβ access to the brain. In AD, Aβ binding to sLRP is compromised by increased levels of oxidized sLRP which does not bind Aβ. Here, we determined plasma oxidized sLRP and Aβ_40/42 sLRP-bound, other proteins-bound and free plasma fractions, cerebrospinal fluid (CSF) tau/Aβ₄₂ ratios, and mini-mental state examination (MMSE) scores in patients with mild cognitive impairment (MCI) who progressed to AD (MCI-AD, n = 14), AD (n = 14) and neurologically healthy controls (n = 14) recruited from the Göteborg MCI study. In MCI-AD patients prior to conversion to AD and AD patients, the respective increases in oxidized sLRP and free plasma Aβ₄₀ and Aβ₄₂ levels were 4.9 and 3.7-fold, 1.8, and 1.7-fold and 4.3 and 3.3-fold (p < 0.05, ANOVA with Tuckey post-hoc test). In MCI-AD and AD patients increases in oxidized sLRP and free plasma Aβ₄₀ and Aβ₄₂ correlated with increases in CSF tau/Aβ₄₂ ratios and reductions in MMSE scores (p < 0.05, Pearson analysis). A heterogeneous group of ‘stable’ MCI patients that was followed over 2–4 years (n = 24) had normal CSF tau/Aβ₄₂ ratios but increased oxidized sLRP levels (p < 0.05, Student's t test). Data suggests that a deficient sLRP-Aβ binding might precede and correlate later in disease with an increase in the tau/Aβ₄₂ CSF ratio and global cognitive decline in MCI individuals converting into AD, and therefore is an early biomarker for AD-type dementia.