Peripheral Transport Proteins Were Associated with 4-Year Cognitive Decline in APOE ɛ4 Non-Carriers: A Longitudinal, Population-Based Study

Abstract

Background: Soluble low-density lipoprotein receptor-related protein-1 (sLRP1) and soluble receptor of advanced glycation end products (sRAGE) play major roles in peripheral clearance of amyloid-β (Aβ). Objective: To determine the relationship between baseline sLRP1/sRAGE and early cognitive decline in a longitudinal study and explore the possible effect of apolipoprotein E (APOE) on their association. Methods: Cognitively normal subjects were followed-up for 4 years. The baseline plasma levels of sLRP1 and sRAGE were measured using commercial ELISA kits. Global cognition was evaluated by Mini-Mental State Examination (MMSE), and cognitive decline was defined as a ≥2-point decrease of MMSE after 4 years. The association between baseline sLRP1/sRAGE and 4-year cognitive decline were analyzed using logistic regression analysis. Interaction analysis was performed to discover the potential effect of APOE genotype on the relationship. Results: 769 participants were included in the final analysis, with 122 subjects (15.86%) were cognitive decline. Baseline sLRP1/sRAGE levels were not associated with 4-year cognitive decline after multivariable adjustments in the total cohort. However, there was significant interaction effect between sRAGE and APOE genotype on cognitive decline (adjusted odds ratio [OR] = 2.09, 95% confidence interval [CI]: 1.13–3.86, p = 0.019). Lower levels of sRAGE were associated with increased risk of cognitive decline among APOE ɛ4 non-carriers (adjusted OR = 1.60, 95% CI: 1.04–2.48, p = 0.034). Conclusion: Individuals with lower levels of sRAGE had an increased risk of 4-year cognitive decline in APOE ɛ4 non-carriers, indicating that the association between sRAGE and cognitive decline might depend on the APOE genotype. However, the specific mechanisms need to be further elucidated.