Apolipoproteins as markers of clinical progression in early Alzheimer's disease
Jagan A Pillai1*, Lynn Bekris1, James Bena1, Sean Maxwell2, Bruce Lamb3, James Leverenz1,
1Lou Ruvo Center for Brain Health, Cleveland Clinic, Cleveland, OH, Center for Proteomics, Case Western Reserve University, Cleveland, OH, 3Indiana University, Bloomington, IN
Among the most replicable AD genome-wide association studies (GWAS) positive 'hits' are APOE and genes relating to protein-lipid complex pathways: ABCA7, BIN1, APOC1. Metabolomics in AD have also described changes in lipid pathways. These studies have yet to relate lipoprotein changes to AD CSF biomarker levels and/or rate of clinical progression in the MCI stage of AD.
Functional analysis by gene ontology (GO) enrichment software identified 'protein-lipid complex subunit organization' related proteins from a multiplex panel of 86 protein analytes, concomitantly in the CSF and plasma of MCI-AD patients (n=48). These lipoproteins were APOC1, APOA2, APOA1, APOC3, Apolipoprotein A and Myeloperoxidase. In this longitudinal observational study subjects had cognitive and biomarker evaluations at baseline and a follow up cognitive evaluation at 15 months by Dementia Rating Scale (DRS) and Clinical Dementia Rating: Sum of Boxes (CDR-SB)(n=30). Results corrected for false discovery rate (0.05).
CSF Aβ42 levels were significantly correlated to CSF APOCI (ρ=0.30, p=0.04). CSF total-tau and phosphorylated-tau levels did not correlate with lipoproteins noted above. DRS change over 15 months, was related to CSF APOCI among APOE ε4 carriers (ρ=0.5, p=0.038) and CDR-SB change over 15 months was related to plasma APOCIII among all subjects (ρ=0.6, p=0.001) and among APOE ε4 carriers. A multiple regression model with all age, sex, baseline MMSE and plasma APOCIII predictors produced R² = 0.554, F(4, 23) = 7.1, p = 0.001.Baseline MMSE and APOCIII levels had significant negative regression weights indicating patients with lower MMSE and plasma APOCIII were expected to have a larger CDR change.
Clinical disease progression in MCI-AD was related to the plasma apolipoprotein APOCIII. This effect was more notable among APOE ε4 carriers.
Funding: K23AG055685, NIRG-305310