Reelin plasma levels predict cognitive decline in Alcohol Use Disorder: peak levels in patients expressing plasma APOE4 protein

Abstract

ABSTRACTBackgroundHuman apolipoprotein (APO)-E4 has been related to neuropsychiatric disorders such as Alzheimer’s disease and cognitive decline. Reelin and Clusterin share the VLDLR and ApoER2 receptors with APOE4. Here we checked the role of these components in Alcohol Use Disorder (AUD)-induced cognitive decline.MethodsThis is a cross-sectional study with AUD-diagnosed patients (DSM-5) (n=24) recruited from an outpatient ‘Alcohol Programme’ and matched controls (n=34). Participants were assessed by the validated ‘Test of Detection of Cognitive Impairment in Alcoholism’ (TEDCA). APOE4 presence in plasma (distinguishing APOE4 carriers and no carriers subjects) and its levels were performed by ‘e4Quant’ technique. The rest of biological markers were tested by Enzyme-Linked Immunosorbent Assay kits.ResultsPlasma APOE4 isoform was present in 37.5% and 58.8% of patients and controls, respectively. Quantification analyses revealed that APOE4 reached similar plasma levels in carriers independently if they were AUD subjects or controls. Circulant plasma APOE4 had a negative effect on AUD’s cognition, specifically affecting Memory/Learning (p<0.01, η2=0.15). Plasma Clusterin and Reelin increased in patients but, interestingly, Reelin plasma levels peaked in patients expressing APOE4 (p<0.05, η2=0.09), who showed reduced VLDL and ApoER2 expression in peripheral blood mononuclear cells (PBMCs). Reelin was a good predictor of cognitive loss in patients, accounting for the 42.3% and 54.0% of general intelligence and executive function impairments, respectively.ConclusionsReelin plasma levels are increased in AUD patients who express the APOE4 isoform, predicting cognitive deterioration to a great extent. Remarkably, plasma Reelin helps to differentiate between AUD patients with and without cognitive decline.Significance StatementFinding biological markers that predict a worse evolution in neuropsychiatric disorders may help to assist vulnerable patients appropriately. In this sense, in this study we found a biological marker, Reelin, which is elevated in patients with diagnosis of alcohol use disorder (AUD) that underwent an outpatient treatment. Interestingly, Reelin plasma levels were elevated in patients that also express APOE4, an aberrant protein present only in a small percentage of the population which is related to neuroinflammation and cognitive impairment (i.e. it is involved in Alzheimer’s disease). We observed that Reelin plasma levels negatively correlate with cognitive scores, being Reelin a good predictor of cognitive impairment in patients. These results may have implications for the follow-up of AUD patients in outpatient treatment.