Reelin Plasma Levels Identify Cognitive Decline in Alcohol Use Disorder Patients During Early Abstinence: The Influence of APOE4 Expression

Abstract

Background Apolipoprotein E (APOE)-4 isoform, Reelin and Clusterin share VLDLR and APOER2 receptors and are related to cognition in neuropsychiatric disorders. These proteins are expressed in plasma and brain but studies involving plasma expression and cognition are scarce. Methods We studied the peripheral expression (plasma and PBMCs) of these proteins in 24 Alcohol Use Disorder (AUD)-diagnosed middle-aged subjects at 4-12 weeks of abstinence (t=0) and 34 controls. Cognition was assessed using the 'Test of Detection of Cognitive Impairment in Alcoholism' (TEDCA). In a follow-up study (t=1), we measured Reelin levels and evaluated cognitive improvement at six months of abstinence. Results APOE4 isoform was present in 37.5% and 58.8% of patients and controls, respectively, reaching similar plasma levels in ε4 carriers, regardless of whether they were AUD subjects or controls. Plasma Reelin and Clusterin were higher in the AUD group, and Reelin levels peaked inpatients expressing APOE4 (p<0.05, ⴄ 2=0.09), who showed reduced VLDLR and ApoER2 expression in PBMCs. APOE4 had a negative effect on Memory/Learning mainly in the AUD group (p<0.01, ⴄ 2=0.15).Multivariate logistic regression analyses identified plasma Reelin as a good indicator of AUD cognitive impairment at t=0.At t=1, AUD subjects showed lower Reelin levels versus controls, along with some cognitive improvement. Conclusions Reelin plasma levels are elevated during early abstinence in AUD subjects who express the APOE4 isoform, identifying cognitive deterioration to a great extent, and it may participate as a homeostatic signal for cognitive recovery in the long-term.

Divergent Roles of APOAI and APOM in the Identification of Alcohol Use Disorder and Their Association With Inflammation and Cognitive Decline: A Pilot Study

“…In patients, AUD diagnosis was conducted by expert clinicians based on DSM-5 criteria ( APA, 2014 ). Abstinence, at least 4 weeks to minimize the potential influence of recent alcohol use ( Escudero et al, 2023 ), was monitored through exhaled breath control.…”

“…The blood was drawn by venipuncture into BD vacutainer tubes containing K2-EDTA anticoagulant (BD, Franklin Lakes, NJ, USA). Plasma was obtained by centrifugation at 1800 rpm for 10 minutes at 4°C following our previous studies ( Escudero et al, 2023 ). All samples were coded anonymously and stored at −80°C until immunoassay analysis.…”

“…Alcohol abuse induces neuroinflammation, contributing to cognitive and emotional alterations ( Spear, 2018 ). Exploring the microbiota-gut-brain axis and alcohol-induced inflammation offers new avenues for identifying potential biomarkers of cognitive decline in AUD ( Orio et al, 2019 ; Rodriguez-Gonzalez et al, 2020 ; Escudero et al, 2023 ). Our previous studies showed that elevations in proinflammatory molecules in peripheral blood mononuclear cells or plasma of women binge drinkers were associated with worse scores in cognitive flexibility and episodic memory ( Orio et al, 2018 ).…”

“…Specifically, elevated endotoxin lipopolysaccharide (LPS) plasma levels were negatively correlated with scores on delayed recall ( Orio et al, 2018 ). Recent studies highlight the potential of peripheral cytokines and inflammatory-related molecules as biomarkers of alcohol consumption or cognitive impairment in AUD patients ( García-Marchena et al, 2020 ; Requena-Ocaña et al, 2022 ; Escudero et al, 2023 ). However, identifying reliable peripheral biomarkers for detecting cognitive impairment in AUD remains a scientific challenge.…”

“…APOE is the most studied in the context of alcohol abuse ( Downer et al, 2014 ; Slayday et al, 2021 ), since the isoform APOE4 appears to have a role in neuroinflammation ( Kloske and Wilcock, 2020 ; Duro et al, 2022 ) and cognitive impairment (reviewed in Parhizkar et al, 2022 ). Recently, we observed that AUD patients carrying the APOE4 isoform exhibited higher levels of plasma Reelin (a protein that shares receptors with APOE4) and more severe cognitive impairment ( Escudero et al, 2023 ). There are other plasma apolipoproteins, such as APOAI, APOB, APOCIII, APOE, APOH, APOM, or APOJ that emerge as interesting candidates in this field.…”