APOE Genotype and Fluid Biomarkers of Blood-Brain Barrier Integrity: A Systematic Review and Meta-Analysis

Abstract

Apolipoprotein E (APOE) genotype is theorised to influence dementia risk partly through effects on blood-brain barrier (BBB) function, but clinical studies examining APOE effects on BBB biomarkers report inconsistent results. Therefore, this systematic review and meta-analysis quantified associations between APOE genotype and two commonly used fluid biomarkers of CNS barrier function: cerebrospinal fluid (CSF)/serum albumin quotient (Q-Alb), and soluble platelet-derived growth factor receptor beta (sPDGFR{beta}). Ovid MEDLINE, Embase, and Web of Science were searched on 30th June, 2026. Eligible peer-reviewed human studies reported Q-Alb or blood or CSF sPDGFR{beta} by APOE genotype. Risk of bias was assessed using the Joanna Briggs Institute checklist. Twenty-eight studies involving 5,375 participants were included: 17 assessed Q-Alb and 11 assessed sPDGFR{beta}. Random-effects meta-analyses determined that APOE {varepsilon}2 carriage was associated with higher Q-Alb (g = 0.29, 95% CI 0.11 to 0.46). APOE {varepsilon}4 carriage was not associated with Q-Alb overall (g = .13, 95% CI -.17 to .43) or sPDGFR{beta} overall (g = .10, 95% CI -.21 to .40). Genotype-specific Q-Alb analyses suggested medium positive but non-significant effects among {varepsilon}4/{varepsilon}4 and {varepsilon}2/{varepsilon}4 carrier subgroups. For sPDGFR{beta}, exploratory subgroup analysis revealed effect estimates near zero in cognitively unimpaired participants, and a small positive non-significant effect in cognitively impaired participants. Larger effects were also observed in samples with an older mean age, although this was not statistically significant. Overall, evidence for APOE {varepsilon}4-associated alterations in Q-Alb and sPDGFR{beta} remained inconclusive, highlighting the need for further study across the spectrum of cognitive ageing and dementia. In contrast, APOE {varepsilon}2 carriage was associated with greater barrier dysfunction as indexed by Q-Alb, broadening the predominant focus on APOE {varepsilon}4 and identifying {varepsilon}2 as a potentially important but understudied contributor to altered neurovascular function.