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

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 (sPDGFRβ). Ovid MEDLINE, Embase, and Web of Science were searched on 30 ^th June, 2026. Eligible peer-reviewed human studies reported Q-Alb or blood or CSF sPDGFRβ 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 sPDGFRβ. Random-effects meta-analyses determined that APOE ε2 carriage was associated with higher Q-Alb ( g = 0.29, 95% CI 0.11 to 0.46). APOE ε4 carriage was not associated with Q-Alb overall ( g = .13, 95% CI -.17 to .43) or sPDGFRβ overall ( g = .10, 95% CI -.21 to .40). Genotype-specific Q-Alb analyses suggested medium positive but non-significant effects among ε4/ε4 and ε2/ε4 carrier subgroups. For sPDGFRβ, 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 ε4-associated alterations in Q-Alb and sPDGFRβ remained inconclusive, highlighting the need for further study across the spectrum of cognitive ageing and dementia. In contrast, APOE ε2 carriage was associated with greater barrier dysfunction as indexed by Q-Alb, broadening the predominant focus on APOE ε4 and identifying ε2 as a potentially important but understudied contributor to altered neurovascular function.