APOE ε4 Modifies Stage-Dependent Alterations in Circulating Brain-Derived Neurotrophic Factor Across the Alzheimer’s Disease Continuum: A Systematic Review and Meta-Analysis

Circulating Brain-Derived Neurotrophic Factor (BDNF) has been proposed as a blood-based marker of synaptic vulnerability in Alzheimer’s Disease (AD), but published findings vary across disease stages and cohorts. This review and meta-analysis examined whether APOE ε4 carrier status modifies stage-dependent alterations in serum or plasma BDNF across the AD continuum. PubMed, Web of Science, Scopus, and Google Scholar were searched using terms for BDNF, Alzheimer’s disease or Mild Cognitive Impairment (MCI), and APOE ε4. Eligible human studies reported circulating BDNF in AD, MCI, or cognitively normal participants, with extractable quantitative data and, where available, genotype-stratified results. Random-effects models pooled Standardized Mean Differences (SMDs); risk of bias, heterogeneity, publication bias, and evidence certainty were appraised using PRISMA 2020, NOS/RoB 2-aligned domains, and GRADE. AD was associated with lower circulating BDNF than cognitively normal status (SMD −0.28, 95% CI −0.47 to −0.09), whereas the overall MCI-control comparison was small and non-significant (SMD −0.12, 95% CI −0.31 to +0.07) with high heterogeneity. Genotype stratification clarified this heterogeneity: MCI ε4 carriers showed a meaningful reduction (SMD −0.48), while ε4 non-carriers showed no reduction. Older age and lower baseline Mini-Mental State Examination scores also explained part of MCI heterogeneity. Circulating BDNF is unlikely to function as a stand-alone diagnostic biomarker, but it may be clinically informative when interpreted alongside APOE ε4 status, disease stage, age, and cognitive severity. Future studies should standardize biospecimen handling and prospectively test BDNF as a prognostic and treatment-response marker.