Impact of apolipoprotein Ε4 (APOE ε4) on neuroimaging outcomes in cognitively healthy midlife adults: A systematic review

BACKGROUND: The apolipoprotein E ε4 (APOE ε4) allele is the strongest genetic risk factor for Alzheimer's disease (AD); however, its neurobiological impact assessed by neuroimaging outcomes during midlife, before the onset of cognitive impairment, has not been summarised. This systematic review synthesises evidence on neuroimaging differences associated with APOE ε4-carrier status in cognitively healthy midlife adults and evaluates whether AD-related risk can be detected across imaging modalities. METHODS: A literature search was conducted up until November 2025 to identify studies reporting neuroimaging outcomes in healthy adults aged 30-60 years with known APOE genotype. Eligible studies employed positron emission tomography (PET) and/or magnetic resonance imaging (MRI) and reported outcomes stratified by APOE ε4-carrier status. Risk of bias was assessed using the ROBINS-E tool, and a narrative synthesis was performed. RESULTS: Searches yielded 7786 articles, and 46 studies met the inclusion criteria. Nine studies used PET, forty used MRI, and three of these studies employed both modalities. Substantial heterogeneity in methods and outcome reporting meant that a meta-analysis was not feasible. PET evidence consistently identified greater amyloid deposition and lower glucose metabolism in midlife APOE ε4-carriers compared with non-carriers, while MRI findings most reliably indicate higher cerebral blood flow. In contrast, other MRI-derived structural, microstructural, functional, and metabolic findings were mixed and largely inconclusive. CONCLUSION: Cognitively healthy APOE ε4-carriers demonstrate measurable neurobiological differences as early as midlife, consistent with a preclinical vulnerability associated with genetic risk for AD. These findings highlight the importance of characterising APOE-related mechanisms during midlife to inform early detection strategies and the development of preventative interventions for AD.