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Accumulating evidence suggests vascular dysregulation in preclinical Alzheimer's disease. In this study, cerebral hemodynamics and their coupling with cognition in middle-aged apolipoprotein ε4 carriers (APOEε4+) were investigated. Longitudinal 3 T T1-weighted and arterial spin labelling MRI data from 158 participants (40–59 years old) in the PREVENT-Dementia study were analysed (125 two-year follow-up). Cognition was evaluated using the COGNITO battery. Cerebral blood flow (CBF) and cerebrovascular resistance index (CVRi) were quantified for the flow territories of the anterior, middle and posterior cerebral arteries. CBF was corrected for underlying atrophy and individual hematocrit. Hemodynamic measures were the dependent variables in linear regression models, with age, sex, years of education and APOEε4 carriership as predictors. Further analyses were conducted with cognitive outcomes as dependent variables, using the same model as before with additional APOEε4 × hemodynamics interactions. At baseline, APOEε4+ showed increased CBF and decreased CVRi compared to non-carriers in the anterior and middle cerebral arteries, suggestive of potential vasodilation. Hemodynamic changes were similar between groups. Interaction analysis revealed positive associations between CBF changes and performance changes in delayed recall (for APOEε4 non-carriers) and verbal fluency (for APOEε4 carriers) cognitive tests. These observations are consistent with neurovascular dysregulation in middle-aged APOEε4+. [ABSTRACT FROM AUTHOR]

In the last decade, extensive research has emerged into understanding the impact of risk factors for Alzheimer's Disease (AD) on brain in pre-symptomatic stages. We investigated the neuroimaging correlates of the APOEe4 genetic risk factor for AD in young adulthood, its relationship with cognition, and potential effects of other variables on the findings. While conventional volumetric analyses revealed no consistent differences, more sophisticated analyses identified subtle structural differences between APOEe4 carriers and non-carriers. Findings from diffusion studies were limited, but functional studies demonstrated consistent alterations in connectivity and activity. The complex relationship between APOE genotype, neuroimaging variables, and cognition revealed no consensus on the directionality of findings. Methodological choices, including analytical approaches, sample size, and the influence of other genes, gender, and ethnicity, varied across studies, impacting comparability and generalizability. Recommendations for future research include multimodal and longitudinal imaging, standardisation of pipelines, advanced analytical techniques, and collaborative data pooling. • Genetic-related vulnerability in brain structure/function occurs in early adulthood. • Functional differences were more consistent than structural differences. • Exploring microstructure seems to be a promising avenue for future research. • Relationship between imaging variables and results from multiple cognitive domains. [ABSTRACT FROM AUTHOR]