Vascular burden is associated with a decline in default-mode and global resting-state functional connectivity in individuals at risk for Alzheimer’s disease

Introduction. Cross-sectional studies suggest that cardiovascular risk factors and Alzheimer’s disease (AD) biomarkers are associated with abnormal brain resting-state functional connectivity in aging and AD; however, evidence is missing regarding longitudinal changes in functional connectivity. In this study, we investigate whether cholesterol levels and blood pressure are associated with changes in functional connectivity over time in asymptomatic individuals at risk for AD. The analyses were repeated with cerebral β-amyloid (Ab) and tau deposition in a subset of the participants. Methods. The study sample included 247 cognitively unimpaired individuals (185 women/ 62 men; mean [SD] age of 63 [5.3] years) of the PREVENT-AD cohort with a parental or multiple-sibling history of sporadic AD. Plasma total-, HDL-, and LDL-cholesterol and systolic and diastolic blood pressure were measured at baseline. Global brain functional connectivity, and connectivity from canonical functional networks, were computed from resting-state functional MRI obtained at baseline and up to four years of annual follow-ups, using a predefined functional parcellation. A subset of participants underwent tau-PET ([¹⁸F]Flortaucipir) and AβPET ([¹⁸F]NAV4694). Vascular and AD measures were examined as predictors of brain functional connectivity changes in linear mixed-effects models. Results. Higher total-cholesterol and LDL-cholesterol levels were associated with greater reduction of functional connectivity in the default-mode network over time. In addition, while overall whole-brain functional connectivity showed an increase over time across the entire sample higher diastolic blood pressure was associated with reduction in whole-brain functional connectivity. The associations were similar when the analyses were repeated using two other functional brain parcellations. The findings with total-cholesterol and diastolic blood pressure were also similar but attenuated when performed in a subsample of participants with PET (n=91), whereas AD biomarkers were not associated with changes in functional connectivity over time in this subsample. Conclusion. These findings provide evidence that vascular burden is associated with a decrease in brain functional connectivity over time in older adults with elevated risk for AD. The impact of vascular risk factors on functional brain changes might precede AD pathology-related changes.