Pulse pressure trajectories predict brain microstructure in an APOE‐dependent manner among cognitively normal older adults

Abstract

AbstractBackgroundArterial stiffness is associated with increased risk of cognitive decline and dementia in older adults; however, the mechanisms by which arterial stiffness impacts brain health remain unclear. We examined whether trajectories of pulse pressure (PP), a surrogate marker of arterial stiffness, beginning in midlife predicted brain microstructure at older age, using the multicompartment diffusion MRI technique restriction spectrum imaging (RSI). We assessed whether effects of PP on executive function were mediated by brain microstructure, and whether APOE genotype modified associations between PP and microstructure.MethodWe included 146 cognitively normal adults (mean age=76.6, SD=6.8 years) who underwent RSI and cognitive testing in 2014‐2016 and measurements of PP up to eight times before MRI, from 1984‐2016. Participants were classified according to PP trajectory using latent class growth modeling. Restricted isotropic diffusion (RI), neurite density, isotropic free water (IFW), and hindered isotropic diffusion (HI) were computed in five subcortical regions and 15 white matter tracts. Multiple linear regression examined associations between PP trajectories and microstructure, and between microstructure and Trails B performance. Mediation analyses, adjusted for covariates, evaluated whether microstructure mediated effects of PP trajectories on executive function. Age‐and‐sex‐adjusted partial correlations tested associations between continuous PP and RSI metrics by APOE genotype (ε4 carriers versus non‐carriers).ResultParticipants with high PP trajectories (n=50) had lower RI and higher HI and IFW in multiple subcortical regions and fiber tracts compared to those with low PP trajectories (n=96), and of these, eight were also associated with Trails B performance. Associations between high PP trajectories and worse executive function were mediated by lower RI in the amygdala (βa*βb=4.13, 95%CI=0.91‐11.01) and in several fiber tracts including the parachippocampal cingulum (βa*βb=3.77, 95%CI=0.95‐9.93) and fornix (βa*βb=3.71, 95%CI=0.59‐10.19). High PP more strongly correlated with lower RI in the hippocampus, uncinate fasciculus, and inferior fronto‐occipital fasciculus (IFO); with high IFW in the IFO and superior corticostriatal fasciculus, and with high amygdala HI, among APOE4 ε4 carriers than non‐carriers (Figure).ConclusionProlonged elevated PP predicts subcortical and white mater microstructural abnormalities, particularly for those at greater risk for dementia, and may contribute to impaired executive function via microstructural injury.