Functional connectivity of the frontoparietal control network is positively associated with cognition, independent of amyloid and tau burden, in the A4 study

Abstract

AbstractBackgroundThe Anti‐Amyloid in Asymptomatic Alzheimer’s Disease (A4) study is the first secondary prevention trial of an anti‐amyloid therapy, solanezumab, in cognitively unimpaired older adults with elevated amyloid‐beta (Ab)‐PET burden. The inclusion of resting‐state functional connectivity MRI (fcMRI) as a secondary outcome measure is a novelty for clinical trials. Despite promising longitudinal findings, there is mixed evidence for cross‐sectional associations between functional connectivity in the default mode (DMN) and frontoparietal control (FPCN) networks, with Ab, tau, and cognition. Here, in a large cross‐sectional sample, we investigate these associations and assess whether fcMRI accounts for variability in cognition that is not attributable to Ab or tau.Method1,641 participants from A4 and the LEARN observational arm with fcMRI passed quality control and had complete data for sociodemographics, cognition, and Ab (Florbetapir)‐PET (Table 1). A subset had tau (Flortaucipir)‐PET (n = 420). Within‐network connectivity estimates of the default mode (DMN) and left and right frontoparietal control networks (FPCN) were obtained using template‐based rotation (Fig. 1).Using hierarchical regressions, we examined the independent associations of functional connectivity with Ab burden (mean cortical standardized uptake value [SUVr]), tau burden (mean of inferior temporal and entorhinal SUVrs), and cognition (Preclinical Alzheimer’s Cognitive Composite), independent of covariates (age, sex, education level, head motion, scanner and, where applicable, Ab and/or tau burden).ResultAb and tau burden were not independently associated with DMN or right FPCN connectivity. Higher tau was associated with reduced left FPCN connectivity, independent of Ab. Stronger left and right FPCN connectivity were associated with better cognition, independent of Ab and tau (Table 2). This association was stronger for the left FPCN.ConclusionFPCN functional connectivity is associated with better cognition, independent of Ab and tau burden. This association was strongest in the left FPCN and supports evidence that implicates FPCN connectivity in cognitive reserve and resilience. While this association is robust, weak effect sizes suggest that functional connectivity explains a limited amount of variability in cognition after accounting for covariates and AD pathology. Future release of the A4 study longitudinal data will enable quantification of the added value of fcMRI in AD clinical trials.