Alzheimers risk markers and resting-state dynamic functional connectivity: Cross-Sectional Findings from the AGUEDA Study

Background and ObjectivesAlzheimers disease (AD) is characterized by early disruptions in brain connectivity. However, how genetic and biological markers of AD risk relate to dynamic functional connectivity (dFC) remains unclear. This study examined whether AD-related pathology, genetic risk, and blood-based biomarkers (BBMs) of neurodegeneration are associated with local and distant resting-state dFC patterns, and whether these relate to cognitive performance in cognitively normal older adults. Research Design and MethodsWe analyzed baseline data from 86 cognitively normal older adults (71.6 {+/-} 3.9 years; 60.5% female) enrolled in the AGUEDA trial (NCT05186090). Participants underwent A{beta}-PET imaging, APOE4 genotyping, and plasma quantification of BBMs (A{beta}42/40, BD-tau, GFAP, NfL, p-tau181, p-tau217). Resting-state fMRI was used to compute voxel-wise local and distant dFC using a stepwise connectivity framework. General linear models tested associations between AD pathology, APOE4 status, and BBMs with dFC, adjusting for age, sex, and education. Additional models examined links between dFC and six cognitive domains ResultsA{beta}-positive individuals and APOE4 carriers showed lower local connectivity in frontal regions, while APOE4 carriers exhibited higher distant connectivity in the superior motor area, inferior frontal gyrus, and anterior insula. Among BBMs, only neurofilament light chain (NfL) was associated with both lower local (insula, cingulate) and higher distant (precuneus, putamen, thalamus, supramarginal, superior motor area) connectivity. Regions showing higher distant connectivity related to APOE4 or NfL were associated with poorer cognitive performance. Discussion and ImplicationsDynamic functional connectivity reveals early network alterations in AD risk, characterized by reduced local and elevated distant connectivity--patterns linked to poorer cognition and potential early neurofunctional vulnerability in aging.