Amyloid‐related default mode network hyperconnectivity and longitudinal decline in network distinctiveness in preclinical Alzheimer's disease

Abstract INTRODUCTION We investigated stage‐specific alterations in functional connectivity (FC) of the default mode network (DMN) across the Alzheimer's disease (AD) continuum and tested whether early amyloid beta (Aβ)–related changes in within‐DMN FC (DMN‐FC within ) predicted longitudinal alterations in DMN between‐network connectivity (DMN‐FC between ). METHODS Resting‐state functional magnetic resonance imaging (fMRI) data were analyzed from 396 older adults: Aβ‐negative cognitively normal (CN−, n = 213), Aβ‐positive CN (CN+, n = 37), Aβ‐positive mild cognitive impairment (MCI+, n = 72), and Aβ‐positive dementia (dementia+, n = 74). Cross‐sectional analyses compared DMN‐FC across groups and examined associations with continuous Aβ burden at baseline. Longitudinal analyses in 171 CN participants with 2‐year follow‐up (CN−, n = 147; CN+, n = 24) tested whether baseline DMN‐FC within predicted changes in DMN‐FC between . RESULTS CN+ individuals showed elevated DMN‐FC within and reduced DMN‐FC between relative to other groups. In CN, Aβ burden was associated with FC, and baseline DMN‐FC within predicted longitudinal increases in DMN‐FC between only in CN+. DISCUSSION Aβ‐related hyperconnectivity characterizes preclinical AD and may drive progressive network‐level vulnerability. Highlights Cognitively normal amyloid beta (Aβ)–positive (CN+) individuals showed stronger connectivity within the default mode network (DMN). CN+ individuals also showed weaker links between the DMN and other brain networks. Amyloid was not linked to connectivity changes in cognitively impaired adults. Higher DMN connectivity predicted broader network changes in CN+ individuals.