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Alterations in cognitive performance have been noted in nondemented subjects with elevated accumulation of amyloid-β (Aβ) fibrils. However, it is not yet understood whether brain function is already influenced by Aβ deposition during the very earliest stages of the disease. We therefore investigated associations between [ 18 F]Flutemetamol PET, resting-state functional connectivity, gray and white matter structure and cognitive performance in 133 cognitively normal elderly that exhibited normal global Aβ PET levels. [ 18 F]Flutemetamol uptake in regions known to accumulate Aβ fibrils early in preclinical AD (i.e., mainly certain parts of the default-mode network) was positively associated with dynamic but not static functional connectivity ( r  = 0.77). Dynamic functional connectivity was further related to better cognitive performance ( r  = 0.21–0.72). No significant associations were found for Aβ uptake with gray matter volume or white matter diffusivity. The findings demonstrate that the earliest accumulation of Aβ fibrils is associated with increased functional connectivity, which occurs before any structural alterations. The enhanced functional connectivity may reflect a compensatory mechanism to maintain high cognitive performance in the presence of increasing amyloid accumulation during the earliest phases of AD.

Association Between Earliest Amyloid Uptake and Functional Connectivity in Cognitively Unimpaired Elderly