Amyloid-β Deposition Predicts Oscillatory Slowing of Magnetoencephalography Signals and a Reduction of Functional Connectivity over Time in Cognitively Unimpaired Adults

With the ongoing developments in the field of anti-amyloid therapy for Alzheimer's disease, it is crucial to better understand the longitudinal associations between amyloid-β deposition and altered network activity in the living human brain. We included 110 cognitively unimpaired individuals (67.9 ± 5.7 years), who underwent [F]flutemetamol (amyloid-β)-PET imaging and resting-state magnetoencephalography (MEG) recording at baseline and 4-year follow-up. We tested associations between baseline amyloid-β deposition and MEG measures (oscillatory power and functional connectivity). Next, we examined the relationship between baseline amyloid-β deposition and longitudinal MEG measures, as well as between baseline MEG measures and longitudinal amyloid-β deposition. Finally, we assessed associations between longitudinal changes in both amyloid-β deposition and MEG measures. Analyses were performed using linear mixed models corrected for age, sex and family. At baseline, amyloid-β deposition in orbitofrontal-posterior cingulate regions (i.e. early Alzheimer's disease regions) was associated with higher theta (4-8 Hz) power ( = 0.17, < 0.01) in- and lower functional connectivity [inverted Joint Permutation Entropy (JPE) theta, = -0.24, < 0.001] of these regions, lower whole-brain beta (13-30 Hz) power ( = -0.13, < 0.05) and lower whole-brain functional connectivity (JPE theta, = -0.18, < 0.001). Whole-brain amyloid-β deposition was associated with higher whole-brain theta power ( = 0.17, < 0.05), lower whole-brain beta power ( = -0.13, < 0.05) and lower whole-brain functional connectivity (JPE theta, = -0.21, < 0.001). Baseline amyloid-β deposition in early Alzheimer's disease regions also predicted future oscillatory slowing, reflected by increased theta power over time in early Alzheimer's disease regions and across the whole brain ( = 0.11, = 0.08, < 0.001), as well as decreased whole-brain beta power over time ( = -0.04, < 0.05). Baseline amyloid-β deposition in early Alzheimer's disease regions also predicted a reduction in functional connectivity between these regions and the rest of the brain over time (JPE theta, = -0.07, < 0.05). Baseline whole-brain amyloid-β deposition was associated with increased whole-brain theta power over time ( = 0.08, < 0.01). Baseline MEG measures were not associated with longitudinal amyloid-β deposition. Longitudinal changes in amyloid-β deposition in early Alzheimer's disease regions were associated with longitudinal changes in functional connectivity of early Alzheimer's disease regions (JPE theta, = -0.19, < 0.05) and the whole brain [corrected amplitude envelope correlations alpha (8-13 Hz), = -0.22, < 0.05]. Finally, longitudinal changes in whole-brain amyloid-β deposition were associated with longitudinal changes in whole-brain relative theta power ( = 0.21, < 0.05). Disruptions of oscillatory power and functional connectivity appear to represent early functional consequences of emerging amyloid-β deposition in cognitively unimpaired individuals. These findings suggest a role for neurophysiology in monitoring disease progression and potential treatment effects in pre-clinical Alzheimer's disease.