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 [ ¹⁸F]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 (β = 0.17, P < 0.01) in- and lower functional connectivity [inverted Joint Permutation Entropy (JPE _inv) theta, β = −0.24, P < 0.001] of these regions, lower whole-brain beta (13–30 Hz) power (β = −0.13, P < 0.05) and lower whole-brain functional connectivity (JPE _inv theta, β = −0.18, P < 0.001). Whole-brain amyloid-β deposition was associated with higher whole-brain theta power (β = 0.17, P < 0.05), lower whole-brain beta power (β = −0.13, P < 0.05) and lower whole-brain functional connectivity (JPE _inv theta, β = −0.21, P < 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 (β = 0.11, β = 0.08, P < 0.001), as well as decreased whole-brain beta power over time (β = −0.04, P < 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 _inv theta, β = −0.07, P < 0.05). Baseline whole-brain amyloid-β deposition was associated with increased whole-brain theta power over time (β = 0.08, P < 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 _inv theta, β = −0.19, P < 0.05) and the whole brain [corrected amplitude envelope correlations alpha (8–13 Hz), β = −0.22, P < 0.05]. Finally, longitudinal changes in whole-brain amyloid-β deposition were associated with longitudinal changes in whole-brain relative theta power (β = 0.21, P < 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.