An Inverse U-Shaped Curve of Resting-State Networks in Individuals at High Risk of Alzheimer’s Disease

Objective: Higher functional connectivity (FC) in resting-state networks has been shown in individuals at risk of Alzheimer’s disease (AD) by many studies. However, the longitudinal trajectories of the FC remain unknown. The present 35-month follow-up study aimed to explore longitudinal changes in higher FC in multiple resting-state networks in subjects with the apolipoprotein E ε4 allele (ApoE4) and/or amnestic mild cognitive impairment (aMCI).

Methods: Fifty-one subjects with aMCI and 64 cognitively normal (CN) subjects underwent neuropsychological tests and resting-state functional magnetic resonance imaging (fMRI) scans twice from April 2011 to June 2015. Subjects were divided into 4 groups according to diagnosis and ApoE4 status. The CN non-ApoE4 group served as a control group, and other groups served as AD risk groups. The cross-sectional and longitudinal patterns of multiple resting-state networks, including default mode network, hippocampus network, executive control network, and salience network, were explored by comparing FC data between groups and between time points, respectively.

Results: At baseline, compared with the control group, the AD risk groups showed higher FC with 8 regions in multiple networks. At follow-up, 6 of the regions displayed longitudinally decreased FC in AD risk groups. In contrast, the FC with all of these regions was maintained in the control group. Notably, among the 3 risk groups, most of the higher FC at baseline (5 of the 8 regions) and longitudinally decreased FC at follow-up (4 of the 6 regions) were shown in the aMCI ApoE4 group.

Conclusions: Higher resting-state FC is followed by a decline in subjects at AD risk, and this inverse U-shaped trajectory is more notable in subjects with higher risk.