Functional Connectivity Alterations in Asymptomatic Familial Early-Onset Alzheimer's Disease Caused by APP Duplication

BACKGROUND AND OBJECTIVESAutosomal dominant mutations of Alzheimers Disease (AD) are highly penetrant allowing to characterize the asymptomatic phase of this devastating condition. We investigated brain-wide functional alterations in the asymptomatic phase of autosomal dominant early-onset AD (ADEOAD) and explored whether a functional brain fingerprint of the disease can be found prior to clinical manifestation. METHODSIn this cross-sectional study fourteen asymptomatic APP-dup carriers and eight APP-dup non-carriers from the same kindred underwent neurological and neuropsychological examination and resting-state fMRI scanning. The functional connectome of each participant was constructed based on 264 pre-defined brain regions, which were classified into seven different sensory (Visual and Somatomotor) and association (Default, Frontoparietal, Ventral Attention, Dorsal Attention, Limbic) cortical networks. Time courses were extracted from all regions in each participant and brain-wide Fishers z-transformed Pearson correlation (z(r)) from each region to all other regions was calculated, resulting in a 264 x 264 connectivity matrix per participant. These matrices were used for network similarity and connectome-based predictive modelling (CPM) analyses aimed to characterize age-dependent functional connectivity alterations within the carriers group that reflect their position along the neurodegeneration trajectory. RESULTSComparing individual connectomes within the carriers group to the average connectome in the non-carrier group, we found that network similarity between groups decreased in an age-dependent manner. With age the APP-dup connectome diverged from the non-carriers connectome, with this difference being driven primarily by alterations in association networks and specifically involving the Default and Frontoparietal networks. Moreover, decreases in network similarity of association networks correlated with decreased performance on a visuospatial memory task. Using CPM, we found that in this family, carriers age can be predicted independent of the non-carriers control group and that this prediction is based mainly on connections within and between association networks. DISCUSSIONFunctional connectivity was used to assess the progress of AD pathology in asymptomatic carriers of an autosomal-dominant deterministic gene. Our results show that in asymptomatic APP-dup carriers, aging is associated with functional connectivity alterations that preferentially involve association networks. Understanding these alterations might lay the foundation for development of novel diagnostic markers and assist in determining the appropriate timing of therapeutic interventions in ADEOAD.