Directed functional brain connectivity is altered in sub-threshold amyloid-β accumulators

Several studies have shown that amyloid-{beta} (A{beta}) deposition below the clinically relevant cut-off levels is associated with subtle changes in cognitive function and increases the risk for developing future Alzheimers disease (AD). Although functional MRI is sensitive to early alterations occurring during AD, sub-threshold changes in A{beta} levels have not been linked to functional connectivity measures. This study aimed to apply directed functional connectivity to identify early changes in network function in cognitively unimpaired participants who, at baseline, exhibit A{beta} accumulation below the clinically relevant threshold. To this end, we analyzed baseline functional MRI data from 113 cognitively unimpaired participants of the Alzheimers Disease Neuroimaging Initiative cohort who underwent at least one 18F-florbetapir-PET after the baseline scan. Using the longitudinal PET data, we classified these participants as A{beta} negative (A{beta}-) non-accumulators (n=46) and A{beta}-accumulators (n=31). We also included 36 individuals who were amyloid-positive (A{beta}+) at baseline and continued to accumulate A{beta} (A{beta}+ accumulators). For each participant, we calculated whole-brain directed functional connectivity networks using our own anti-symmetric correlation method and evaluated their global and nodal properties using measures of network segregation (clustering coefficient) and integration (global efficiency). When compared to A{beta}-non-accumulators, the A{beta}-accumulators showed lower global clustering coefficient. Moreover, the A{beta}+ accumulator group exhibited reduced global efficiency and clustering coefficient, which at the nodal level mainly affected the superior frontal gyrus, anterior cingulate cortex and caudate nucleus. In A{beta}-accumulators, global measures were associated with lower baseline regional PET uptake values, as well as higher scores on the Modified Preclinical Alzheimer Cognitive Composite. Our findings indicate that directed connectivity network properties are sensitive to subtle changes occurring in individuals who have not yet reached the threshold for A{beta} positivity, which makes them a potentially viable marker to detect negative downstream effects of very early A{beta} pathology. Significance StatementO_LIDirected functional connectivity measures are sensitive to very early changes in amyloid-{beta} deposition. C_LIO_LIAmyloid-{beta} burden is associated with decreases in global and nodal directed measures of network integration and segregation. C_LIO_LIMeasures of directed network integration and segregation are associated with subclinical cognitive changes in A{beta}-negative accumulators. C_LI