AbstractAlzheimer’s disease (AD) is linked to changes in fMRI task activations and fMRI resting-state functional connectivity (restFC), which can emerge early in the timecourse of illness. Study of these fMRI correlates of unhealthy aging has been conducted in largely separate subfields. Taking inspiration from neural network simulations, we propose a unifying mechanism wherein restFC network alterations associated with Alzheimer’s disease disrupt the ability for activations to flow between brain regions, leading to aberrant task activations. We apply this activity flow modeling framework in a large sample of clinically unimpaired older adults, which was segregated into healthy (low-risk) and at-risk subgroups based on established imaging (positron emission tomography amyloid) and genetic (apolipoprotein) risk factors for AD. We identified healthy task activations in individuals at low risk for AD, and then by estimating activity flow using at-risk AD restFC data we were able to predict the altered at-risk AD task activations. Thus, modeling the flow of healthy activations over at-risk AD connectivity effectively transformed the healthy aged activations into unhealthy aged activations. These results provide evidence that activity flow over altered intrinsic functional connections may act as a mechanism underlying Alzheimer’s-related dysfunction, even in very early stages of the illness. Beyond these mechanistic insights linking restFC with cognitive task activations, this approach has potential clinical utility as it enables prediction of task activations and associated cognitive dysfunction in individuals without requiring them to perform in-scanner cognitive tasks.Significance StatementDeveloping analytic approaches that can reliably predict features of Alzheimer’s disease is a major goal for cognitive and clinical neuroscience, with particular emphasis on identifying such diagnostic features early in the timeline of disease. We demonstrate the utility of an activity flow modeling approach, which predicts fMRI cognitive task activations in subjects identified as at-risk for Alzheimer’s disease. The approach makes activation predictions by transforming a healthy aged activation template via the at-risk subjects’ individual pattern of fMRI resting-state functional connectivity (restFC). The observed prediction accuracy supports activity flow as a mechanism linking age-related alterations in restFC and task activations, thereby providing a theoretical basis for incorporating restFC into imaging biomarker and personalized medicine interventions.
Accelerated functional brain aging in pre-clinical familial Alzheimer’s disease