Increasing beta-amyloid deposition in cognitively healthy aging predicts nonlinear change in BOLD modulation to difficulty.

Recent evidence indicates that the relationship between increased beta-amyloid (Aβ) deposition and functional task-activation can be characterized by a non-linear trajectory of change in functional activation (Foster et al., 2017), explaining mixed results in prior literature showing both increases and decreases in activation as a function of beta-amyloid burden in cognitively normal adults. Here we sought to replicate this nonlinear effect in the same sample using a different functional paradigm to test the generalizability of this phenomenon. Participants (N = 68 healthy adults aged 49-94) underwent fMRI (0-, 2-, 3-, 4-back working memory task; WM) and 18F-Florbetapir PET scanning. A parametric WM load contrast was used as the dependent variable in a model with age, mean cortical Aβ, and Aβ2 as predictors. Results revealed that nonlinear amyloid (Aβ2) was a significant negative predictor of modulation of activation to WM load in two large inferior clusters: bilateral subcortical nuclei and bilateral lateral cerebellum. Individuals with slightly elevated Aβ burden evidenced greater modulation as compared to individuals with little or no Aβ burden, whereas individuals with the greatest Aβ burden evidenced lesser modulation as compared to individuals with slightly elevated Aβ. Increased modulation to WM load predicted better task accuracy and executive function measured outside the scanner. The current study provides further evidence for a dose-response, nonlinear relationship between increasing Aβ burden and alteration in brain activation in cognitively healthy adults, extending the existing evidence to dynamic range of activation to task difficulty, and reconciling seemingly discrepant effects of amyloid on brain function.