Dopamine Compensates for Amyloid-Induced Default Mode Network Dysfunction to Support Learning

Abstract

Throughout the preclinical phase of Alzheimers disease (AD) {beta}-amyloid (A{beta}) accumulates preferentially within the default mode network (DMN), yet the functional and behavioural consequences of this pathological burden remain poorly understood. Using task-based fMRI combined with A{beta}, tau, and dopamine PET in cognitively normal older adults, we show that A{beta} burden impairs learning independent of tau, but this learning performance is recovered with higher dorsolateral striatal dopamine synthesis capacity. Investigating the neural mechanisms that support this learning, we observe that A{beta} positive individuals show attenuated DMN activity to error related feedback, a metric that relates to poorer learning. When estimating the effective connectivity during feedback, computational modelling reveals that A{beta} induces dis-inhibition of the DMN during error processing. Critically, dopamine synthesis capacity in the dorsolateral striatum rebalances effective connectivity between the DMN and frontostriatal network, thereby opposing A{beta} related disruption. These findings establish a systems-level framework in which A{beta} impairs learning by disrupting dynamic DMN modulation during feedback, a disruption for which dopaminergic function can partially compensate. This suggests that learning in the presence of A{beta} may be subserved by dopamine-dependent network rebalancing, a candidate mechanism of cognitive resilience to support learning in preclinical AD.