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

In cognitively normal older adults, β-amyloid (Aβ) buildup in the default mode network impairs learning independently of tau, but higher dopamine synthesis capacity in the dorsolateral striatum can recover that learning performance. Aβ-positive individuals show reduced default mode network activity in response to error feedback, which relates to poorer learning. Computational modeling indicates that Aβ disinhibits the default mode network during error processing, and dopamine synthesis capacity in the dorsolateral striatum rebalances effective connectivity between the default mode network and frontostriatal network, counteracting Aβ-related disruption. These findings suggest that dopaminergic function can partially compensate for Aβ-related learning deficits through network rebalancing, offering a candidate mechanism for cognitive resilience in preclinical Alzheimer's disease.

Study at a glance

Abstract

Throughout the preclinical phase of Alzheimer's disease (AD) β-amyloid (Aβ) 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 Aβ, tau, and dopamine PET in cognitively normal older adults, we show that Aβ 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 Aβ 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 Aβ 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 Aβ related disruption. These findings establish a systems-level framework in which Aβ 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 Aβ may be subserved by dopamine-dependent network rebalancing, a candidate mechanism of cognitive resilience to support learning in preclinical AD.