Dopamine Compensates for Amyloid-Induced Default Mode Network Dysfunction to Support Learning
Joseph Giorgio, Thomas Morin, Hsiang-Yu Chen, Anne S. Berry, Michael Breakspear, William J. Jagust
bioRxiv (Cold Spring Harbor Laboratory) July 10, 2026 preprint DOI: 10.64898/2026.07.07.736872 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Observational cohort |
|---|---|
| Population | Cognitively normal older adults |
| Topics | Default mode network |
| Keywords | Dopaminergic Cognition Striatum Mechanism biology Disease Cognitive flexibility |
| Key findings | Aβ burden impairs learning independent of tau, but higher dorsolateral striatal dopamine synthesis capacity can recover learning performance by rebalancing default mode network and frontostriatal connectivity. |
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.
Comparable studies
Other observational and cohort studies on default mode network, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| A default mode of brain function Normal adult human brain | 2001 | Observational study | |
| Resting-State Functional Connectivity Reflects Structural Connectivity in the Default Mode Network Healthy subjects | 2008 | Observational cohort | |
| Meditation experience is associated with increased cortical thickness Participants with extensive Insight meditation experience and matched controls | 2005 | Observational cohort | n = 20 |
| Meditation experience is associated with differences in default mode network activity and connectivity Experienced meditators and matched meditation-naive controls | 2011 | Observational cohort | |
| The precuneus/posterior cingulate cortex plays a pivotal role in the default mode network: Evidence from a partial correlation network analysis Healthy subjects | 2008 | Observational study |
Citations in the library
Cites 4
- 20 years of the default mode network: A review and synthesis Neuron May 10, 2023
- Amyloid induced hyperexcitability in default mode network drives medial temporal hyperactivity and early tau accumulation. Neuron December 1, 2023
- Dark control: The default mode network as a reinforcement learning agent Human Brain Mapping June 5, 2020
- The surprising role of the default mode network in naturalistic perception Communications Biology May 20, 2020