Aging affects glutamate-enriched functional networks in resting and movie-watching states

As the global population ages, understanding the impact of aging on brain function, particularly the role of the glutamatergic system in cognitive decline, has become increasingly critical. This study is the first to investigate age-related effects on metabotropic glutamate receptor subtype 5 (mGluR5)-enriched functional connectivity during resting and movie-watching states. Using fMRI data from 198 younger and 155 older adults from the Cambridge Centre for Ageing and Neuroscience, we applied the Receptor-Enriched Analysis of Functional Connectivity by Targets (REACT) method. Glutamate-enriched functional connectivity was compared between the two groups in resting and movie-watching states. Group comparisons revealed state-dependent differences in glutamate-enriched functional connectivity within the cortical-subcortical pathways, especially in cortical-thalamic pathway. Moreover, glutamate-enriched functional connectivity within these pathways showed state-dependent, aging-associated relationships with cognitive function across the pooled sample. Mediation analysis further revealed an, age-related, state-dependent thalamic mediation pattern linking cortical glutamate-enriched functional connectivity-particularly in regions showing more prominent aging-related changes-and fluid intelligence in the resting state, but not in the movie-watching state. These findings highlight the state-dependent nature of aging effects on glutamate-enriched functional connectivity, underscoring the role of cortical-thalamic interactions in cognitive aging and emphasizing the importance of glutamatergic signaling as a potential target for preserving cognitive function in older adults.