Age and sex-dependent alteration in AMPA receptor density in living human brain

The excitatory glutamate α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) play a pivotal role in neurotransmission and neuronal function. However, the effects of age and sex on AMPAR distribution in the living human brain and their associations with cognitive function remain unclear. The purpose of this study was to characterize age- and sex-dependent changes in brain AMPAR density and their relationships with cognitive performance in healthy individuals.

Using a positron emission tomography tracer for AMPAR, [¹¹C]K-2, we imaged 143 healthy participants aged 20-79 years. AMPAR density was evaluated using standard uptake value ratios with white matter as a reference. Age- and sex-related changes in AMPAR density were assessed across the brain, hierarchical clustering was used to characterize sex-dependent regional patterns of age-related change, and associations with cognitive performance were examined using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS).

Age-dependent differences in cell-surface AMPAR density was observed across most brain regions. Females in their 50 s showed a surge in the upregulation of AMPAR density across brain. Hierarchical clustering revealed five distinct age-related trajectories, featuring marked sex-dependent regional patterns. AMPAR density was positively associated with cognitive performance; delayed memory correlated with whole-brain AMPAR density in both sexes, whereas other cognitive domains showed sex-specific regional associations.

These findings demonstrated age- and sex-related alteration of AMPAR distribution and propose a model of AMPAR related synaptic aging in the living human brain over the life span. Furthermore, they may help to elucidate the pathophysiology of neurodegenerative disorders.