Severe worry and anxiety in late life are linked to increased risk of Alzheimer’s disease (AD), but underlying neural mechanisms remain unclear. Severe worry is associated with reduced hippocampal volume. One proposed mechanism is stress-related glutamate excitotoxicity, which may contribute to hippocampal atrophy and cognitive decline. This pilot study examined whether anxiety, worry, and cognitive function are associated with markers of glutamate excitotoxicity, specifically hippocampal glutamate and N-acetyl aspartate (NAA). Eighteen older adults with varying worry underwent 7T magnetic resonance spectroscopy of left and right hippocampus and clinical and cognitive assessments. Linear regression analyses examined associations between anxiety, cognitive performance, and hippocampal metabolites, controlling for volume. Exploratory analyses assessed additional metabolites, including creatine, gamma-aminobutyric acid (GABA), glutathione, and myo-inositol. Greater worry severity and lower overall cognitive function were associated with reduced hippocampal NAA levels. Higher global anxiety was associated with lower hippocampal glutamate. Exploratory analyses revealed additional relationships between other metabolites and both mood symptoms and cognition. These preliminary findings suggest hippocampal metabolic markers may play a role in late-life anxiety and worry. However, results provide only partial support for glutamate excitotoxicity as a mechanism linking anxiety to cognitive impairment, highlighting the need for larger studies.
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