Gray Matter Gamma‐hydroxy‐butyric Acid and Glutamate Reflect Beta‐amyloid Burden at Old Age

AbstractGamma‐hydroxy‐butyric acid (GABA) and glutamate are neurotransmitters with essential importance for cognitive processing. Here, we investigate relationships between GABA, glutamate, and brain ß‐amyloid (Aß) burden before clinical manifestation of Alzheimer's disease (AD). Thirty cognitively healthy adults (age 69.9 ± 6 years) received high‐resolution atlas‐based 1H‐magnetic resonance spectroscopic imaging (MRSI) at ultra‐high magnetic field strength of 7 Tesla for gray matter‐specific assessment of GABA and glutamate. We assessed Aß burden with positron emission tomography and risk factors for AD. Higher gray matter GABA and glutamate related to higher Aß‐burden (ß = 0.60, p < 0.05; ß = 0.64, p < 0.02), with positive effect modification by apolipoprotein‐E‐epsilon‐4‐allele (APOE4) (p = 0.01‐0.03). GABA and glutamate negatively related to longitudinal change in verbal episodic memory performance (ß = ‐0.48; p = 0.02; ß = ‐0.50; p = 0.01). In vivo measures of GABA and glutamate reflect early AD pathology at old age, in an APOE4‐dependent manner. GABA and glutamate may represent promising biomarkers and potential targets for early therapeutic intervention and prevention.Highlights Gray matter‐specific metabolic imaging with high‐resolution atlas‐based MRSI at 7 Tesla. Higher GABA and glutamate relate to ß‐amyloid burden, in an APOE4‐dependent manner. Gray matter GABA and glutamate identify older adults with high risk of future AD. GABA and glutamate might reflect altered synaptic and neuronal activity at early AD.