Longitudinal 7T MRS Study of Glutamate and GABA Dynamics in Alzheimer’s Disease Progression: From hyper- to hypoexcitation

Abstract Functional neuroimaging studies suggested a biphasic trajectory of neuronal activity in Alzheimer’s disease (AD), with early hyperactivity followed by later hypoactivity. However, the underlying neurochemical mechanisms in humans remain unclear. Animal studies suggested that amyloid-beta (Aβ) causes intrasynaptic glutamate increases through impaired astrocytic clearance. This study aimed to build a mechanistic bridge between findings from human neuroimaging studies and preclinical models by providing in vivo measurements of glutamate, GABA, and glutamine across the AD continuum using 7T magnetic resonance spectroscopy (MRS). We acquired longitudinal data from cognitively normal (CN) individuals with and without Aβ pathology (CN Aβ-n=43, CN Aβ+ n=17), individuals with mild cognitive impairment (MCI Aβ+, n=20) or AD dementia (AD Aβ+, n=24). Over the course of up to 5 years, glutamate levels increased in the CN Aβ+ and MCI Aβ+ groups but decreased in the AD Aβ+ group. Consistent with a transient homeostatic response to glutamatergic hyperexcitation, GABA levels showed modest increases in both CN Aβ+ and MCI Aβ+ groups. Elevated plasma GFAP was associated with reduced glutamine, suggesting astrocytic dysfunction and impaired glutamate–glutamine cycling as contributors to early hyperexcitability. Together, our results provide the first direct demonstration in patients with AD that glutamate alterations underlie the biphasic trajectory of neuronal activity and that astrocytic glutamate regulation might be a potential therapeutic target.