Introducing the SAGE study: a multimodal protocol for testing a GABAergic mechanism of age-related episodic memory impairment across the sexes
Joan Jiménez-Balado, Andrew Prescot, Craig Stark, Jonas Kaplan, Wendy J Mack, Barbara Knowlton, Georg Oeltzschner, Teal EichIntroduction
Alzheimer’s disease (AD) is a neurodegenerative disorder that severely hinders quality of life. Hippocampal hyperactivity is recognised as a biological marker of AD pathology and is associated with episodic memory impairments, the hallmark cognitive symptom of AD. What drives this hyperactivity, however, is not well understood. γ-aminobutyric acid (GABA) is the principal inhibitory neurotransmitter in the brain. Animal models show that age-related GABAergic dysregulation drives hippocampal hyperactivity and cognitive impairment. However, whether this same mechanism translates to humans remains untested. Further, the role of biological sex has not been considered despite the fact that oestrogen modulates GABA receptor expression and GABA release in the hippocampus. Here, we introduce the Sex, Age, GABA, Episodic memory (SAGE) study, a protocol aimed to test an age and sex based GABAergic mechanism of memory impairment in humans.
Methods and analysis
The SAGE study, which will collect multimodal data from 300 healthy adults (100 per decade from age 50 years to 79 years, two-thirds women), aims to test whether age-related GABAergic dysregulation drives hippocampal hyperactivity and episodic memory decline in humans and whether this mechanism is moderated by sex.