Ali, Dina N.

Abstract Aims Excessive alcohol use is associated with an increased risk of cognitive impairment. Since increased amyloid plaque burden exacerbates cognitive decline, we sought to assess the potential impact of alcohol use disorder (AUD) on cognition, memory, and amyloid burden corresponding with age. Methods We conducted the retrospective analysis with 6036 subjects, including 269 AUD+ subjects. A four-item CAGE (C—Cutting Down, A—Annoyance by Criticism, G—Guilty Feeling, E—Eye-openers) alcohol questionnaire was given during the recruitment to determine AUD in each participant. We assessed cognitive function, focusing on memory using neuropsychological testing. For 1038 participants, including 57 AUD+ subjects, we measured amyloid burden using the 11C Pittsburgh Compound B tracer-based positron emission tomography imaging. Results AUD+ was significantly associated with lower scores of cognition and memory function relative to AUD− individuals. No significant association was found with AUD and elevated brain amyloid under the age of 65. However, further analysis showed that those aged ≥65 showed greater odds for abnormal amyloid in AUD+ compared to AUD− participants. Conclusions Our results underscore AUD as a risk factor for cognitive decline and diminished memory, particularly in aging populations. The role of AUD in brain amyloid accumulation requires further study.

Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system (CNS). Most GABAergic neurons synthesize GABA from glutamate and release it in the synaptic cleft in the CNS. However, astrocytes can also synthesize and release GABA, activating GABA receptors in the neighboring neurons in physiological and pathological conditions. As the primary homeostatic glial cells in the brain, astrocytes play a crucial role in regulating GABA homeostasis and synaptic neurotransmission. Accumulating evidence demonstrates that astrocytic GABA dysregulation is implicated in psychiatric disorders, including alcohol use disorder (AUD) and major depressive disorder (MDD), the most prevalent co-occurring psychiatric disorders. Several current medications and emerging pharmacological agents targeting GABA levels are in clinical trials for treating AUD and MDD. This review offers a concise summary of the role of astrocytic GABA regulation in AUD and MDD. We also provide an overview of the current understanding and areas of debate regarding the mechanisms by which astrocytes regulate GABA in the CNS and their potential significance in the molecular basis of AUD and MDD, paving the way toward future research directions and potential therapeutic target areas within this field.