Use of Drugs Affecting GABAA Receptors and the Risk of Developing Alzheimer's Disease and Dementia: a Meta-Analysis and Literature Review

Abstract

The gamma-aminobutyric acid (GABA) system is known for its role in cognitive functions and memory processes. However, the activity of GABA_A receptors and their associated pathways influence the accumulation of β-amyloid peptide (Aβ), a key hallmark in the development and prognosis of research examining the relationship between the use of drugs affecting GABA_A receptors and the risk of developing Alzheimer's disease (AD) and dementia. This study aimed to examine the association between GABAA receptor-affecting drugs and the risk of AD and dementia, focusing on benzodiazepines, zolpidem, and anesthetics. This meta-analysis included all English articles on AD, dementia, and GABA_A receptor agonist medications published before May 2024. The articles were identified through searches conducted on PubMed and Scopus databases. The extracted data were analyzed using STATA software (version 14.2). Q statistics and the I² index were used to evaluate heterogeneity, while Egger's test and funnel plot were utilized to detect publication bias. A total of 19 articles (10 case-control and 9 cohort articles) were eligible for the analysis, involving 2,953,980 patients. The use of GABA agonists was found to have a statistically significant relationship with the development of dementia (RR = 1.15, 95% CI: 1.02-1.29, I² = 87.6%) and AD (RR = 1.21, 95% CI: 1.04-1.40, I² = 97.6%). In the drug-based subgroup, we observed that zolpidem consumption was associated with an increased incidence of AD and dementia (RR = 1.28, 95% CI: 1.08-1.52, I² = 24.3%), similar to the effects of benzodiazepines (BZDs; RR = 1.11, 95% CI: 1.04-1.18, I² = 87.2%). Meta-regression analysis showed that the duration of follow-up, which ranged from 5 to 11 years across the studies, was significantly associated with heterogeneity (P = 0.036). Our findings indicate that the use of zolpidem and BZD is associated with an increased risk of dementia and AD.

Keywords: Alzheimer’s disease; GABA-A receptor; Prognosis.