Use of Drugs Affecting GABA(A) 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 beta-amyloid peptide (Abeta), 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 I(2) 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, I(2) = 87.6) and AD (RR = 1.21, 95 CI: 1.04-1.40, I(2) = 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, I(2) = 24.3), similar to the effects of benzodiazepines (BZDs; RR = 1.11, 95 CI: 1.04-1.18, I(2) = 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.