GABAergic dysfunction in excitatory and inhibitory (E/I) imbalance drives the pathogenesis of Alzheimer's disease

OBJECTIVE: To propose a new hypothesis that GABAergic dysfunction in excitatory and inhibitory (E/I) imbalance drives the pathogenesis of Alzheimer's disease (AD). BACKGROUND: Synaptic dysfunction and E/I imbalance emerge decades before the appearance of cognitive decline in AD patients, which contribute to neurodegeneration. Initially, E/I imbalance was thought to occur first, due to dysfunction of the glutamatergic and cholinergic systems. However, new evidence has demonstrated that the GABAergic system, the counterpart of E/I balance and the major inhibitory neurotransmitter system in the central nervous system, is altered enormously and that this contributes to E/I imbalance and further AD pathogenesis. NEW HYPOTHESIS: Alterations to the GABAergic system, induced by multiple AD pathogenic or risk factors, contribute to E/I imbalance and AD pathogenesis. MAJOR CHALLENGES FOR THE HYPOTHESIS: This GABAergic hypothesis accounts for many critical questions and common challenges confronting a new hypothesis of AD pathogenesis. More specifically, it explains why amyloid beta (Aβ), β-secretase (BACE1), apolipoprotein E4 gene (APOE ε4), hyperactive glia cells, contributes to AD pathogenesis and why age and sex are the risk factors of AD. GABAergic dysfunction promotes the spread of Aβ pathology throughout the AD brain and associated cognitive impairments, and the induction of dysfunction induced by these varied risk factors shares this common neurobiology leading to E/I imbalance. In turn, some of these factors exacerbate GABAergic dysfunction and E/I imbalance. Moreover, the GABAergic system modulates various brain functions and thus, the GABAergic hypothesis accounts for nonamnestic manifestations. Furthermore, corrections of E/I balance through manipulation of GABAergic functions have shown positive outcomes in preclinical and clinical studies, suggesting the potential of the GABAergic system as a therapeutic target in AD. LINKAGE TO OTHER MAJOR THEORIES: Dysfunction of the GABAergic system is induced by multiple critical signaling pathways, which include the existing major theories of AD pathogenesis, such as the Aβ and neuroinflammation hypotheses. In a new perspective, this GABAergic hypothesis accounts for the E/I imbalance and related excitotoxicity, which contribute to cognitive decline and AD pathogenesis. Therefore, the GABAergic system could be a key target to restore, at least partially, the E/I balance and cognitive function in AD patients.