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Elevated BACE1 levels in the brains of Alzheimer\u2019s disease (AD) patients implicate that dysregulated BACE1 expression is crucial to AD pathogenesis. However, the underlying regulatory mechanisms remain unclear. Here, we identified that the G protein subunit \u03b25 gene (<jats:italic>Gnb5<\/jats:italic>), a component of the G protein-coupled receptor (GPCR) signaling pathway, is significantly downregulated in both human AD patients and AD mouse models. Conditional knockout of <jats:italic>Gnb5<\/jats:italic> in excitatory neurons resulted in cognitive impairments, whereas adeno-associated virus (AAV)-mediated overexpression of Gnb5 in the hippocampus ameliorated cognitive deficits and reduced A\u03b2 deposition in 5xFAD mice. Mechanistically, we demonstrated that Gnb5 interacts with BACE1, modulating its expression and potentially influencing A\u03b2 generation. We further identify the first tryptophan\u2013aspartate domain (WD domain) of Gnb5 and the Ser81 residue as crucial for this regulation. Expression of this WD domain alone is sufficient to reduce A\u03b2 deposition in 5xFAD mice, whereas a point mutation at Ser81 (S81L) abolishes this effect. 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