This study investigates the role of isocitrate dehydrogenase 3β (IDH3β) in Alzheimer's disease (AD) progression. The authors found that IDH3β levels are significantly reduced in both AD patients and AD-transgenic mice, leading to impaired tricarboxylic acid (TCA) cycle function and reduced energy metabolism. This reduction in energy metabolism results in increased lactate accumulation, which promotes histone lactylation and enhances the expression of paired-box gene 6 (PAX6). PAX6, as an inhibitory transcription factor of IDH3β, further suppresses IDH3β expression, creating a positive feedback loop that accelerates AD pathology. The study demonstrates that upregulating IDH3β and downregulating PAX6 can improve cognitive function and reverse AD-like pathologies in AD-transgenic mice, suggesting a potential therapeutic target for AD.This study investigates the role of isocitrate dehydrogenase 3β (IDH3β) in Alzheimer's disease (AD) progression. The authors found that IDH3β levels are significantly reduced in both AD patients and AD-transgenic mice, leading to impaired tricarboxylic acid (TCA) cycle function and reduced energy metabolism. This reduction in energy metabolism results in increased lactate accumulation, which promotes histone lactylation and enhances the expression of paired-box gene 6 (PAX6). PAX6, as an inhibitory transcription factor of IDH3β, further suppresses IDH3β expression, creating a positive feedback loop that accelerates AD pathology. The study demonstrates that upregulating IDH3β and downregulating PAX6 can improve cognitive function and reverse AD-like pathologies in AD-transgenic mice, suggesting a potential therapeutic target for AD.