This study investigates the role of mitochondrial dysfunction in the early stages of Alzheimer's disease (AD) pathology using a female triple transgenic AD mouse model (3xTg-AD). Key findings include: 1. **Mitochondrial Dysfunction in Early Stages**: Mitochondrial dysfunction, characterized by decreased respiration and reduced levels of pyruvate dehydrogenase (PDH) protein and activity, was observed in 3xTg-AD mice as early as 3 months of age. This dysfunction was accompanied by increased oxidative stress, as evidenced by higher hydrogen peroxide production and lipid peroxidation. 2. **Amyloid Beta (Aβ) Accumulation**: Increased levels of mitochondrial Aβ were detected at 9 months of age, correlating with increased binding of Aβ to alcohol dehydrogenase (ABAD). Embryonic neurons derived from 3xTg-AD mouse hippocampus showed decreased mitochondrial respiration and increased glycolysis. 3. **Age-Dependent Pathology**: The onset of mitochondrial dysfunction in 3xTg-AD mice preceded the development of amyloid plaques, the classical histopathological marker of AD. Reproductive senescence exacerbated mitochondrial dysfunction, particularly at 12 months of age. 4. **Neuronal Respiration**: Primary hippocampal neurons from 3xTg-AD mice exhibited significantly lower basal rates of mitochondrial respiration and increased glycolysis compared to non-Tg neurons, suggesting a compensatory response to declining mitochondrial function. 5. **Therapeutic Implications**: The findings suggest that mitochondrial dysfunction may be an early and critical factor in AD pathogenesis, providing a potential therapeutic target for preventing or delaying the onset of AD. Overall, the study highlights the importance of mitochondrial dysfunction in the early stages of AD and its potential as a therapeutic target.This study investigates the role of mitochondrial dysfunction in the early stages of Alzheimer's disease (AD) pathology using a female triple transgenic AD mouse model (3xTg-AD). Key findings include: 1. **Mitochondrial Dysfunction in Early Stages**: Mitochondrial dysfunction, characterized by decreased respiration and reduced levels of pyruvate dehydrogenase (PDH) protein and activity, was observed in 3xTg-AD mice as early as 3 months of age. This dysfunction was accompanied by increased oxidative stress, as evidenced by higher hydrogen peroxide production and lipid peroxidation. 2. **Amyloid Beta (Aβ) Accumulation**: Increased levels of mitochondrial Aβ were detected at 9 months of age, correlating with increased binding of Aβ to alcohol dehydrogenase (ABAD). Embryonic neurons derived from 3xTg-AD mouse hippocampus showed decreased mitochondrial respiration and increased glycolysis. 3. **Age-Dependent Pathology**: The onset of mitochondrial dysfunction in 3xTg-AD mice preceded the development of amyloid plaques, the classical histopathological marker of AD. Reproductive senescence exacerbated mitochondrial dysfunction, particularly at 12 months of age. 4. **Neuronal Respiration**: Primary hippocampal neurons from 3xTg-AD mice exhibited significantly lower basal rates of mitochondrial respiration and increased glycolysis compared to non-Tg neurons, suggesting a compensatory response to declining mitochondrial function. 5. **Therapeutic Implications**: The findings suggest that mitochondrial dysfunction may be an early and critical factor in AD pathogenesis, providing a potential therapeutic target for preventing or delaying the onset of AD. Overall, the study highlights the importance of mitochondrial dysfunction in the early stages of AD and its potential as a therapeutic target.