Mitochondrial dysfunction precedes Alzheimer's pathology in female 3xTg-AD mice. This study investigated mitochondrial function in female triple transgenic Alzheimer's (3xTg-AD) mice and age-matched nontransgenic (nonTg) mice. Mitochondrial dysfunction in 3xTg-AD mice was evident as early as 3 months of age, characterized by reduced mitochondrial respiration, decreased pyruvate dehydrogenase (PDH) activity, and increased oxidative stress. Amyloid beta (Aβ) levels in 3xTg-AD mice increased at 9 months, correlating with increased Aβ binding to alcohol dehydrogenase (ABAD). Embryonic neurons from 3xTg-AD mice showed reduced mitochondrial respiration and increased glycolysis. Mitochondrial dysfunction in 3xTg-AD mice was sustained throughout the reproductive period and worsened during reproductive senescence. NonTg mice showed oxidative stress coinciding with reproductive senescence and mitochondrial dysfunction. The study suggests that mitochondrial dysfunction is a key factor in the early stages of Alzheimer's disease pathogenesis in female mice. Mitochondrial dysfunction may explain the hypometabolism observed before AD diagnosis and could be a therapeutic target for prevention. The findings highlight the importance of mitochondrial bioenergetics in AD pathogenesis and suggest that targeting mitochondrial function could be a strategy for preventing or delaying AD. The study also indicates that mitochondrial dysfunction may be a causal factor in AD, with implications for the role of environmental and genetic factors in late-onset sporadic AD.Mitochondrial dysfunction precedes Alzheimer's pathology in female 3xTg-AD mice. This study investigated mitochondrial function in female triple transgenic Alzheimer's (3xTg-AD) mice and age-matched nontransgenic (nonTg) mice. Mitochondrial dysfunction in 3xTg-AD mice was evident as early as 3 months of age, characterized by reduced mitochondrial respiration, decreased pyruvate dehydrogenase (PDH) activity, and increased oxidative stress. Amyloid beta (Aβ) levels in 3xTg-AD mice increased at 9 months, correlating with increased Aβ binding to alcohol dehydrogenase (ABAD). Embryonic neurons from 3xTg-AD mice showed reduced mitochondrial respiration and increased glycolysis. Mitochondrial dysfunction in 3xTg-AD mice was sustained throughout the reproductive period and worsened during reproductive senescence. NonTg mice showed oxidative stress coinciding with reproductive senescence and mitochondrial dysfunction. The study suggests that mitochondrial dysfunction is a key factor in the early stages of Alzheimer's disease pathogenesis in female mice. Mitochondrial dysfunction may explain the hypometabolism observed before AD diagnosis and could be a therapeutic target for prevention. The findings highlight the importance of mitochondrial bioenergetics in AD pathogenesis and suggest that targeting mitochondrial function could be a strategy for preventing or delaying AD. The study also indicates that mitochondrial dysfunction may be a causal factor in AD, with implications for the role of environmental and genetic factors in late-onset sporadic AD.