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Abstract: Most cases of Alzheimer''s disease (AD) arise through interactions between genetic and environmental factors. It is believed that hypoxia is an important environmental factor influencing the development of AD. Our group has previously demonstrated that hypoxia increased β-amyloid (Aβ) generation in aged AD mice. Here, we further investigate the pathological role of prenatal hypoxia in AD. We exposed the pregnant APPSwe/PS1A246E transgenic mice to high-altitude hypoxia in a hypobaric chamber during days 7–20 of gestation. We found that prenatal hypoxic mice exhibited a remarkable deficit in spatial learning and memory and a significant decrease in synapses. We also documented a significantly higher level of amyloid precursor protein, lower level of the Aβ-degrading enzyme neprilysin, and increased Aβ accumulation in the brain of prenatal hypoxic mice. Finally, we demonstrated striking neuropathologic changes in prenatal hypoxic AD mice, showing increased phosphorylation of tau, decreased hypoxia-induced factor, and enhanced activation of astrocytes and microglia. These data suggest that although the characteristic features of AD appear later in life, hypoxemia in the prenatal stage may contribute to the pathogenesis of the disease, supporting the notion that environmental factors can trigger or aggravate AD. [Copyright &y& Elsevier]