Alzheimer’s disease (AD) is a multifactorial disease, thus multi-target treatments are needed. Tetrahydrobiopterin (BH4) has been shown to be decreased in elderly and in AD patients. BH4 is an enzymatic cofactor required for the synthesis of serotonin (5-HT), dopamine (DA) and nitric oxide. It also exerts strong antioxidant and anti-inflammatory effects. Thus, BH4 administration could ameliorate monoaminergic neurotransmission but also other key physiological processes such as vascularization, metabolism, inflammatory and oxidative status. Surprisingly, despite its crucial role in the CNS, the potential of BH4 as a treatment in AD has never been investigated. Thus, we hypothesized that BH4 administration can ameliorate both cognitive symptoms and AD neuropathology. Non-transgenic (NonTg) and 3xTg-AD mice, which display age-related behavior impairment, tau and Aβ neuropathologies, were subject to a high-fat diet (35% fat - HFD) or control diet (5% fat - CD) from 6 to 13 months in order to exacerbate inflammatory and metabolic disturbances. Then, mice were injected intraperitoneally with BH4 (15mg/kg) or control solution during ten days. To verify whether BH4 is a suitable therapeutic for the CNS, we first demonstrated that peripheral administration of BH4 (50mg/kg) was sufficient to double BH4 brain content within 3h. Using in-situ brain perfusion, we found that the brain uptake clearance (Clup) of BH4 was approximately 0.08μl/g/sec, consistent with a modest transfer across the BBB. For the first time, we report that ten days of chronic administration of BH4 induced a total rescue of memory impairment in 13-month-old 3xTg-AD mice as determined with the novel object recognition test. Interestingly, this improvement was observed even over a HFD background. Moreover, glucose intolerance induced by HFD in 3xTg-AD mice was completely reversed by BH4 treatment while no difference on diet consumption, mice weight and voluntary locomotion in open-field were observed. BH4 treatment had no effect on total or phosphorylated tau assessed in soluble and insoluble fractions extracted from the hippocampus. As BH4 is involved in monoamine synthesis, we also measured striatal DA and 5-HT content without detecting any significant changes. Amyloid pathology and pro-inflammatory cytokines measurements are currently ongoing. Overall, our data show that BH4 supplementation leads to a rescue in object recognition memory and metabolic impairments in the 3xTg-AD mouse model, without altering tau neuropathology.