Alzheimer’s Disease (AD) is the most common cause of dementia and currently there is no cure or means to slow disease progression. This represents a clear, unmet medical need in light of the ageing population worldwide. While much of the current AD research focuses on the hallmark pathologies (amyloid plaques and neurofibrillary tangles), their appearance is extremely end stage and therapeutic interventions to alleviate them have failed to halt symptom progression. It may therefore be beneficial to look at earlier changes, with reduced glucose metabolism among the earliest defects seen in the AD brain (1). While the exact mechanism of neuronal energy supply remains debated, it is known that the primary substrates are glucose and lactate. Indeed, glucose is a required substrate for a number of neuronal functions, such as induction of long-term potentiation (2) and the consolidation of short to long-term memories. Evidence suggests the aspartyl protease β-site Amyloid precursor protein Cleaving Enzyme 1 (BACE1) as a key enzyme in the progression of AD. Previous work from our laboratory has also observed a role in metabolism, with BACE1 knock out mice displaying enhanced glucose disposal and insulin sensitivity (3). This study aimed to investigate the role of BACE1 in neuronal glucose metabolism. We utilised wild type SH-SY5Y neuronal cells stably overexpressing either an empty vector or BACE1. Radiolabelled 2-deoxyglucose uptake and glucose oxidation assays were performed to observe the effect of BACE1 on utilisation of primary neuronal energy sources. All data expressed as mean ± standard error of the mean, and statistical significance determined by Student’s t-test. Stable overexpression of BACE1 resulted in numerous derangements to neuronal metabolism, significantly impairing the utilisation of preferential substrates, lactate and glucose (uptake reduced to 67 ± 5 per cent, p < 0.0001 and oxidation reduced to 74 ± 4 per cent, p < 0.01 compared to control). As well as this fundamentally compromised substrate use, BACE1 overexpressing cells displayed an inability to respond to metabolic challenge. There were also significant reductions in the activity of key metabolic enzymes hexokinase (HK, activity reduced to 75 ± 6 per cent, p < 0.01) and pyruvate dehydrogenase (PDH, reduced to 69 ± 8 per cent, p < 0.05). This impairment in glucose use was effectively attenuated through application of ketone bodies. These data suggest that BACE1 overexpression alters neuronal metabolism towards ketone bodies, which in the short-term can overcome impaired glucose and lactate utilisation. However, this adaptation leaves cells unable to respond effectively to further challenge or perform energy intensive tasks. This further supports the idea that regulation of BACE1 can alter glucose homeostasis.