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 aimed at alleviating them have failed to halt symptom progression. It may therefore be beneficial to look at earlier events, with reduced glucose metabolism and a regional switch to aerobic glycolysis among the earliest changes reported in the AD brain (1, 2). Glucose is a required substrate for neuronal function and important for the induction of long-term potentiation (3) 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 aetiology of AD. Previous work from our laboratory has also suggested a role in metabolism, with BACE1 knock out mice displaying enhanced whole-body glucose disposal and insulin sensitivity (4). We have also previously shown that BACE1 overexpression impairs glucose metabolism in neuronal cells (5). This study aimed to further investigate the role of BACE1 in neuronal glucose metabolism. We utilised the human SH-SY5Y neuronal cell line stably overexpressing BACE1. Pyruvate dehydrogenase (PDH) activity was determined by activity assay (Mitosciences). A Seahorse extracellular flux analyser was used to determine cellular respiration in real-time. All data are expressed as mean ± standard error of the mean, and statistical significance determined by Student’s t-test. Chronic elevation in BACE1 resulted in impaired functioning of a key fuel-partitioning enzyme, PDH (activity reduced to 69 ± 8 per cent, p < 0.05, n=6). This reduced substrate delivery to the mitochondria and increased reliance upon aerobic glycolysis for ATP generation (oxygen consumption rate (OCR) reduced to 65 ± 9%, p < 0.01, n=7 and extracellular acidification rate (ECAR) increased to 165 ± 16%, p < 0.01, n=7). These deficits were significantly attenuated by treatment with the PDH kinase inhibitor dicholoracetate (DCA, 10µM). Thus BACE1 overexpression impairs neuronal glucose oxidation resulting in an increased reliance upon aerobic glycolysis for ATP generation. Therefore this BACE1-dependent change in metabolism may account for some of the earliest clinical observations in people who later develop AD.