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 research focuses on analysing the brain once hallmark amyloid plaque and tau tangle pathologies are present, their appearance is extremely end stage. In addition, to date, any attempts 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 observed prior to symptom presentation (1, 2). These changes may subsequently precipitate cognitive decline as glucose is a required substrate for induction of long-term potentiation (3) and conversion of short- to long-term memories. Evidence implicates 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 metabolism and insulin sensitivity (4). We have also previously presented that overexpression of BACE1 impairs glucose uptake and use (5). The present study aimed to elucidate the mechanisms underlying this altered glucose handling in SH-SY5Y human, neuroblastoma cells stably overexpressing BACE1. 14C-radiolabelled glucose oxidation and extracellular flux analyses were utilised to assess cellular respiration in real-time. Enzyme assay kits were used to monitor the activity of protein complexes regulating glucose metabolism (pyruvate (PDH), isocitrate (IDH) and α-ketoglutarate dehydrogenases (α-KGDH)). All data are presented as mean ± standard error of the mean and statistical significance determined by Student’s t-test or ANOVA. Chronic elevation of BACE1 resulted in impaired activity of key fuel partitioning enzymes: PDH (reduced to 69 ± 8 per cent, p < 0.01, n = 5), total IDH (reduced to 49 ± 3 per cent, p < 0.001, n = 4) and α-KGDH (reduced to 61 ± 6 per cent, p < 0.01, n = 6). This attenuated enzyme functioning lead to a preferential use of aerobic glycolysis over oxidative phosphorylation for ATP generation (oxygen consumption rate (OCR) reduced to 65 ± 9 per cent, p < 0.01, n = 7 and extracellular acidification rate (ECAR) increased to 165 ± 16 per cent, p < 0.01, n = 7). These deficits in glucose oxidation could however be effectively attenuated through supplementation of the cells with α-lipoic acid or ketone bodies. Taken together these data show that overexpression of BACE1 effectively phenocopies some of the earliest pathophysiological changes seen in the brain during progression towards AD. It also highlights novel targets and supports a potential role for neutraceutical supplementation to alleviate these deficits at the cellular level.