ims/hypothesis: Obesity is a major risk factor for development of insulin resistance, a proximal cause of type 2 diabetes and is also associated with an increased relative risk of Alzheimer's disease. We therefore investigated the susceptibility of transgenic mice carrying human mutated transgenes for amyloid precursor protein ( APP) and presenilin 1 ( PSEN1) ( APP/ PSEN1), or PSEN1 alone, which are well-characterised animal models of Alzheimer's disease, to develop obesity, glucose intolerance and insulin resistance, and whether this was age- and/or diet-dependent. Methods: We analysed the effects of age and/or diet on body weight of wild-type, PSEN1 and APP/ PSEN1 mice. We also analysed the effects of diet on glucose homeostasis and insulin signalling in these mice. Results: While there were no body weight differences between 16-17- and 20-21-month-old PSEN1 mice, APP/ PSEN1 mice and their wild-type controls on standard, low-fat, chow diet, the APP/ PSEN1 mice still exhibited impaired glucose homeostasis, as investigated by glucose tolerance tests. This was associated with increased brain protein tyrosine phosphatase 1B protein levels in APP/ PSEN1 mice. Interestingly, short-term high-fat diet (HFD) feeding of wild-type, PSEN1 and APP/ PSEN1 mice for a period of 8 weeks led to higher body weight gain in APP/ PSEN1 than in PSEN1 mice and wild-type controls. In addition, HFD-feeding caused fasting hyperglycaemia and worsening of glucose maintenance in PSEN1 mice, the former being further exacerbated in APP/ PSEN1 mice. The mechanism(s) behind this glucose intolerance in PSEN1 and APP/ PSEN1 mice appeared to involve increased levels of brain retinol-binding protein 4 and basal phosphorylation of S6 ribosomal protein, and decreased insulin-stimulated phosphorylation of Akt/protein kinase B and extracellular signal-regulated kinase 1/2 in the brain. Conclusions/interpretation: Our results indicate that Alzheimer's disease increases susceptibility to body weight gain induced by HFD, and to the associated glucose intolerance and insulin resistance. [ABSTRACT FROM AUTHOR]