The observation that a high fat/low carbohydrate (CHO) diet has a beneficial effect on a mouse model of Alzheimer's disease (AD) published today is notable given previous results showing that high fat diets have a deleterious effect on AD. Van de Auwera, et al. [1] reported that mice fed a ketogenic diet (<1% carbohydrate, 80% fat) were found to have a 25% decrease in the protein Aβ42 compared to mice fed a standard high-carbohydrate, low-fat chow diet. Aβ42 is a particularly amyloidogenic mutant form of the amyloid precursor protein whose proteolytic product β-amyloid peptide is contained in the plaques and neurofibrillar tangles that are characteristic of AD. Any suggestion of an environmental or dietary attack on AD is welcome given the devastating effects of the disease. Beyond the potential application, however, Van de Auwera, et al.'s results have general implications for nutritional approaches in biochemistry and cell biology, and ultimately on disease processes. The physiologic effect of dietary fat can be significantly modulated by the presence of carbohydrate and the associated hormonal changes. The description "high fat diet" is thus an inadequate way to characterize a diet. One must also specify the level of carbohydrate. The principle that dietary fat might play a relatively passive role in metabolism and that the disposition of fat is regulated by the hormonal state stimulated by carbohydrate is taught in elementary courses in biochemistry but remains an under-appreciated factor in many studies, possibly due to the emphasis on low-fat recommendations of nutritional agencies. Because of the requirement of brain cells for glucose (or ketones) for energy metabolism and, in particular, because of the known involvement of insulin in regulating secretase (proteolytic enzyme in β-amyloid production) (e.g. [2]), it is pertinent to inquire about the role of macronutrient composition in the diet in neuronal disorders. The role of energy metabolism in brain function has been discussed in a recent review and hypothesis by Mukherjee and Seyfried [3]. In explaining the importance of macronutrient composition to students we emphasize energy metabolism and gain or loss of body weight and we stress the need to get away from the principle that "you are what you eat," and replace it with the idea that "you are what you do with what you eat [4]." A common analogy, that fat is the bomb and carbohydrate is the fuse, or in its original description, powder keg and tinder box, may be too broad for appreciation of fine control of metabolism but is probably good enough to illustrate the principle here. Although there are many effects of dietary change, to a first order approximation, carbohydrate is the major stimulus for insulin secretion and as an anabolic hormone, leads to repression of lipolysis and glycogenolysis. Continued hyperinsulinemia, therefore, may predispose to a state where dietary fat is stored rather than oxidized. In addition, current thinking on insulin resistance emphasizes the role of free fatty acids and other fat metabolites (e.g. [5,6]). One theory of the etiology of insulin resistance is that insulin resistance in the adipocyte represents down regulation of response due to continued hyperinsulinemia. This causes increased lipolysis and excessive liberation of fatty acids which may have several effects in peripheral tissues. Thus, the regulation of the TAG-fatty acid axis may be more important than the dietary levels of fat itself.