In another study ketosis was induced by

In another study, ketosis was induced by a diet very low in ARQ 621 [71]. Twenty-three older adults with mild cognitive impairment were randomly assigned to either a high carbohydrate or very low carbohydrate diet. Following the 6-week intervention period, improved verbal memory performance was observed in participants receiving the low carbohydrate diet [71]. Changes in calorie intake, insulin level, and weight were not correlated with memory performance for the entire sample, although a trend toward a moderate relationship between insulin and memory was observed within the low carbohydrate group [71]. Ketone levels were positively correlated with memory performance [71]. These findings indicate that a very low carbohydrate diet can improve memory function in older adults with increased risk for AD. The mechanism of action underlying this cognitive change remains to be established. A new way to produce therapeutic hyperketonemia has recently been described [72]. In a 63-year-old patient with younger-onset sporadic AD for 12 years and a pretreatment Mini-Mental State Examination score of 12, a first trial was conducted of prolonged oral administration of a potent ketogenic agent, (R)-3-hydroxybutyl (R)-3-hydroxybutyrate (ketone monoester) [73]. This ketone monoester has been shown to improve cognitive performance and reduce Aβ and tau deposition in cognition-relevant areas in a mouse model of AD [64]. The compound was administered as a food supplement without changes in the habitual diet. In the 20-month trial, the ketone ester produced repeated diurnal increases in plasma β-hydroxybutyrate levels and improved cognitive performance, mood, affect, behavior and activities of daily living [72]. Plasma ketone levels and the patient’s performance seemed to be running parallel, with interaction and conversation improving noticeably at higher levels and declining as ketone concentrations approached baseline. An increase in the patient’s self-sufficiency and a reduced need for supervision were also noted [72]. However, properly designed case–control studies need to confirm these observations. In summary, a moderate improvement in AD symptoms has been found following dietary supplementation with relatively low concentrations of ketone bodies. In individuals with epilepsy, the highest possible portion of the calorie need may have to be provided in the form of ketone bodies in order to decrease glucose metabolism sufficiently to compromise glutamate production in neurons. By contrast, much lower amounts of ketone bodies can have therapeutic effects in AD probably by different mechanisms. The smaller ketone body doses administered in AD may owe their effect mainly to the support of energy metabolism, but they might also inhibit the release of gliotransmitter glutamate [32].
Possible problems with ketogenic diets in AD Physicians are commonly afraid of ketosis because severe hyperketonemia induced by insulin deficiency may be a life-threatening condition in patients with type 1 diabetes. It is, however, important to distinguish between diabetic ketoacidosis and nutritional ketosis (“physiological ketosis” [74]). Ketoacidosis is a pathological metabolic state characterized by extreme ketosis which cannot be adequately regulated due to a lack of insulin. The resulting pH imbalance may be fatal. However, this kind of metabolic derangement is not possible in ketosis induced by dietary changes. The evaluation of side effects of ketogenic diets in patients with AD is difficult due to the small number of available clinical trials. Major adverse reactions have not been reported in the literature. Transient, mild to moderate gastrointestinal effects such as diarrhea, dyspepsia, and flatulence were reported in patients receiving a formulation of medium chain triglycerides [68,69]. The administration of a ketogenic diet to 83 obese patients for 24 weeks did not produce any significant adverse effects [75]. Strict adherence to low carbohydrate consumption is needed in ketogenic diets. This may be difficult for AD patients due to their altered food preference toward carbohydrate-rich and sweet foods [76,77]. The administration of medium chain triglycerides in order to induce ketosis may be favorable in AD since there is no need for dietary change.