Reger et al. [23] to explore, in individuals with memory disorders, whether hyperketonemia

improves cognitive functioning (change from baseline in the Alzheimer’s disease (AD) Assessment Scale-Cognitive subscale, ADAS-Cog). 20 individuals, mean age 74.7 (S . D . = 6 . 7), with probable AD ( n = 15; National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA criteria; 9 = ε 4+) or amnestic mild cognitive impairment ( n = 5; 1 = ε 4+); mildly to moderately cognitively impaired with a mean

Mini-Mental State Examination (MMSE) of 22.0 (S . D . = 5 . 5). double-blind placebo controlled design with two study visits; during each visit, subjects received one of two isocaloric conditions (690 calories) in a randomized order: emulsified medium chain triglycerides (MCTs), or emulsified long chain triglycerides as a placebo. significant increases in levels of the ketone body β-hydroxybutyrate (β-OHB) were observed 90 min after treatment ( p = 0 . 007) when cognitive tests were administered; MCT treatment facilitated performance on the ADAS-Cog for ε4− subjects, but not for ε4+ subjects ( p = 0.04). β-OHB elevations were moderated by apolipoprotein E (APOE) genotype ( p = 0 . 036).

Henderson et al. [24]. to assess whether 90-day daily dosing of the oral ketogenic product AC-1202 (medium chain triglyceride composed of glycerin and caprylic acid, C8:0) improve cognitive performance; additional outcomes included how cognitive scores were influenced by APOE4 genotype status. 152 subjects diagnosed with mild to moderate AD according to NINCDS-ADRDA criteria and Diagnostic and Statistical Manual of mental disorders-IV (DSM-IV) criteria, with a MMSE score of between 14 and 24 (inclusive) at screen (86, age 76.9 ± 8.9 years, were allocated to AC-102, and 66, age 76.8 ± 7.4 years, to placebo). AC-1202 was compared to Placebo in a randomized, double-blind, placebo-controlled, parallel-group study; subjects were on a normal diet and continued taking approved AD medications; pre- and post-dosing serum β-hydroxybutyrate (β-OHB) levels were evaluated. Cognitive performance change from baseline was assessed after 90 days by ADAS-Cog and AD Cooperative Study—Clinical Global Impression of Change (ADCS-CGIC). AC-1202 rapidly elevated serum ketone bodies in AD patients and resulted in significant differences in ADAS-Cog scores compared to the Placebo after 45 and 90 days of treatment. Effects were most notable in APOE4(-) subjects who were dosage compliant. adverse events were more frequently observed in participants receiving AC-1202 and concerned mainly transient, mild to moderate gastrointestinal effects; this medium-chain triglyceride preparation of fractionated coconut oil (caprylic trigyceride) has been approved for the treatment of AD in the USA.

Krikorian et al. [25] the primary outcomes included measures of executive ability, long term memory, and mood obtained at pretreatment baseline and after the 6-week of the intervention: high carbohydrate or very low carbohydrate diet. 23 (10 men, 13 women) older adults with mild cognitive impairment (Clinical Dementia Rating, CDR), age 70.1 ± 6.2 years. the subjects were randomly assigned to the 6-week dietary interventions consisted of high carbohydrate (50% of calories) and very low carbohydrate (5% to 10% of calories) diets, the latter intended to induce ketosis; all subjects also provided urine samples at the baseline and final visits for urinary ketone assessment; working memory and set switching aspects of executive ability was evaluated by The Trail Making Test part B, secondary or long term memory with the Verbal Paired Associate Learning and mood with the Geriatric Depression Scale; waist circumference, fasting serum glucose and insulin level were analyzed. ketone levels were positively correlated with memory performance ( p = 0.04); the primary finding indicated improved secondary memory performances for the low carbohydrate subjects; there was no effect of the intervention on the Trail Making Test part B and Geriatric Depression Scale; there were significant changes in anthropometric and metabolic values and in dietary parameters; after the intervention, weight, waist circumference, fasting glucose and insulin value were lower for the low carbohydrate but not high carbohydrate group. these preliminary data provide evidence that dietary ketosis by means of carbohydrate restriction can provide neurocognitive benefit for older adults with early memory decline and increased risk for neurodegeneration.

Correction of hyperinsulinemia and other mechanisms associated with ketosis such as reduced inflammation and enhanced energy metabolism also may have contributed to improved neurocognitive function; a prominent issue will be duration of the effects and whether there is persistence of benefit beyond the period of active intervention.

Rebello et al. [26] to evaluated the effect of the daily consumption of an oil, composed of medium chain triglycerides (MCTs) for 24 weeks on serum ketone body concentrations (β-hydroxybutyrate [βHB]) and cognitive performance. 6 individuals ≥50 (58–78) years, with mild cognitive impairment (MCI). pilot and feasibility, randomized double blind placebo-controlled parallel trial; participants received 56 g/day of either medium chain triglycerides (MCTs) or placebo for 24 weeks; serum β-hydroxybutyrate concentrations, apolipoprotein-E4 status, and cognitive assessments (Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog), Trail Making Test, and Digit Symbol Test) were carried out. intake of MCT oil increased serum ketone bodies and improved memory, only in subjects with mild Alzheimer’s disease who did not have an APOE ε4 allele while intake of placebo did not show improvement in any of the cognitive measures tested. Due to the small number of participants only the raw scores were examined.

Consumption of 56 g/day of MCTs for 24weeks increases serum ketone concentrations and appears to be a candidate for larger randomized control trials in the future

Ota et al. [27] to examine the effects of a single MCT supplemented ketogenic meal serving on cognition in elderly non-demented subjects subjects were 19 non-demented elderly adults over 60 years old (13 females; mean age: 66.1 ± 2.9 years) subjects underwent neurocognitive tests 90 and 180 min after oral intake of a ketogenic meal (Ketonformula®) containing 20 g of MCTs and an socaloric placebo meal without MCTs on separate days. elevation of plasma ketone concentration after intake of a single ketogenic meal containing 20 g of MCTs was

confirmed (all p < 0.001); as for cognition, improvements were observed in the digit span test, Trail-Making Test B, and the global score (Z = −2.4, p = 0.017) following the ketogenic meal and the change in the executive functioning score was positively correlated with that of the plasma β-

hydroxybutyrate level; the cognition-enhancing effect was observed predominantly for individuals who had a relatively low global score at baseline (Z = −2.8, p = 0.005), compared to individuals with a high global score (Z = −0.7, p = 0.51). plasma levels of ketone bodies were successfully increased after intake of the ketogenic meal; the ketogenic meal was suggested to have positive effects on working memory, visual attention, and task switching in non-demented elderly;

the study is limited by the small sample size which may have resulted in false-positive and -negative results of the effect of the

ketogenic meal in some cognitive tests.

Ohnuma et al. [28] This clinical trial, carried out in Japan, analyzed the effect of 90-day administration of a ketogenic meal “Axona” (40 g of powder containing 20 g of caprylic triglycerides) on cognitive function in mild-to-moderate Alzheimer’s disease (AD) patients. 22 Japanese patients with sporadic AD at a mild-to-moderate stage (ten females, 12 males), mean age (± standard deviation) 63.9 (± 8.5) years, Mini-Mental State Examination (MMSE) score, 10–25, seven patients were ApoE4-positive. prospective, open-label, observational study; Axona was administered for 3 months using an indurating, four-step dose-titration method (from 10 to 40 g per day) for 7 days before the trial, and examined the tolerance and adverse effects of this intervention; blood tests included: haemogram, alanine aminotransferase and aspartate aminotransferase, creatinine and urea nitrogen, glucose, glycohaemoglobin A1C, low-density lipoprotein and high-density lipoprotein, triacylglycerol, albumin, and total protein, and sodium, chloride, and potassium; serum total ketone bodies (acetoacetic acid and β-hydroxybutyric acid); the effect on cognitive function was assessed using the MMSE and Alzheimer’s Disease Assessment Scale (ADAS) cognitive subscale, Japanese version (ADAS-Jcog); ApoE genotypes were determined. the tolerance of Axona was good, without severe gastrointestinal adverse effects; Axona did not improve cognitive function in our sample of AD patients, even in those patients without the ApoE4 allele; however, some ApoE4-negative patients with baseline MMSE score ≥14 showed improvement in their cognitive functions. the modified dose-titration method, starting with a low dose of Axona, decreased gastrointestinal adverse effects in Japanese patients. Axona might be effective for some relatively mildly affected patients with AD (with cognitive function MMSE score of ≥14 and lacking the ApoE4 allele).