November/December 2018 The Ketogenic Diet and Alzheimer's Disease

By KC Wright, MS, RDN

Today's Geriatric Medicine

Vol. 11 No. 6 P. 12 This very high-fat, very low-carbohydrate diet may be a promising treatment option. Despite recent progress in the understanding of the neurobiology and pathophysiology of Alzheimer's disease (AD), no definitive pharmaceutical treatments are available; the few drugs that address symptoms1 offer only temporary improvements in cognition and function or delay the decline resulting from the disease.2 In AD, the most common form of dementia, loss of recent memory and cognitive deficits are associated with extracellular deposition of amyloid-β peptide, intracellular neurofibrillary tangles, and hippocampal neuronal death.3 There are various theories about the etiology of the overall AD process, but mitochondrial dysfunction and glucose hypometabolism are recognized biochemical hallmarks.4 Reduced uptake and metabolism of glucose have been strongly linked to progressive cognitive degeneration, as neurons starve due to inefficient glycolysis.5 This reduction is associated with downregulation of the glucose transporter GLUT1 in the brain of individuals with AD.6,7 There's increasing evidence of an association between a high-glycemic diet and cerebral amyloid burden,8 indicating that increased insulin resistance contributes to the development of sporadic AD.9,10 Identifying these metabolic challenges creates opportunities to consider diet as a potential modifiable behavior to prevent cerebral amyloid accumulation and reduce AD risk. Ketogenicity and Alzheimer's

The ketogenic diet (KD) was initially developed in the 1920s as a treatment for refractory epilepsy.1 And while there's extensive evidence documenting the use of KDs for both epilepsy and weight loss, the diet has garnered increased interest as a potential treatment for AD.11,12 It's been hypothesized that the ketone bodies (KBs)—acetoacetate and β-hydroxybutyrate—can be used as alternative energy sources by neurons with impaired glucose utilization. The KD is a very high-fat, very low-carbohydrate diet that reduces insulin, which in turn stimulates liver oxidation of fatty acids into KB without depriving the body of necessary calories.13,14 KBs enter the bloodstream and are taken up by organs, including the brain, where they are further metabolized in mitochondria to generate energy for cells within the nervous system. The KB acetone, produced by spontaneous decarboxylation of acetoacetate, is then rapidly eliminated through the lungs and urine. The Ketogenic Diet

The composition of the classic KD typically is based on a macronutrient ratio of 3 to 4:1 (4 g fat to every 1 g protein plus carbohydrates combined), which approximates 90% of total calorie intake from fat, 6% from protein, and 4% from carbohydrate,1 thus shifting the predominant source of calories from carbohydrate to fat. The moderate protein intake avoids amino acid–induced gluconeogenesis and promotes KB formation. The resulting metabolic profile is characterized by a slight reduction of blood glucose concentration with increasing KBs that the brain starts to use to generate cellular energy. As the very low carbohydrate intake of the classic KD can often be difficult to maintain, other diet variations have been developed, including the lower fat-to-protein plus carbohydrate ratios of 3:1, 2:1, or 1:1 (referred to as a modified KD), and may be used depending on tolerability, ketosis level, and protein requirements.15 To further enhance palatability and flexibility, less stringent variations of the diet include the modified Atkins diet, which allows for 10 to 20 g carbohydrate daily, having an approximate ratio of 1 to 2:1 of fat to protein plus carbohydrate.16,17 Another alternative, the low-glycemic index treatment, calls for 40 to 60 g carbohydrate daily from foods having glycemic indices less than 50%, with roughly 60% of dietary energy derived from fat and 20% to 30% from protein.18 Another diet variant combines the KD with medium-chain triglyceride (MCT) oil as a supplement, allowing for greater carbohydrate and protein intake than even a lower-ratio classic KD that may help to improve compliance.19 Although dietary fatty acid and chain length usually are not specified with diet prescriptions, a KD typically includes mostly saturated fats having 16 to 20 carbon atoms. The alternative MCT KD comprises roughly 60% octanoic acid (an 8-carbon fatty acid) and about 40% decanoic acid (a 10-carbon fatty acid). The quick metabolism of shorter-chain fatty acids results in more efficient generation of KB, allowing the KD to contain a greater proportion of dietary carbohydrate, with only 45% of lipid energy intake.20,21 Preclinical Research

Insight into potential mechanisms through which KDs and ketones may influence AD risk and pathology has evolved through preclinical work. In vitro studies showed reduced amyloid-β induced effects in rat cortical neurons by pretreatment with MCT via activation of signaling pathways that affect glucose metabolism.22 Similarly, animal models of dementia demonstrated reduced amyloid-β brain levels, protection from amyloid-β toxicity, and better mitochondrial function following administration of the KD, ketones, and MCT.23-26 Ketone body suppression of mitochondrial amyloid entry has been further shown to improve learning and memory ability in a symptomatic mouse model of AD.27 Older rats following a KD for three weeks had improved learning and memory associated with increased angiogenesis and capillary density, suggesting the KD may support cognition through improved vascular function.28 This preclinical research laid a foundation for subsequent studies in humans. Clinical Evidence

In an early study of the KD in humans, 20 subjects with AD or mild cognitive impairment (MCI) consumed either a drink containing emulsified MCTs or a placebo during two study visits. Fasting blood was drawn before and 90 minutes after subjects consumed the test beverages, after which there was a cognitive testing session and a final blood draw. Results demonstrated expected elevations in serum ketone levels.29 Only patients without the apolipoprotein e4 allele (APOE ε4) showed enhanced short-term cognitive performance on a brief screening tool measuring cognitive domains that included attention, memory, language, and praxis. (In people older than 65 with AD, the strongest genetic risk factor identified is carriage of the APOE ε4.30) The study was replicated, with similar improvements in working memory, visual attention, and task switching seen in 19 nondemented elderly patients after a ketogenic meal.31 In another study involving 23 older adults with MCI treated with either a very low- (5% to 10%) or high- (50%) carbohydrate diet over six weeks, improved verbal memory performance correlated with ketone levels in the KD group.32 Three more studies were conducted in patients with MCI or mild to moderate AD following a minimum of three-month protocols—two randomized studies of MCT or a ketogenic product compared with placebo for three to six months, and one observational study that implemented a daily ketogenic meal over three months. The two randomized studies reported that the cognitive benefit of ketogenic therapies was greatest in patients who did not have the APOE ε4 allele,33,34 while the benefits were limited to APOE ε4-negative patients with mild AD in the observational study.35 In a recent study, patients with mild to moderate AD treated with one month of MCT supplements demonstrated increased ketone consumption quantified by brain 11C-acetoacetate positron emission tomography imaging before and after administration, suggesting ketones from MCT can compensate for the brain glucose deficit observed in AD.36 In one case report, supplementation with a potent ketone agent—ketone monoester—in a patient with AD produced repeated daily elevations in circulating serum β-hydroxybutyrate levels and improved cognitive and daily activity performance over 20 months.37 The prescription ketogen supplement caprylidene, an MCT of caprylic acid, showed increased regional cerebral blood flow over 45 days in subjects with mild to moderate AD in a randomized double-blind pilot study.38 The Ketogenic Diet Retention and Feasibility Trial—a single-arm pilot clinical study in 15 patients with mild to moderate AD—involved consumption of an MCT-supplemented >1:1 ratio KD for three months. Nine of 10 patients who completed the study and achieved ketosis (as measured by elevated serum β-hydroxybutyrate levels at follow-up) showed improved scores on the Alzheimer's Disease Assessment Scale-Cognitive Subscale.39 This clinical evidence lends support for the use of KDs and/or supplements to improve cognitive outcomes in patients with AD. It should be noted that the stage or level of disease progression and presence of the APOE ε4 genotype might affect clinical results. Mechanism of Action

Under normal dietary conditions, the brain uses glucose as an energy source. In contrast, during fasting conditions, ketones are the main energy source.5,40-42 Starvation induces ketone generation, which might be the therapeutic mechanism of action. The main effect of the KD has been related to improved mitochondrial function and decreased oxidative stress. Beta-hydroxybutyrate, the most studied ketone body, has been shown to reduce the production of reactive oxygen species, improving mitochondrial respiration that stimulates the cellular antioxidant system.1 Additionally, a low-carbohydrate diet causing an increase of KB serum levels parallels a reduction in several inflammatory parameters.43 The KD has been shown to revert the increased expression of inflammatory cytokines.44 The advances in the understanding of MCTs' mechanisms of action have more recently shifted attention away from KB to the direct role of fatty acids as therapeutic effectors, paving the way for novel dietary and drug therapies as described in a recent review.21 According to this study, medium-chain fatty acids are able to reach the brain quickly to provide brain cells (neurons and astrocytes) with an energy source that is more efficient than glucose. Octanoic acid seems to undergo β-oxidation in astrocytes more easily than does decanoic acid and readily produces KB, whereas decanoic acid stimulates glycolysis, producing lactate available as fuel for the brain cells. As previously stated, mitochondrial dysfunction has been implicated in the pathogenesis of AD. Structural abnormalities of mitochondria, imbalances in mitochondrial fission and fusion, and defective electron transport chain activity have been reported in an AD model.45 With mitochondria intrinsically linked to cell signaling, mitochondrial damage consequentially leads to cell death and might cause the synaptic degeneration seen in in AD. Although the mechanisms of these observed effects remain unknown, there remains a potential for the role of MCTs in this context. Adverse Effects

The most commonly reported side effects in clinical studies of KD use in AD are gastrointestinal, although the true risk of such effects in these populations is difficult to assess due to the small number of trials, short duration of follow-up, and heterogeneity in KD therapy applied.1 Constipation, diarrhea, and occasional nausea and vomiting are typically mild, improve with time, can often be managed with dietary adjustments with the guidance of a registered dietitian nutritionist (RDN), and seldom have required medical intervention. Smaller meals, more fiber, physical activity, and increased sodium and fluids often can prevent or alleviate these adverse effects. Very low-carbohydrate diets that induce ketosis have contributed to reductions in serum triglycerides and LDL and total cholesterol while increasing HDL cholesterol in adults.11 However, in children, the KD has led to progressive bone mineral loss resulting from vitamin and mineral deficiencies secondary to carbohydrate restriction and prolonged ketonemia.46 With any dietary restriction, the standard practice of supplementing a recommended daily allowance of multivitamin and mineral supplements should be followed to reduce the risk of deficiencies. Dietary Adherence

Following a rigid diet in an ambulatory setting often can be more difficult to achieve than taking a pharmaceutical medication. Adults with AD may have difficulty adhering to a prescribed diet and may lack the ability to self-report. Accurate data collection often depends on caregivers to monitor intake with varying attention to detail. Some caregivers had to assume varying degrees of additional responsibility, including compliance with complex meal preparation instructions, MCT administration, urinary ketone assessment, and food diary completion. The recent three-month single-arm AD pilot trial of an MCT-supplemented KD reported a 33% (five out of 15) attrition rate due to caregiver burden.39 Measurements of serum β-hydroxybutyrate or urine acetoacetate concentrations during the first few weeks on the diet can be used to assess KD adherence.47 To improve KD compliance, RDNs can provide patients and family members with resources and menus and demonstrate recipes during initial diet training and at subsequent visits, emphasizing food variety and practical tips to improve diet ease. Implementing electronic applications such as the KetoDietCalculator may also help to emphasize progress and improve compliance.48 Summary

Overall, the benefits of dietary interventions in AD are that they are noninvasive, relatively low risk, generally without serious side effects with clinical monitoring, and may be useful as an adjunct to pharmacologic interventions. The effect of ketones on metabolic activity in the brain highlights the potential of the KD as a treatment for the metabolic changes underlying AD.49,50 Reduced uptake and metabolism of glucose have been strongly linked to progressive cognitive and motor degeneration as neurons starve because of inefficient glycolysis.5 Research to date shows that the disruption in energy metabolism and increased oxidative stress and neuro-inflammation with AD can be influenced through dietary intervention. Despite challenges with adherence and compliance, KDs appear to be effective, and the clinical literature continues to grow. Ongoing registered randomized clinical trials continue in individuals with subjective memory impairment, mild AD, and/or healthy controls.51-56 Primary research outcomes could inform precision medicine approaches to dietary prescription. — KC Wright, MS, RDN, is a registered dietitian nutritionist who advocates for healthy lifestyles and sustainable food systems at www.wildberrycommunications.com. References

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