Summary
An early feature of Alzheimer’s disease (AD) is region-specific declines in brain glucose metabolism. Unlike other tissues in the body, the brain does not efficiently metabolize fats; hence the adult human brain relies almost exclusively on glucose as an energy substrate. Therefore, inhibition of glucose metabolism can have profound effects on brain function. The hypometabolism seen in AD has recently attracted attention as a possible target for intervention in the disease process. One promising approach is to supplement the normal glucose supply of the brain with ketone bodies (KB), which include acetoacetate, β-hydroxybutyrate, and acetone. KB are normally produced from fat stores when glucose supplies are limited, such as during prolonged fasting. KB have been induced both by direct infusion and by the administration of a high-fat, low-carbohydrate, low-protein, ketogenic diets. Both approaches have demonstrated efficacy in animal models of neurodegenerative disorders and in human clinical trials, including AD trials. Much of the benefit of KB can be attributed to their ability to increase mitochondrial efficiency and supplement the brain’s normal reliance on glucose. Research into the therapeutic potential of KB and ketosis represents a promising new area of AD research.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Strittmatter WJ, Roses AD. Apolipoprotein E and Alzheimer’s disease. Annu Rev Neurosci 1996;19: 53–77.
Mosconi L, Brys M, Glodzik-Sobanska L, De Santi S, Rusinek H, de Leon MJ. Early detection of Alzheimer’s disease using neuroimaging. Exp Gerontol 2007;42: 129–138.
Clarke DD, Sokoloff L. Circulation and energy metabolism of the brain. In: Siegel GJ, Agranoff BW, Albers RW, Molinoff PB, eds. Basic neurochemistry. New York: Raven Press, 1994: 645–680.
Shulman RG, Rothman DL, Behar KL, Hyder F. Energetic basis of brain activity: implications for neuroimaging. Trends Neurosci 2004;27: 489–495.
Raichle ME, Mintun MA. Brain work and brain imaging. Annu Rev Neurosci 2006;29: 449–476.
Buckner RL, Andrews-Hanna JR, Schacter DL. The brain’s default network: anatomy, function, and relevance to disease. Ann N Y Acad Sci 2008;1124: 1–38.
Kety SS, Woodford RB, Harmel MH, Freyman FA, Appel KE, Schmidt CF. Cerebral blood flow and metabolism in schizophrenia. The effects of barbiturate semi-narcosis, insulin coma and electroshock.1948. Am J Psychiatry 1994;151: 203–209.
Dwyer DS, Vannucci SJ, Simpson IA. Expression, regulation, and functional role of glucose transporters (GLUTs) in brain. In: Dwyer DS, ed. Glucose metabolism in the Brain. London: Academic Press, 2002: 159–188.
Wang D, Pascual JM, Yang H, et al. Glut-1 deficiency syndrome: clinical, genetic, and therapeutic aspects. Ann Neurol 2005;57: 111–118.
Seidner G, Alvarez MG, Yeh JI, et al. GLUT-1 deficiency syndrome caused by haploinsufficiency of the blood-brain barrier hexose carrier. Nat Genet 1998;18: 188–191.
de Leon MJ, Ferris SH, George AE, et al. Positron emission tomographic studies of aging and Alzheimer disease. AJNR Am J Neuroradiol 1983;4: 568–571.
Reiman EM, Caselli RJ, Yun LS, et al. Preclinical evidence of Alzheimer’s disease in persons homozygous for the epsilon 4 allele for apolipoprotein E. N Engl J Med 1996;334: 752–758.
Small GW, Ercoli LM, Silverman DH, et al. Cerebral metabolic and cognitive decline in persons at genetic risk for Alzheimer’s disease. Proc Natl Acad Sci U S A 2000;97: 6037–6042.
Buckner RL, Snyder AZ, Shannon BJ, et al. Molecular, structural, and functional characterization of Alzheimer’s disease: evidence for a relationship between default activity, amyloid, and memory. J Neurosci 2005;25: 7709–7717.
Reiman EM, Chen K, Alexander GE, et al. Functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer’s dementia. Proc Natl Acad Sci U S A 2004;101: 284–289.
Corder EH, Jelic V, Basun H, et al. No difference in cerebral glucose metabolism in patients with Alzheimer disease and differing apolipoprotein E genotypes. Arch Neurol 1997;54: 273–277.
Hirono N, Hashimoto M, Yasuda M, et al. The effect of APOE epsilon4 allele on cerebral glucose metabolism in AD is a function of age at onset. Neurology 2002;58: 743–750.
Mosconi L, Nacmias B, Sorbi S, et al. Brain metabolic decreases related to the dose of the ApoE e4 allele in Alzheimer’s disease. J Neurol Neurosurg Psychiatry 2004;75: 370–376.
Lehtovirta M, Kuikka J, Helisalmi S, et al. Longitudinal SPECT study in Alzheimer’s disease: relation to apolipoprotein E polymorphism. J Neurol Neurosurg Psychiatry 1998;64: 742–746.
Mahley RW, Huang Y. Apolipoprotein (apo) E4 and Alzheimer’s disease: unique conformational and biophysical properties of apoE4 can modulate neuropathology. Acta Neurol Scand Suppl 2006;185: 8–14.
Atamna H, Frey WH, 2nd. Mechanisms of mitochondrial dysfunction and energy deficiency in Alzheimer’s disease. Mitochondrion 2007;7: 297–310.
Veech RL, Chance B, Kashiwaya Y, Lardy HA, Cahill GF, Jr. Ketone bodies, potential therapeutic uses. IUBMB Life 2001;51: 241–247.
Liang WS, Reiman EM, Valla J, et al. Alzheimer’s disease is associated with reduced expression of energy metabolism genes in posterior cingulate neurons. Proc Natl Acad Sci U S A 2008;105: 4441–4446.
Gabuzda D, Busciglio J, Chen LB, Matsudaira P, Yankner BA. Inhibition of energy metabolism alters the processing of amyloid precursor protein and induces a potentially amyloidogenic derivative. J Biol Chem 1994;269: 13623–13628.
Velliquette RA, O’Connor T, Vassar R. Energy inhibition elevates beta-secretase levels and activity and is potentially amyloidogenic in APP transgenic mice: possible early events in Alzheimer’s disease pathogenesis. J Neurosci 2005;25: 10874–10883.
Calon F, Cole G. Neuroprotective action of omega-3 polyunsaturated fatty acids against neurodegenerative diseases: evidence from animal studies. Prostaglandins Leukot Essent Fatty Acids 2007;77: 287–293.
Henderson ST. High carbohydrate diets and Alzheimer’s disease. Med Hypotheses 2004;62: 689–700.
Owen OE, Morgan AP, Kemp HG, Sullivan JM, Herrera MG, Cahill GF, Jr. Brain metabolism during fasting. J Clin Invest 1967;46: 1589–1595.
Taggart AK, Kero J, Gan X, et al. (D)-beta-Hydroxybutyrate inhibits adipocyte lipolysis via the nicotinic acid receptor PUMA-G. J Biol Chem 2005;280: 26649–26652.
Lardy HA, Hansen RG, Phillips PH. The metabolism of bovine epididymal spermatazoa. Arch Biochem 1945;6: 41–51.
Lardy HA, Phillips PH. Studies of fat and carbohydrate oxidation in mammalian spermatozoa. Arch Biochem 1945;6: 53–61.
Sato K, Yoshihiro K, Keon CA, et al. Insulin, ketone bodies, and mitochondrial energy transduction. Faseb J 1995;9: 651–658.
Tieu K, Perier C, Caspersen C, et al. D-beta-hydroxybutyrate rescues mitochondrial respiration and mitigates features of Parkinson disease. J Clin Invest 2003;112: 892–901.
Gasior M, Rogawski MA, Hartman AL. Neuroprotective and disease-modifying effects of the ketogenic diet. Behav Pharmacol 2006;17: 431–439.
Prins ML. Cerebral metabolic adaptation and ketone metabolism after brain injury. J Cereb Blood Flow Metab 2008;28: 1–16.
Finn PF, Dice JF. Ketone bodies stimulate chaperone-mediated autophagy. J Biol Chem 2005.
Martinez-Vicente M, Cuervo AM. Autophagy and neurodegeneration: when the cleaning crew goes on strike. Lancet Neurol 2007; 6: 352–361.
Stokin GB, Goldstein LS. Axonal transport and Alzheimer’s disease. Annu Rev Biochem 2006;75: 607–627.
Freeman J, Veggiotti P, Lanzi G, Tagliabue A, Perucca E. The ketogenic diet: from molecular mechanisms to clinical effects. Epilepsy Res 2006;68: 145–180.
Klepper J, Scheffer H, Leiendecker B, et al. Scizure control and acceptance of the ketogenic diet in GLUT1 deficiency syndrome: a 2- to 5-year follow-up of 15 children enrolled prospectively. Neuropediatrics 2005;36: 302–308.
Zhao Z, Lange DJ, Voustianiouk A, et al. A ketogenic diet as a potential novel therapeutic intervention in amyotrophic lateral sclerosis. BMC Neurosci 2006;7: 29.
Prins ML, Fujima LS, Hovda DA. Age-dependent reduction of cortical contusion volume by ketones after traumatic brain injury. J Neurosci Res 2005;82: 413–420.
Vanitallie TB, Nonas C, Di Rocco A, Boyar K, Hyams K, Heyms-field SB. Treatment of Parkinson disease with diet-induced hyper-ketonemia: a feasibility study. Neurology 2005;64: 728–730.
Van der Auwera I, Wera S, Van Leuven F, Henderson ST. A ketogenic diet reduces amyloid beta 40 and 42 in a mouse model of Alzheimer’s disease. Nutr Metab (Lond) 2005;2: 28.
Moechars D, Dewachter I, Lorent K, et al. Early phenotypic changes in transgenic mice that overexpress different mutants of amyloid precursor protein in brain. J Biol Chem 1999;274: 6483–6492.
Ho L, Qin W, Pompl PN, et al. Diet-induced insulin resistance promotes amyloidosis in a transgenic mouse model of Alzheimer’s disease. Faseb J 2004;18: 902–904.
Levin-Allerhand JA, Lominska CE, Smith JD. Increased amyloid-levels in APPSWE transgenic mice treated chronically with a physiological high-fat high-cholesterol diet. J Nutr Health Aging 2002;6: 315–319.
Feinman RD. When is a high fat diet not a high fat diet? Nutr Metab (Lond) 2005;2: 27.
Sullivan PG, Rippy NA, Dorenbos K, Concepcion RC, Agarwal AK, Rho JM. The ketogenic diet increases mitochondrial uncoupling protein levels and activity. Ann Neurol 2004;55: 576–580.
Noh HS, Hah YS, Nilufar R, et al. Acetoacetate protects neuronal cells from oxidative glutamate toxicity. J Neurosci Res 2006;83: 702–709.
Suzuki M, Suzuki M, Kitamura Y, et al. Beta-hydroxybutyrate, a cerebral function improving agent, protects rat brain against ischemic damage caused by permanent and transient focal cerebral ischemia. Jpn J Pharmacol 2002;89: 36–43.
Kashiwaya Y, Takeshima T, Mori N, Nakashima K, Clarke K, Veech RL. D-beta-hydroxybutyrate protects neurons in models of Alzheimer’s and Parkinson’s disease. Proc Natl Acad Sci USA 2000;97: 5440–5444.
Bach AC, Babayan VK. Medium-chain triglycerides: an update. Am J Clin Nutr 1982;36: 950–962.
Reger MA, Henderson ST, Hale C, et al. Effects of beta-hydroxybutyrate on cognition in memory-impaired adults. Neurobiol Aging 2004;25: 311–314.
Craft S, Asthana S, Schellenberg G, et al. Insulin effects on glucose metabolism, memory, and plasma amyloid precursor protein in Alzheimer’s disease differ according to apolipoprotein-E genotype. Ann N Y Acad Sci 2000;903: 222–228.
Reger MA, Watson GS, Frey WH, 2nd, et al. Effects of intranasal insulin on cognition in memory-impaired older adults: modulation by APOE genotype. Neurobiol Aging 2006;27: 451–458.
Risner ME, Saunders AM, Altman JF, et al. Efficacy of rosiglitazone in a genetically defined population with mild-to-moderate Alzheimer’s disease. Pharmacogenomics J 2006;6: 246–254.
Craft S, Peskind E, Schwartz MW, Schellenberg GD, Raskind M, Porte D, Jr. Cerebrospinal fluid and plasma insulin levels in Alzheimer’s disease: relationship to severity of dementia and apolipoprotein E genotype. Neurology 1998;50: 164–168.
Halestrap AP, Price NT. The proton-linked monocarboxylate transporter (MCT) family: structure, function and regulation. Biochem J 1999;343(Pt 2): 281–299.
Froberg MK, Gerhart DZ, Enerson BE, et al. Expression of monocarboxylate transporter MCT1 in normal and neoplastic human CNS tissues. Neuroreport 2001;12: 761–765.
Robinson AM, Williamson DH. Physiological roles of ketone bodies as substrates and signals in mammalian tissues. Physiol Rev 1980;60: 143–187.
Noh HS, Kim YS, Lee HP, et al. The protective effect of a ketogenic diet on kainic acid-induced hippocampal cell death in the male ICR mice. Epilepsy Res 2003;53: 119–128.
Klepper J, Leiendecker B. GLUT1 deficiency syndrome—2007 update. Dev Med Child Neurol 2007;49: 707–716.
Massieu L, Haces ML, Montiel T, Hernandez-Fonseca K. Acetoacetate protects hippocampal neurons against glutamate-mediated neuronal damage during glycolysis inhibition. Neuroscience 2003; 120: 365–378.
Mejia-Toiber J, Montiel T, Massieu L. D-beta-hydroxybutyrate prevents glutamate-mediated lipoperoxidation and neuronal damage elicited during glycolysis inhibition in vivo. Neurochem Res 2006;31: 1399–1408.
Maalouf M, Sullivan PG, Davis L, Kim DY, Rho JM. Ketones inhibit mitochondrial production of reactive oxygen species production following glutamate excitotoxicity by increasing NADH oxidation. Neuroscience 2007;145: 256–264.
Masuda R, Monahan JW, Kashiwaya Y. D-beta-hydroxybutyrate is neuroprotective against hypoxia in serum-free hippocampal primary cultures. J Neurosci Res 2005;80: 501–509.
Suzuki M, Suzuki M, Sato K, et al. Effect of beta-hydroxybutyrate, a cerebral function improving agent, on cerebral hypoxia, anoxia and ischemia in mice and rats. Jpn J Pharmacol 2001;87: 143–150.
Prins ML, Lee SM, Fujima LS, Hovda DA. Increased cerebral uptake and oxidation of exogenous beta HB improves ATP following traumatic brain injury in adult rats. J Neurochem 2004;90: 666–672.
Imamura K, Takeshima T, Kashiwaya Y, Nakaso K, Nakashima K. D-beta-hydroxybutyrate protects dopaminergic SH-SY5Y cells in a rotenone model of Parkinson’s disease. J Neurosci Res 2006;84: 1376–1384.
Dardzinski BJ, Smith SL, Towfighi J, Williams GD, Vannucci RC, Smith MB. Increased plasma beta-hydroxybutyrate, preserved cerebral energy metabolism, and amelioration of brain damage during neonatal hypoxia ischemia with dexamethasone pretreatment. Pediatr Res 2000;48: 248–255.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Henderson, S.T. Ketone bodies as a therapeutic for Alzheimer’s disease. Neurotherapeutics 5, 470–480 (2008). https://doi.org/10.1016/j.nurt.2008.05.004
Issue Date:
DOI: https://doi.org/10.1016/j.nurt.2008.05.004