Advertisement

Neurotherapeutics

, Volume 5, Issue 3, pp 470–480 | Cite as

Ketone bodies as a therapeutic for Alzheimer’s disease

  • Samuel T. HendersonEmail author
Review Article

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.

Key Words

Alzheimer’s disease hypometabolism ketone bodies acetoacetate β-hydroxybutyrate glucose insulin apolipoprotein E ketogenic diet 

References

  1. 1.
    Strittmatter WJ, Roses AD. Apolipoprotein E and Alzheimer’s disease. Annu Rev Neurosci 1996;19: 53–77.CrossRefPubMedGoogle Scholar
  2. 2.
    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.CrossRefPubMedGoogle Scholar
  3. 3.
    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.Google Scholar
  4. 4.
    Shulman RG, Rothman DL, Behar KL, Hyder F. Energetic basis of brain activity: implications for neuroimaging. Trends Neurosci 2004;27: 489–495.CrossRefPubMedGoogle Scholar
  5. 5.
    Raichle ME, Mintun MA. Brain work and brain imaging. Annu Rev Neurosci 2006;29: 449–476.CrossRefPubMedGoogle Scholar
  6. 6.
    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.CrossRefPubMedGoogle Scholar
  7. 7.
    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.PubMedGoogle Scholar
  8. 8.
    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.Google Scholar
  9. 9.
    Wang D, Pascual JM, Yang H, et al. Glut-1 deficiency syndrome: clinical, genetic, and therapeutic aspects. Ann Neurol 2005;57: 111–118.CrossRefPubMedGoogle Scholar
  10. 10.
    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.CrossRefPubMedGoogle Scholar
  11. 11.
    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.PubMedGoogle Scholar
  12. 12.
    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.CrossRefPubMedGoogle Scholar
  13. 13.
    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.CrossRefPubMedGoogle Scholar
  14. 14.
    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.CrossRefPubMedGoogle Scholar
  15. 15.
    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.CrossRefPubMedGoogle Scholar
  16. 16.
    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.PubMedGoogle Scholar
  17. 17.
    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.PubMedGoogle Scholar
  18. 18.
    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.CrossRefPubMedGoogle Scholar
  19. 19.
    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.CrossRefPubMedGoogle Scholar
  20. 20.
    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.CrossRefPubMedGoogle Scholar
  21. 21.
    Atamna H, Frey WH, 2nd. Mechanisms of mitochondrial dysfunction and energy deficiency in Alzheimer’s disease. Mitochondrion 2007;7: 297–310.CrossRefPubMedGoogle Scholar
  22. 22.
    Veech RL, Chance B, Kashiwaya Y, Lardy HA, Cahill GF, Jr. Ketone bodies, potential therapeutic uses. IUBMB Life 2001;51: 241–247.CrossRefPubMedGoogle Scholar
  23. 23.
    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.CrossRefPubMedGoogle Scholar
  24. 24.
    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.PubMedGoogle Scholar
  25. 25.
    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.CrossRefPubMedGoogle Scholar
  26. 26.
    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.CrossRefPubMedGoogle Scholar
  27. 27.
    Henderson ST. High carbohydrate diets and Alzheimer’s disease. Med Hypotheses 2004;62: 689–700.CrossRefPubMedGoogle Scholar
  28. 28.
    Owen OE, Morgan AP, Kemp HG, Sullivan JM, Herrera MG, Cahill GF, Jr. Brain metabolism during fasting. J Clin Invest 1967;46: 1589–1595.CrossRefPubMedGoogle Scholar
  29. 29.
    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.CrossRefPubMedGoogle Scholar
  30. 30.
    Lardy HA, Hansen RG, Phillips PH. The metabolism of bovine epididymal spermatazoa. Arch Biochem 1945;6: 41–51.Google Scholar
  31. 31.
    Lardy HA, Phillips PH. Studies of fat and carbohydrate oxidation in mammalian spermatozoa. Arch Biochem 1945;6: 53–61.Google Scholar
  32. 32.
    Sato K, Yoshihiro K, Keon CA, et al. Insulin, ketone bodies, and mitochondrial energy transduction. Faseb J 1995;9: 651–658.PubMedGoogle Scholar
  33. 33.
    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.PubMedGoogle Scholar
  34. 34.
    Gasior M, Rogawski MA, Hartman AL. Neuroprotective and disease-modifying effects of the ketogenic diet. Behav Pharmacol 2006;17: 431–439.CrossRefPubMedGoogle Scholar
  35. 35.
    Prins ML. Cerebral metabolic adaptation and ketone metabolism after brain injury. J Cereb Blood Flow Metab 2008;28: 1–16.CrossRefPubMedGoogle Scholar
  36. 36.
    Finn PF, Dice JF. Ketone bodies stimulate chaperone-mediated autophagy. J Biol Chem 2005.Google Scholar
  37. 37.
    Martinez-Vicente M, Cuervo AM. Autophagy and neurodegeneration: when the cleaning crew goes on strike. Lancet Neurol 2007; 6: 352–361.CrossRefPubMedGoogle Scholar
  38. 38.
    Stokin GB, Goldstein LS. Axonal transport and Alzheimer’s disease. Annu Rev Biochem 2006;75: 607–627.CrossRefPubMedGoogle Scholar
  39. 39.
    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.CrossRefPubMedGoogle Scholar
  40. 40.
    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.CrossRefPubMedGoogle Scholar
  41. 41.
    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.CrossRefPubMedGoogle Scholar
  42. 42.
    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.CrossRefPubMedGoogle Scholar
  43. 43.
    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.PubMedGoogle Scholar
  44. 44.
    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.CrossRefGoogle Scholar
  45. 45.
    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.CrossRefPubMedGoogle Scholar
  46. 46.
    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.PubMedGoogle Scholar
  47. 47.
    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.PubMedGoogle Scholar
  48. 48.
    Feinman RD. When is a high fat diet not a high fat diet? Nutr Metab (Lond) 2005;2: 27.CrossRefGoogle Scholar
  49. 49.
    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.CrossRefPubMedGoogle Scholar
  50. 50.
    Noh HS, Hah YS, Nilufar R, et al. Acetoacetate protects neuronal cells from oxidative glutamate toxicity. J Neurosci Res 2006;83: 702–709.CrossRefPubMedGoogle Scholar
  51. 51.
    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.CrossRefPubMedGoogle Scholar
  52. 52.
    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.CrossRefPubMedGoogle Scholar
  53. 53.
    Bach AC, Babayan VK. Medium-chain triglycerides: an update. Am J Clin Nutr 1982;36: 950–962.PubMedGoogle Scholar
  54. 54.
    Reger MA, Henderson ST, Hale C, et al. Effects of beta-hydroxybutyrate on cognition in memory-impaired adults. Neurobiol Aging 2004;25: 311–314.CrossRefPubMedGoogle Scholar
  55. 55.
    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.CrossRefPubMedGoogle Scholar
  56. 56.
    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.CrossRefPubMedGoogle Scholar
  57. 57.
    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.PubMedGoogle Scholar
  58. 58.
    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.PubMedGoogle Scholar
  59. 59.
    Halestrap AP, Price NT. The proton-linked monocarboxylate transporter (MCT) family: structure, function and regulation. Biochem J 1999;343(Pt 2): 281–299.CrossRefPubMedGoogle Scholar
  60. 60.
    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.CrossRefPubMedGoogle Scholar
  61. 61.
    Robinson AM, Williamson DH. Physiological roles of ketone bodies as substrates and signals in mammalian tissues. Physiol Rev 1980;60: 143–187.PubMedGoogle Scholar
  62. 62.
    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.CrossRefPubMedGoogle Scholar
  63. 63.
    Klepper J, Leiendecker B. GLUT1 deficiency syndrome—2007 update. Dev Med Child Neurol 2007;49: 707–716.CrossRefPubMedGoogle Scholar
  64. 64.
    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.CrossRefPubMedGoogle Scholar
  65. 65.
    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.CrossRefPubMedGoogle Scholar
  66. 66.
    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.CrossRefPubMedGoogle Scholar
  67. 67.
    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.CrossRefPubMedGoogle Scholar
  68. 68.
    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.CrossRefPubMedGoogle Scholar
  69. 69.
    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.CrossRefPubMedGoogle Scholar
  70. 70.
    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.CrossRefPubMedGoogle Scholar
  71. 71.
    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.CrossRefPubMedGoogle Scholar

Copyright information

© The American Society for Experimental NeuroTherapeutics, Inc. 2008

Authors and Affiliations

  1. 1.Accera, Inc.Broomfield

Personalised recommendations