Cellular and Molecular Neurobiology

, Volume 25, Issue 3–4, pp 475–483 | Cite as

Alzheimer’s Disease—A Dysfunction in Cholesterol and Lipid Metabolism

  • Walter J. LukiwEmail author
  • Miguel Pappolla
  • Ricardo Palacios Pelaez
  • Nicolas G. Bazan


1. Strong etiological association exists between dysfunctional metabolism of brain lipids, age-related changes in the cerebral vasculature and neurodegenerative features characteristic of Alzheimer’s disease (AD) brain.

2. In this short review, recent experimental evidence for these associations is further discussed below.

Key Words

Alzheimer amyloid cholesterol lipids oxidation statins 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Aliev, G., Smith, M. A., Obrenovich, M. E., de la Torre, J. C., and Perry, G. (2003). Role of vascular hypoperfusion-induced oxidative stress and mitochondria failure in the pathogenesis of Azheimer disease. Neurotox. Res. 5:491–504.PubMedGoogle Scholar
  2. Bazan, N. G., and Flower, R. J. (2002). Lipid signals in pain control. Nature 420:135–138.CrossRefPubMedGoogle Scholar
  3. Bazan, N. G., Colangelo, V., and Lukiw, W. J. (2002). Prostaglandins and other lipid mediators in Alzheimer’s disease. Prostaglandins and Other Lipid Mediators 68–69:197–210.CrossRefPubMedGoogle Scholar
  4. Baskin, F., Rosenberg, R. N., Fang, X., Hynan, L. S., Moore, C. B., Weiner, M., and Vega, G. L. (2003). Correlation of statin-increased platelet APP ratios and reduced blood lipids in AD patients. Neurology 60:2006–2007.PubMedGoogle Scholar
  5. Bodovitz, S., Klein, W. L. (1996). Cholesterol modulates alpha-secretase cleavage of amyloid precursor protein. J. Biol. Chem. 271:4436–4440.CrossRefPubMedGoogle Scholar
  6. Cacabelos, R., Fernandez-Novoa, L., Lombardi, V., Corzo, L., Pichel, V., and Kubota, Y. (2003). Cerebrovascular risk factors in Alzheimer’s disease: Brain hemodynamics and pharmacogenomic implications. Neurol. Res. 25:567–580.CrossRefPubMedGoogle Scholar
  7. Chaney, M. O., Baudry, J., Esh, C., Childress, J., Luehrs, D. C., Kokjohn, T. A., and Roher, A. E. (2003). A beta, aging, and Alzheimer’s disease: A tale, models, and hypotheses. Neurol. Res. 25:581–589.CrossRefPubMedGoogle Scholar
  8. Colangelo, V., Schurr, J., Ball, M. J., Pelaez, R. P., Bazan, N. G., and Lukiw, W. J. (2002). Gene expression profiling of 12633 genes in Alzheimer hippocampal CA1: transcription and neurotrophic factor down-regulation and up-regulation of apoptotic and pro-inflammatory signaling. J. Neurosci. Res. 70:462–473.CrossRefPubMedGoogle Scholar
  9. Cutler, R. G., Kelly, J., Storie, K., Pedersen, W. A., Tammara, A., Hatanpaa, K., Troncoso, J. C., and Mattson, M. P. (2004). Involvement of oxidative stress-induced abnormalities in ceramide and cholesterol metabolism in brain aging and Alzheimer’s disease. Proc. Natl. Acad. Sci. USA. 101:2070–2075.CrossRefPubMedGoogle Scholar
  10. Dietschy, J. M., and Turley, S. D. (2001). Cholesterol metabolism in the brain. Curr. Opin. Lipidol. 12:105–112.CrossRefPubMedGoogle Scholar
  11. Edwards, J. E., and Moore, R. A. (2003). Statins in hypercholesterolaemia: A dose-specific meta-analysis of lipid changes in randomised, double blind trials. BMC Family Pract4: 18.CrossRefGoogle Scholar
  12. Fitzpatrick, A. L., Kuller, L. H., Ives, D. G., Lopez, O. L., Jagust, W., Breitner, J. C., Jones, B., Lyketsos, C., and Dulberg, C. (2004). Incidence and prevalence of dementia in the Cardiovascular Health Study. J. Am. Geriatr. Soc. 52:195–204.CrossRefPubMedGoogle Scholar
  13. Flood, D. G., Reaume, A. G., Dorfman, K. S., Lin, Y. G., Lang, D. M., Trusko, S. P., Savage, M. J., Annaert, W. G., De Strooper, B., Siman, R., and Scott, R. W. (2002). FAD mutant PS-1 gene-targeted mice: increased Abeta 42 and Abeta deposition without APP overproduction. Neurobiol. Aging 23:335–348.CrossRefPubMedGoogle Scholar
  14. Frears, E. R., Stephens, D. J., Walters, C. E., Davies, H., and Austen, B. M. (1999). The role of cholesterol in the biosynthesis of beta-amyloid. Neuroreport 10:1699–1705.PubMedGoogle Scholar
  15. Fukumoto, H., Rosene, D. L., Moss, M. B., Raju, S., Hyman, B. T., and Irizarry, M. C. (2004). Beta-secretase activity increases with aging in human, monkey, and mouse brain. Am. J. Pathol. 164:719–725.PubMedGoogle Scholar
  16. Gibson Wood, W., Eckert, G. P., Igbavboa, U., and Muller, W. E. (2003). Amyloid beta-protein interactions with membranes and cholesterol: Causes or casualties of Alzheimer’s disease. Biochim. Biophys. Acta 1610:281–290.PubMedGoogle Scholar
  17. Grant, W. B. (1999). Dietary links to Alzheimer’s Disease: 1999 update, J. Alzheimer Dis. 1:197–201.Google Scholar
  18. Hoglund, K., Wiklund, O., Vanderstichel, H., Eikenberg, O., Vanmechelen, E., and Blennow, K. (2004). Plasma levels of beta-amyloid(1–40), beta-amyloid(1–42), and total beta-amyloid remain unaffected in adult patients with hypercholesterolemia after treatment with statins. Arch Neurol. 61:333–337.CrossRefPubMedGoogle Scholar
  19. Jankowsky, J. L., Fadale, D. J., Anderson, J., Xu, G. M., Gonzales, V., Jenkins, N. A., Copeland, N. G., Lee, M. K., Younkin, L. H., Wagner, S. L., Younkin, S. G., and Borchelt, D. R. (2004). Mutant presenilins specifically elevate the levels of the 42 residue beta-amyloid peptide in vivo: Evidence for augmentation of a 42-specific gamma secretase. Hum. Mol. Genet. 13:159–170.CrossRefPubMedGoogle Scholar
  20. Jick, H., Zornberg, G. L., Jick, S. S., Seshadri, S., and Drachman, D. A. (2000). Statins and the risk of dementia. Lancet 356:1627–1631.CrossRefPubMedGoogle Scholar
  21. Kolsch, H., Lutjohann, D., von Bergmann, K., and Heun, R. (2003). The role of 24S-hydroxycholesterol in Alzheimer’s disease. J. Nutr. Health Aging 7:37–41.PubMedGoogle Scholar
  22. Launer, L. (2003). Nonsteroidal anti-inflammatory drug use and the risk for Alzheimer’s disease: Dissecting the epidemiological evidence. Drugs 63:731–739.PubMedGoogle Scholar
  23. Lukiw, W. J. (2004). Gene Expression Profiling in Fetal, Aged and Alzheimer Hippocampus—A Continuum of Stress-Related Signaling. Neurochem. Res. 29:1287–1297.CrossRefPubMedGoogle Scholar
  24. Lutjohann, D., and von Bergmann, K. (2003). 24S-hydroxycholesterol: A marker of brain cholesterol metabolism. Pharmacopsychiatry 36:S102–S106.CrossRefPubMedGoogle Scholar
  25. Marcheselli, V. L., Hong, S., Lukiw, W. J., Tian, X. H., Gronert, K., Musto, A., Hardy, M., Gimenez, J. M., Chiang, N., Serhan, C. N., and Bazan, N. G. (2003). Novel docosanoids inhibit brain ischemia-reperfusion-mediated leukocyte infiltration and pro-inflammatory gene expression. J. Biol. Chem. 278:43807–43817.CrossRefPubMedGoogle Scholar
  26. Mason, R. P., Shoemaker, W. J., Shajenko, L., Chambers, T. E., and Herbette, G. (1992). Evidence for changes in the Alzheimer’s disease brain cortical membrane structure mediated by cholesterol. Neurobiol. Aging 13:413–419.CrossRefPubMedGoogle Scholar
  27. McGeer, P. L., Schulzer, M., and McGeer, E. G. (1996). Arthritis and anti-inflammatory agents as possible protective factors for Alzheimer’s disease: A review of 17 epidemiologic studies. Neurology 47:425–432.PubMedGoogle Scholar
  28. Miller, L. J., and Chacko, R. (2004). The role of cholesterol and statins in Alzheimer’s disease. Ann. Pharmacother. 38:91–98.CrossRefPubMedGoogle Scholar
  29. Mirra, S. S., Heyman, A., McKeel, D., Sumi, S. M., Crain, B. J., Brownlee, L. M., Vogel, F. S., Hughes, J. P., van Belle, G., and Berg, L. (1991). The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer’s disease. Neurology 41:479–486.PubMedGoogle Scholar
  30. Mizuno, T., Haass, C., Michikawa, M., and Yanagisawa, K. (1998). Cholesterol-dependent generation of a unique amyloid beta-protein from atypically missorted amyloid precursor protein in MDCK cells. Biochem. Biophys. Acta 1373:119–130.PubMedGoogle Scholar
  31. Murphy, M. P., Das, P., Nyborg, A. C., Rochette, M. J., Dodson, M. W., Loosbrock, N. M., Souder, T. M., McLendon, C., Merit, S. L., Piper, S. C., Jansen, K. R., and Golde, T. E. (2003). Overexpression of nicastrin increases Abeta production. FASEB J. 17:1138–1140.PubMedGoogle Scholar
  32. Newschaffer, C. J., Bush, T. L., and Hale, W. E. (1992). Aging and total cholesterol levels: Cohort, period and survivorship effects. Am. J. Epidemiol. 136:23–34.PubMedGoogle Scholar
  33. Notkola, I. L., Sulkava, R., Pekkanen, J., Erkinjuntti, T., Ehnholm, C., Kivinen, P., Tuomilehto, J., and Nissinen, A. (1998). Serum total cholesterol, apolipoprotein E epsilon 4 allele, and Alzheimer’s disease. Neuroepidemiology 17:14–20.CrossRefPubMedGoogle Scholar
  34. Pappolla, M. A., Omar, R. A., Kim, K. S., and Robakis, N. K. (1992). Immunohistochemical evidence of oxidative stress in Alzheimer’s disease. Am. J. Pathol. 140: 621–628.PubMedGoogle Scholar
  35. Pappolla, M. A., Chyan, Y. J., Omar, R. A., Hsiao, K., Perry, G., Smith, M. A., and Bozner, P. (1998). Evidence of oxidative stress and in vivo neurotoxicity of beta-amyloid in a transgenic mouse model of Alzheimer’s disease: A chronic oxidative paradigm for testing antioxidant therapies in vivo. Am. J. Pathol. 152:871–877.PubMedGoogle Scholar
  36. Pappolla, M. A., Bryant-Thomas, T. K., Herbert, D., Pacheco, J., Fabra Garcia, M., Manjon, M., Girones, X., Henry, T. L., Matsubara, E., Zambon, D., Wolozin, B., Petanceska, S. S., Sano, M., Cruz-Sanchez, F. F., Thal, L. J., and Refolo, L. M. (2003). Hypercholesterolemia is an Early Risk Factor for the Development of Alzheimer Amyloid Pathology. Neurology 61:199–205.PubMedGoogle Scholar
  37. Park, I. H., Hwang, E. M., Hong, H. S., Boo, J. H., Oh, S. S., Lee, J., Jung, M. W., Bang, O. Y., Kim, S. U., and Mook-Jung, I. (2003). Lovastatin enhances Abeta production and senile plaque deposition in female Tg2576 mice. Neurobiol Aging. 24:637–643.CrossRefPubMedGoogle Scholar
  38. Pasternak, S. H., Callahan, J. W., and Mahuran, D. J. (2004). The role of the endosomal/lysosomal system in amyloid-beta production and the pathophysiology of Alzheimer’s disease: Reexamining the spatial paradox from a lysosomal perspective. J. Alzheimers Dis. 6:53–65.PubMedGoogle Scholar
  39. Petanceska, S. S., DeRosa, S., Sharma, A., Diaz, N., Duff, K., Tint, S. G., Refolo, L. M., and Pappolla, M. (2003). Changes in apolipoprotein E expression in response to dietary and pharmacological modulation of cholesterol. J. Mol. Neurosci. 20:395–406.CrossRefPubMedGoogle Scholar
  40. Puglielli, L., Tanzi, R. E., and Kovacs, D. M. (2003). Alzheimer’s disease: The cholesterol connection. Nat. Neurosci. 6:345–351.CrossRefPubMedGoogle Scholar
  41. Qin, W., Ho, L., Pompl, P. N., Peng, Y., Zhao, Z., Xiang, Z., Robakis, N. K., Shioi, J., Suh, J., and Pasinetti, G. M. (2003). Cyclooxygenase (COX)-2 and COX-1 potentiate beta-amyloid peptide generation through mechanisms that involve gamma-secretase activity. J. Biol. Chem. 278:50970–50977.CrossRefPubMedGoogle Scholar
  42. Ravona-Springer, R., Davidson, M., and Noy, S. (2003). The role of cardiovascular risk factors in Alzheimer’s disease. CNS Spectr. 8:824–833.PubMedGoogle Scholar
  43. Refolo, L. M., Malester, B., LaFrancois, J., Bryant-Thomas, T., Wang, R., Tint, G. S., Sambamurti, K., Duff, K., and Pappolla, M. A. (2000). Hypercholesterolemia accelerates the Alzheimer’s amyloid pathology in a transgenic mouse model. Neurobiol. Dis. 7:321–331.CrossRefPubMedGoogle Scholar
  44. Rohe, A. E., Kuo, Y. M., Kokjohn, K. M., Emmerling, M. R., and Gracon, S. (1999). Amyloid and lipids in the pathology of Alzheimer disease. Amyloid 6:136–145.PubMedGoogle Scholar
  45. Schenk, D. (2000). Alzheimer’s disease: A partner for presenilin. Nature 407:48–54.CrossRefPubMedGoogle Scholar
  46. Sidera, C., Parsons, R., and Austen, B. (2004). Proteolytic cascade in the amyloido-genesis of Alzheimer’s disease. Biochem. Soc. Trans. 32:33–36.CrossRefPubMedGoogle Scholar
  47. Simons, M., Keller, P., De Strooper, B., Beyreuther, K., Dotti, C. G., and Simons, K. (1998). Cholesterol depletion inhibits the generation of beta-amyloid in hippocampal neurons. Pro. Natl. Acad. Sci. USA 95:6460–6464.CrossRefGoogle Scholar
  48. Sparks, D. L., Martin, T. A., Gross, D. R., and Hunsaker, J. C. III (2000). Link between heart disease, cholesterol, and Alzheimer’s disease: A review. Microsc. Res. Tech. 50:287–290.CrossRefPubMedGoogle Scholar
  49. Strittmatter, W. J., Saunders, A. M., Schmeche, D., Pericak-Vance, M., Enghild, J., Salvesen, G. S., and Roses, A. D. (1993). Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc. Natl. Acad. Sci. USA 90:1977–1981.PubMedGoogle Scholar
  50. Stuve, O., Youssef, S., Steinman, L., and Zamvil, S. S. (2003). Statins as potential therapeutic agents in neuroinflammatory disorders. Curr. Opin. Neurol. 16:393–401.CrossRefPubMedGoogle Scholar
  51. Weir, M. R., Sperling, R. S., Reicin, A., and Gert, B. J. (2003). Selective COX-2 inhibition and cardiovascular effects: A review of the rofecoxib program. Am. Heart J. 146:591–604.CrossRefPubMedGoogle Scholar
  52. Wilson, H. L., Schwartz, D. M., Bhatt, H. R., McCulloch, C. E., and Duncan, J. L. (2004). Statin and aspirin therapy are associated with decreased rates of choroidal neovascularization among patients with age-related macular degeneration. Am. J. Ophthalmol. 137:615–624.CrossRefPubMedGoogle Scholar
  53. Wolozin, B., Kellman, W., Ruosseau, P., Celesia, G. G., and Siegel, G. (2000). Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. Arch. Neurol. 57:1439–1443.CrossRefPubMedGoogle Scholar
  54. Wolozin, B. (2003). Cyp46 (24S-cholesterol hydroxylase): A genetic risk factor for Alzheimer disease. Arch. Neurol. 60:29–35.PubMedGoogle Scholar
  55. Wood, W. G., Schroeder, F., Avdulov, N. A., Chochina, S. V., and Igbavboa, U. (1999). Recent advances in brain cholesterol dynamics: Transport, domains and Alzheimer’s disease. Lipids 34:225–234.PubMedGoogle Scholar
  56. Zatta, P., Zambenedetti, P., Stella, M. P., and Licastro, F. (2002). Astrocytosis, microgliosis, metallothionein-I-II and amyloid expression in high cholesterol-fed rabbits. J. Alzheimers Dis. 4:1–9.PubMedGoogle Scholar
  57. Zlokovic, B. V., Yamada, S., Holtzman, D., Ghiso, J., and Frangione, B. (2000). Clearance of amyloid beta-peptide from brain: Transport or metabolism? Nat. Med. 6:718.CrossRefGoogle Scholar

Copyright information

© Springer Science + Business Media, Inc. 2005

Authors and Affiliations

  • Walter J. Lukiw
    • 1
    • 2
    Email author
  • Miguel Pappolla
    • 1
    • 3
  • Ricardo Palacios Pelaez
    • 4
  • Nicolas G. Bazan
    • 1
    • 2
  1. 1.LSU Neuroscience CenterLouisiana State University Health Sciences CenterNew Orleans
  2. 2.Department of OpthalmologyLouisiana State University Health Sciences CenterNew Orleans
  3. 3.Department of NeurologyLouisiana State University Health Sciences CenterNew Orleans
  4. 4.Diater PharmaceuticalsSpain

Personalised recommendations