Dyslipidemia and the Risk of Alzheimer’s Disease

Coronary Heart Disease (JA Farmer, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Coronary Heart Disease

Abstract

Whether cholesterol is implicated in the pathogenesis of Alzheimer’s disease (AD) is still controversial. Several studies that explored the association between lipids and/or lipid-lowering treatment and AD indicate a harmful effect of dyslipidemia on AD risk. The findings are supported by genetic linkage and association studies that have clearly identified several genes involved in cholesterol metabolism or transport as AD susceptibility genes, including apolipoprotein E (APOE), apolipoprotein J (APOJ, CLU), ATP-binding cassette subfamily A member 7(ABCA7), and sortilin-related receptor (SORL1). Functional cell biology studies further support a critical involvement of lipid raft cholesterol in the modulation of Aβ precursor protein processing by β-secretase and γ-secretase resulting in altered Aβ production. However, conflicting evidence comes from epidemiological studies showing no or controversial association between dyslipidemia and AD risk, randomized clinical trials observing no beneficial effect of statin therapy, and cell biology studies suggesting that there is little exchange between circulating and brain cholesterol, that increased membrane cholesterol level is protective by inhibiting loss of membrane integrity through amyloid cytotoxicity, and that cellular cholesterol inhibits colocalization of β-secretase 1 and Aβ precursor protein in nonraft membrane domains, thereby increasing generation of plasmin, an Aβ-degrading enzyme. The aim of this article is to provide a comprehensive review of the findings of epidemiological, genetic, and cell biology studies aiming to elucidate the role of cholesterol in the pathogenesis of AD.

Keywords

Alzheimer's disease Cholesterol High-density lipoprotein Aβ peptides Aβ precursor protein Neurodegeneration Amyloid 

Notes

Acknowledgment

This study was supported by grants AG07232 and AG07702 from the National Institute on Aging (Washington, DC, USA), the Charles S. Robertson Memorial Gift for Research in Alzheimer's disease, the Blanchette Hooker Rockefeller Foundation, and a Paul B. Beeson Career Development Award (K23AG034550).

Disclosure

No potential conflicts of interest relevant to this article were reported.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Brookmeyer R, Gray S, Kawas C. Projections of Alzheimer's disease in the United States and the public health impact of delaying disease onset. Am J Public Health. 1998;88:1337–42.PubMedCrossRefGoogle Scholar
  2. 2.
    von Strauss E, Viitanen M, De Ronchi D, Winblad B, Fratiglioni L. Aging and the occurrence of dementia: findings from a population-based cohort with a large sample of nonagenarians. Arch Neurol. 1999;56:587–92.CrossRefGoogle Scholar
  3. 3.
    Ferri CP, et al. Global prevalence of dementia: a Delphi consensus study. Lancet. 2005;366:2112–7.PubMedCrossRefGoogle Scholar
  4. 4.
    • Barter P, et al. HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events. N Engl J Med. 2007;357:1301–10. This is a review of the relation between lipid levels and cardiovascular disease.PubMedCrossRefGoogle Scholar
  5. 5.
    World Health Organization (2002) Quantifying selected major risks to health. In: The world health report 2002-reducing risks, promoting healthy life. Geneva: World Health Organization; pp 47–97.Google Scholar
  6. 6.
    Reitz C, et al. A summary risk score for the prediction of Alzheimer disease in elderly persons. Arch Neurol. 2010;67:835–41.PubMedCrossRefGoogle Scholar
  7. 7.
    Pfrieger FW. Cholesterol homeostasis and function in neurons of the central nervous system. Cell Mol Life Sci. 2003;60:1158–71.PubMedGoogle Scholar
  8. 8.
    Grziwa B, et al. The transmembrane domain of the amyloid precursor protein in microsomal membranes is on both sides shorter than predicted. J Biol Chem. 2003;278:6803–8.PubMedCrossRefGoogle Scholar
  9. 9.
    Refolo LM, et al. A cholesterol-lowering drug reduces beta-amyloid pathology in a transgenic mouse model of Alzheimer's disease. Neurobiol Dis. 2001;8:890–9.PubMedCrossRefGoogle Scholar
  10. 10.
    Refolo LM, et al. Hypercholesterolemia accelerates the Alzheimer's amyloid pathology in a transgenic mouse model. Neurobiol Dis. 2000;7:321–31.PubMedCrossRefGoogle Scholar
  11. 11.
    Kojro E, Gimpl G, Lammich S, Marz W, Fahrenholz F. Low cholesterol stimulates the nonamyloidogenic pathway by its effect on the alpha-secretase ADAM 10. Proc Natl Acad Sci U S A. 2001;98:5815–20.PubMedCrossRefGoogle Scholar
  12. 12.
    Simons M, et al. Cholesterol depletion inhibits the generation of beta-amyloid in hippocampal neurons. Proc Natl Acad Sci U S A. 1998;95:6460–4.PubMedCrossRefGoogle Scholar
  13. 13.
    Crameri A, et al. The role of seladin-1/DHCR24 in cholesterol biosynthesis, APP processing and Abeta generation in vivo. EMBO J. 2006;25:432–43.PubMedCrossRefGoogle Scholar
  14. 14.
    McLaurin J, Darabie AA, Morrison MR. Cholesterol, a modulator of membrane-associated Abeta-fibrillogenesis. Pharmacopsychiatry. 2003;36 Suppl 2:S130–135.PubMedGoogle Scholar
  15. 15.
    Zou K, et al. Amyloid beta-protein (Abeta)1-40 protects neurons from damage induced by Abeta1-42 in culture and in rat brain. J Neurochem. 2003;87:609–19.PubMedCrossRefGoogle Scholar
  16. 16.
    Trousson A, et al. 25-hydroxycholesterol provokes oligodendrocyte cell line apoptosis and stimulates the secreted phospholipase A2 type IIA via LXR beta and PXR. J Neurochem. 2009;109:945–58.PubMedCrossRefGoogle Scholar
  17. 17.
    Ma MT, Zhang J, Farooqui AA, Chen P, Ong WY. Effects of cholesterol oxidation products on exocytosis. Neurosci Lett. 2010;476:36–41.PubMedCrossRefGoogle Scholar
  18. 18.
    Papassotiropoulos A, et al. Plasma 24S-hydroxycholesterol: a peripheral indicator of neuronal degeneration and potential state marker for Alzheimer's disease. Neuroreport. 2000;11:1959–62.PubMedCrossRefGoogle Scholar
  19. 19.
    Bjorkhem I, Cedazo-Minguez A, Leoni V, Meaney S. Oxysterols and neurodegenerative diseases. Mol Aspects Med. 2009;30:171–9.PubMedCrossRefGoogle Scholar
  20. 20.
    Luchsinger JA. Diabetes, related conditions, and dementia. J Neurol Sci. 2010;299:35–8.PubMedCrossRefGoogle Scholar
  21. 21.
    Frisardi V, et al. Metabolic-cognitive syndrome: a cross-talk between metabolic syndrome and Alzheimer's disease. Ageing Res Rev. 2010;9:399–417.PubMedCrossRefGoogle Scholar
  22. 22.
    Panza F, et al. Metabolic syndrome, mild cognitive impairment, and dementia. Curr Alzheimer Res. 2011;8:492–509.Google Scholar
  23. 23.
    Li J, et al. Vascular risk factors promote conversion from mild cognitive impairment to Alzheimer disease. Neurology. 2011;76:1485–91.PubMedCrossRefGoogle Scholar
  24. 24.
    Li G, et al. Serum cholesterol and risk of Alzheimer disease: a community-based cohort study. Neurology. 2005;65:1045–50.PubMedCrossRefGoogle Scholar
  25. 25.
    Mainous 3rd AG, Eschenbach SL, Wells BJ, Everett CJ, Gill JM. Cholesterol, transferrin saturation, and the development of dementia and Alzheimer's disease: results from an 18-year population-based cohort. Fam Med. 2005;37:36–42.PubMedGoogle Scholar
  26. 26.
    Romas SN, Tang MX, Berglund L, Mayeux R. APOE genotype, plasma lipids, lipoproteins, and AD in community elderly. Neurology. 1999;53:517–21.PubMedCrossRefGoogle Scholar
  27. 27.
    Tan ZS, et al. Plasma total cholesterol level as a risk factor for Alzheimer disease: the Framingham Study. Arch Intern Med. 2003;163:1053–7.PubMedCrossRefGoogle Scholar
  28. 28.
    Mielke MM, et al. The 32-year relationship between cholesterol and dementia from midlife to late life. Neurology. 2010;75:1888–95.PubMedCrossRefGoogle Scholar
  29. 29.
    •• Kivipelto M, et al. Obesity and vascular risk factors at midlife and the risk of dementia and Alzheimer disease. Arch Neurol. 2005;62:1556–60. This is a longitudinal study relating lipid levels in midlife with late-life dementia.PubMedCrossRefGoogle Scholar
  30. 30.
    Notkola IL, et al. Serum total cholesterol, apolipoprotein E epsilon 4 allele, and Alzheimer's disease. Neuroepidemiology. 1998;17:14–20.PubMedCrossRefGoogle Scholar
  31. 31.
    •• Whitmer RA, Sidney S, Selby J, Johnston SC, Yaffe K. Midlife cardiovascular risk factors and risk of dementia in late life. Neurology. 2005;64:277–81. This is a longitudinal study relating lipid levels in midlife with late-life dementia.PubMedCrossRefGoogle Scholar
  32. 32.
    •• Stewart R, White LR, Xue QL, Launer LJ. Twenty-six-year change in total cholesterol levels and incident dementia: the Honolulu-Asia Aging Study. Arch Neurol. 2007;64:103–7. This is a longitudinal study relating lipid levels in midlife with late-life dementia.PubMedCrossRefGoogle Scholar
  33. 33.
    Beydoun MA, et al. Statins and serum cholesterol's associations with incident dementia and mild cognitive impairment. J Epidemiol Community Health 2011;65:949–57.Google Scholar
  34. 34.
    Pitas RE, Boyles JK, Lee SH, Hui D, Weisgraber KH. Lipoproteins and their receptors in the central nervous system. Characterization of the lipoproteins in cerebrospinal fluid and identification of apolipoprotein B, E(LDL) receptors in the brain. J Biol Chem. 1987;262:14352–60.PubMedGoogle Scholar
  35. 35.
    Mauch DH, et al. CNS synaptogenesis promoted by glia-derived cholesterol. Science. 2001;294:1354–7.PubMedCrossRefGoogle Scholar
  36. 36.
    Eto M, Watanabe K, Chonan N, Ishii K. Familial hypercholesterolemia and apolipoprotein E4. Atherosclerosis. 1988;72:123–8.PubMedCrossRefGoogle Scholar
  37. 37.
    Murakami K, et al. Apolipoprotein E polymorphism is associated with plasma cholesterol response in a 7-day hospitalization study for metabolic and dietary control in NIDDM. Diabetes Care. 1993;16:564–9.PubMedCrossRefGoogle Scholar
  38. 38.
    Corder EH, et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science. 1993;261:921–3.PubMedCrossRefGoogle Scholar
  39. 39.
    Graff-Radford NR, et al. Association between apolipoprotein E genotype and Alzheimer disease in African American subjects. Arch Neurol. 2002;59:594–600.PubMedCrossRefGoogle Scholar
  40. 40.
    Jarvik GP, et al. Interactions of apolipoprotein E genotype, total cholesterol level, age, and sex in prediction of Alzheimer's disease: a case–control study. Neurology. 1995;45:1092–6.PubMedCrossRefGoogle Scholar
  41. 41.
    Rubinsztein DC, Easton DF. Apolipoprotein E genetic variation and Alzheimer's disease. a meta-analysis. Dement Geriatr Cogn Disord. 1999;10:199–209.PubMedCrossRefGoogle Scholar
  42. 42.
    Craft S, et al. Accelerated decline in apolipoprotein E-epsilon4 homozygotes with Alzheimer's disease. Neurology. 1998;51:149–53.PubMedCrossRefGoogle Scholar
  43. 43.
    Reiman EM, et al. Fibrillar amyloid-beta burden in cognitively normal people at 3 levels of genetic risk for Alzheimer's disease. Proc Natl Acad Sci USA. 2009;106:6820–5.PubMedCrossRefGoogle Scholar
  44. 44.
    Greenberg SM, Rebeck GW, Vonsattel JP, Gomez-Isla T, Hyman BT. Apolipoprotein E epsilon 4 and cerebral hemorrhage associated with amyloid angiopathy. Ann Neurol. 1995;38:254–9.PubMedCrossRefGoogle Scholar
  45. 45.
    Christensen DZ, Schneider-Axmann T, Lucassen PJ, Bayer TA, Wirths O. Accumulation of intraneuronal Abeta correlates with ApoE4 genotype. Acta Neuropathol. 2010;119:555–66.PubMedCrossRefGoogle Scholar
  46. 46.
    Lambert JC, et al. A new polymorphism in the APOE promoter associated with risk of developing Alzheimer's disease. Hum Mol Genet. 1998;7:533–40.PubMedCrossRefGoogle Scholar
  47. 47.
    Lee JH, et al. Association between genetic variants in SORL1 and autopsy-confirmed Alzheimer disease. Neurology. 2008;70:887–9.PubMedCrossRefGoogle Scholar
  48. 48.
    Lee JH, et al. Association between genetic variants in sortilin-related receptor 1 (SORL1) and Alzheimer's disease in adults with Down syndrome. Neurosci Lett. 2007;425:105–9.PubMedCrossRefGoogle Scholar
  49. 49.
    Bettens K, et al. SORL1 is genetically associated with increased risk for late-onset Alzheimer disease in the Belgian population. Hum Mutat. 2008;29:769–70.PubMedCrossRefGoogle Scholar
  50. 50.
    Cuenco KT, et al. Association of distinct variants in SORL1 with cerebrovascular and neurodegenerative changes related to Alzheimer disease. Arch Neurol. 2008;65:1640–8.CrossRefGoogle Scholar
  51. 51.
    Dodson SE, et al. LR11/SorLA expression is reduced in sporadic Alzheimer disease but not in familial Alzheimer disease. J Neuropathol Exp Neurol. 2006;65:866–72.PubMedCrossRefGoogle Scholar
  52. 52.
    Grear KE, et al. Expression of SORL1 and a novel SORL1 splice variant in normal and Alzheimers disease brain. Mol Neurodegener. 2009;4:46.PubMedCrossRefGoogle Scholar
  53. 53.
    Kimura R, et al. SORL1 is genetically associated with Alzheimer disease in a Japanese population. Neurosci Lett. 2009;461:177–80.PubMedCrossRefGoogle Scholar
  54. 54.
    Kolsch H, et al. Influence of SORL1 gene variants: association with CSF amyloid-beta products in probable Alzheimer's disease. Neurosci Lett. 2008;440:68–71.PubMedCrossRefGoogle Scholar
  55. 55.
    Kolsch H, et al. Association of SORL1 gene variants with Alzheimer's disease. Brain Res. 2009;1264:1–6.PubMedCrossRefGoogle Scholar
  56. 56.
    Lee JH, Barral S, Reitz C. The neuronal sortilin-related receptor gene SORL1 and late-onset Alzheimer's disease. Curr Neurol Neurosci Rep. 2008;8:384–91.PubMedCrossRefGoogle Scholar
  57. 57.
    Lee JH, Shibata N, Cheng R, Mayeux R. Possible association between SORL1 and Alzheimer disease? Reanalysing the data of Shibata et al. Dement Geriatr Cogn Disord. 2008;26:482.PubMedCrossRefGoogle Scholar
  58. 58.
    Li Y, et al. SORL1 variants and risk of late-onset Alzheimer's disease. Neurobiol Dis. 2008;29:293–6.PubMedCrossRefGoogle Scholar
  59. 59.
    Ma QL, et al. Reduction of SorLA/LR11, a sorting protein limiting beta-amyloid production, in Alzheimer disease cerebrospinal fluid. Arch Neurol. 2009;66:448–57.PubMedCrossRefGoogle Scholar
  60. 60.
    Meng Y, et al. Association between SORL1 and Alzheimer's disease in a genome-wide study. Neuroreport. 2007;18:1761–4.PubMedCrossRefGoogle Scholar
  61. 61.
    Reynolds CA, et al. Sequence variation in SORL1 and dementia risk in Swedes. Neurogenetics. 2009;11:139–42.PubMedCrossRefGoogle Scholar
  62. 62.
    Shibata N, et al. Genetic association between SORL1 polymorphisms and Alzheimer's disease in a Japanese population. Dement Geriatr Cogn Disord. 2008;26:161–4.PubMedGoogle Scholar
  63. 63.
    Tan EK, et al. SORL1 haplotypes modulate risk of Alzheimer's disease in Chinese. Neurobiol Aging. 2009;30:1048–51.PubMedCrossRefGoogle Scholar
  64. 64.
    Webster JA, et al. Sorl1 as an Alzheimer's disease predisposition gene? Neurodegener Dis. 2008;5:60–4.PubMedCrossRefGoogle Scholar
  65. 65.
    Lee JH, Cheng R, Graff-Radford N, Foroud T, Mayeux R. Analyses of the National Institute on Aging Late-Onset Alzheimer's Disease Family Study: implication of additional loci. Archiv Neurol. 2008;65:1518–26.CrossRefGoogle Scholar
  66. 66.
    Tang MX, et al. The APOE-epsilon4 allele and the risk of Alzheimer disease among African Americans, whites, and Hispanics. JAMA. 1998;279:751–5.PubMedCrossRefGoogle Scholar
  67. 67.
    • Reitz C, et al. Meta-analysis of the association between variants in SORL1 and Alzheimer disease. Arch Neurol. 2011;68:99–106. This is a meta-analysis of SORL1 and AD.PubMedCrossRefGoogle Scholar
  68. 68.
    Seshadri S, et al. Genetic correlates of brain aging on MRI and cognitive test measures: a genome-wide association and linkage analysis in the Framingham Study. BMC Med Genet. 2007;8 Suppl 1:S15.PubMedCrossRefGoogle Scholar
  69. 69.
    Reitz C, et al. SORCS1 alters amyloid precursor protein processing and variants may increase Alzheimer's disease risk. Ann Neurol. 2011;69:47–64.PubMedCrossRefGoogle Scholar
  70. 70.
    • Rogaeva E, et al. The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease. Nat Genet. 2007;39:168–77. This is a study implicating SORL1 in AD.PubMedCrossRefGoogle Scholar
  71. 71.
    Gelissen IC, et al. Apolipoprotein J (clusterin) induces cholesterol export from macrophage-foam cells: a potential anti-atherogenic function? Biochem J. 1998;331(Pt 1):231–7.PubMedGoogle Scholar
  72. 72.
    DeMattos RB, et al. ApoE and clusterin cooperatively suppress Abeta levels and deposition: evidence that ApoE regulates extracellular Abeta metabolism in vivo. Neuron. 2004;41:193–202.PubMedCrossRefGoogle Scholar
  73. 73.
    Bell RD, et al. Transport pathways for clearance of human Alzheimer's amyloid beta-peptide and apolipoproteins E and J in the mouse central nervous system. J Cereb Blood Flow Metab. 2007;27:909–18.PubMedGoogle Scholar
  74. 74.
    Yerbury JJ, et al. The extracellular chaperone clusterin influences amyloid formation and toxicity by interacting with prefibrillar structures. FASEB J. 2007;21:2312–22.PubMedCrossRefGoogle Scholar
  75. 75.
    Matsubara E, Frangione B, Ghiso J. Characterization of apolipoprotein J-Alzheimer's A beta interaction. J Biol Chem. 1995;270:7563–7.PubMedCrossRefGoogle Scholar
  76. 76.
    Tanaka N, Abe-Dohmae S, Iwamoto N, Yokoyama S. Roles of ATP-binding cassette transporter A7 in cholesterol homeostasis and host defense system. J Atheroscler Thromb. 2011;18:274–81.PubMedCrossRefGoogle Scholar
  77. 77.
    Chan SL, et al. ATP-binding cassette transporter A7 regulates processing of amyloid precursor protein in vitro. J Neurochem. 2008;106:793–804.PubMedCrossRefGoogle Scholar
  78. 78.
    Furberg CD. Natural statins and stroke risk. Circulation. 1999;99:185–8.PubMedCrossRefGoogle Scholar
  79. 79.
    Green RC, et al. Statin use and the risk of Alzheimer's disease: the MIRAGE study. Alzheimers Dement. 2006;2:96–103.PubMedCrossRefGoogle Scholar
  80. 80.
    Li G, et al. Statin therapy is associated with reduced neuropathologic changes of Alzheimer disease. Neurology. 2007;69:878–85.PubMedCrossRefGoogle Scholar
  81. 81.
    Masse I, et al. Lipid lowering agents are associated with a slower cognitive decline in Alzheimer's disease. J Neurol Neurosurg Psychiatry. 2005;76:1624–9.PubMedCrossRefGoogle Scholar
  82. 82.
    Rea TD, et al. Statin use and the risk of incident dementia: the Cardiovascular Health Study. Arch Neurol. 2005;62:1047–51.PubMedCrossRefGoogle Scholar
  83. 83.
    Rockwood K, et al. Use of lipid-lowering agents, indication bias, and the risk of dementia in community-dwelling elderly people. Arch Neurol. 2002;59:223–7.PubMedCrossRefGoogle Scholar
  84. 84.
    Sjogren M, Mielke M, Gustafson D, Zandi P, Skoog I. Cholesterol and Alzheimer's disease–is there a relation? Mech Ageing Dev. 2006;127:138–47.PubMedCrossRefGoogle Scholar
  85. 85.
    Wolozin B, Kellman W, Ruosseau P, Celesia GG, Siegel G. Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors. Arch Neurol. 2000;57:1439–43.PubMedCrossRefGoogle Scholar
  86. 86.
    Wolozin B, et al. Re-assessing the relationship between cholesterol, statins and Alzheimer's disease. Acta Neurol Scand Suppl. 2006;185:63–70.PubMedCrossRefGoogle Scholar
  87. 87.
    Zandi PP, et al. Do statins reduce risk of incident dementia and Alzheimer disease? The Cache County Study. Arch Gen Psychiatry. 2005;62:217–24.PubMedCrossRefGoogle Scholar
  88. 88.
    Li G, et al. Age-varying association between statin use and incident Alzheimer's disease. J Am Geriatr Soc. 2010;58:1311–7.PubMedCrossRefGoogle Scholar
  89. 89.
    Cramer C, Haan MN, Galea S, Langa KM, Kalbfleisch JD. Use of statins and incidence of dementia and cognitive impairment without dementia in a cohort study. Neurology. 2008;71:344–50.PubMedCrossRefGoogle Scholar
  90. 90.
    Dufouil C, et al. APOE genotype, cholesterol level, lipid-lowering treatment, and dementia: the Three-City Study. Neurology. 2005;64:1531–8.PubMedCrossRefGoogle Scholar
  91. 91.
    Haag MD, Hofman A, Koudstaal PJ, Stricker BH, Breteler MM. Statins are associated with a reduced risk of Alzheimer disease regardless of lipophilicity. The Rotterdam Study. J Neurol Neurosurg Psychiatry. 2009;80:13–7.PubMedCrossRefGoogle Scholar
  92. 92.
    Horsdal HT, et al. Use of statins and risk of hospitalization with dementia: a Danish population-based case–control study. Alzheimer Dis Assoc Disord. 2009;23:18–22.PubMedCrossRefGoogle Scholar
  93. 93.
    • Jones RW, et al. The Atorvastatin/Donepezil in Alzheimer's Disease Study (LEADe): design and baseline characteristics. Alzheimers Dement. 2008;4:145–53. This reports the findings of a randomized controlled trial on the effectiveness of statins in AD.PubMedCrossRefGoogle Scholar
  94. 94.
    • Feldman HH, et al. Randomized controlled trial of atorvastatin in mild to moderate Alzheimer disease: LEADe. Neurology. 2010;74:956–64. This reports the findings of a randomized controlled trial on the effectiveness of statins in AD.PubMedCrossRefGoogle Scholar
  95. 95.
    • Trompet S, et al. Pravastatin and cognitive function in the elderly. Results of the PROSPER study. J Neurol. 2010;257:85–90. This reports the findings of a randomized controlled trial on the effectiveness of statins in AD.PubMedCrossRefGoogle Scholar
  96. 96.
    • MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 360, 7–22 (2002). This reports the findings of a randomized controlled trial on the effectiveness of statins in AD.Google Scholar
  97. 97.
    • Sparks DL, et al. Circulating cholesterol levels, apolipoprotein E genotype and dementia severity influence the benefit of atorvastatin treatment in Alzheimer's disease: results of the Alzheimer's Disease Cholesterol-Lowering Treatment (ADCLT) trial. Acta Neurol Scand Suppl. 2006;185:3–7. This reports the findings of a randomized controlled trial on the effectiveness of statins in AD.PubMedCrossRefGoogle Scholar
  98. 98.
    • Shepherd J, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet. 2002;360:1623–30. This reports the findings of a randomized controlled trial on the effectiveness of statins in AD.PubMedCrossRefGoogle Scholar
  99. 99.
    • Sano M, et al. A randomized, double-blind, placebo-controlled trial of simvastatin to treat Alzheimer disease. Neurology. 2011;77:556–63. This reports the findings of a randomized controlled trial on the effectiveness of statins in AD.PubMedCrossRefGoogle Scholar
  100. 100.
    Kuusisto J, et al. Association between features of the insulin resistance syndrome and Alzheimer's disease independently of apolipoprotein E4 phenotype: cross sectional population based study. BMJ. 1997;315:1045–9.PubMedCrossRefGoogle Scholar
  101. 101.
    Moroney JT, et al. Low-density lipoprotein cholesterol and the risk of dementia with stroke. JAMA. 1999;282:254–60.PubMedCrossRefGoogle Scholar
  102. 102.
    Kalmijn S, et al. Metabolic cardiovascular syndrome and risk of dementia in Japanese-American elderly men. The Honolulu-Asia aging study. Arterioscler Thromb Vasc Biol. 2000;20:2255–60.PubMedCrossRefGoogle Scholar
  103. 103.
    Kivipelto M, et al. Midlife vascular risk factors and Alzheimer's disease in later life: longitudinal, population based study. BMJ. 2001;322:1447–51.PubMedCrossRefGoogle Scholar
  104. 104.
    Reitz C, Tang MX, Luchsinger J, Mayeux R. Relation of plasma lipids to Alzheimer disease and vascular dementia. Arch Neurol. 2004;61:705–14.PubMedCrossRefGoogle Scholar
  105. 105.
    Mielke MM, et al. High total cholesterol levels in late life associated with a reduced risk of dementia. Neurology. 2005;64:1689–95.PubMedCrossRefGoogle Scholar
  106. 106.
    Hayden KM, et al. Vascular risk factors for incident Alzheimer disease and vascular dementia: the Cache County study. Alzheimer Dis Assoc Disord. 2006;20:93–100.PubMedCrossRefGoogle Scholar
  107. 107.
    Solomon A, Kivipelto M, Wolozin B, Zhou J, Whitmer RA. Midlife serum cholesterol and increased risk of Alzheimer's and vascular dementia three decades later. Dement Geriatr Cogn Disord. 2009;28:75–80.PubMedCrossRefGoogle Scholar
  108. 108.
    Reitz C, et al. Association of higher levels of high-density lipoprotein cholesterol in elderly individuals and lower risk of late-onset Alzheimer disease. Arch Neurol. 2010;67:1491–7.PubMedCrossRefGoogle Scholar
  109. 109.
    Solfrizzi V, et al. Metabolic syndrome and the risk of vascular dementia: the Italian Longitudinal Study on Ageing. J Neurol Neurosurg Psychiatry. 2010;81:433–40.PubMedCrossRefGoogle Scholar
  110. 110.
    Reynolds CA, Gatz M, Prince JA, Berg S, Pedersen NL. Serum lipid levels and cognitive change in late life. J Am Geriatr Soc. 2010;58:501–9.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.The Gertrude H. Sergievsky, the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, and the Department of NeurologyColumbia University College of Physicians and SurgeonsNew YorkUSA
  2. 2.Gertrude H. Sergievsky CenterColumbia UniversityNew YorkUSA

Personalised recommendations