Alzheimer's & Dementia: The Journal of the Alzheimer's Association
Volume 2, Issue 2 , Pages 96-103 , April 2006

Statin use and the risk of Alzheimer’s disease: The MIRAGE Study

  • Robert C. Green

      Affiliations

    • Department of Neurology, Boston University School of Medicine, Boston, MA, USA
    • Department of Medicine (Genetics Program), Boston University School of Medicine, Boston, MA, USA
    • Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA
    • Corresponding Author InformationCorresponding author. Tel.: 617-638-5362; Fax: 617-638-4275
    • ,
  • Sally E. McNagny

      Affiliations

    • The Medical Foundation, Boston, MA, USA
    • ,
  • Parimala Jayakumar

      Affiliations

    • Permanente Medical Group, Redwood, CA, USA
    • ,
  • L. Adrienne Cupples

      Affiliations

    • Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA
    • Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA
    • ,
  • Kelly Benke

      Affiliations

    • Department of Medicine (Genetics Program), Boston University School of Medicine, Boston, MA, USA
    • ,
  • Lindsay A. Farrer

      Affiliations

    • Department of Neurology, Boston University School of Medicine, Boston, MA, USA
    • Department of Medicine (Genetics Program), Boston University School of Medicine, Boston, MA, USA
    • Department of Genetics & Genomics, Boston University School of Medicine, Boston, MA, USA
    • Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA
    • ,
  • MIRAGE Study Group

References 

  1. Lautenschlager NT , Cupples LA , Rao VS , Auerbach SA , Becker R , Burke J , et al.   Risk of dementia among relatives of Alzheimer’s disease patients in the MIRAGE study (what is in store for the oldest old?) . Neurology . 1996;46(3):641–650
  2. Green RC , Cupples LA , Go R , Edeki T , Griffith P , Williams MP , et al.   Risk of dementia among White and African American relatives of Alzheimer’s disease patients . JAMA . 2002;287(3):329–336
  3. Rao VS , Cupples LA , van Duijn CM , Kurz A , Green RC , Chui H , et al.   Evidence for major gene inheritance of Alzheimer disease in families of patients with and without ApoE e4 . Am J Hum Genet . 1996;59(3):664–675
  4. Katzman R . Education and the prevalence of dementia and Alzheimer’s disease . Neurology . 1993;43(1):13–20
  5. Green RC , Cupples LA , Kurz A , Auerbach S , Go R , Sadovnick D , et al.   Depression as a risk factor for Alzheimer’s disease (The MIRAGE Study) . Arch Neurol . 2003;60(5):753–759
  6. Guo Z , Cupples LA , Kurz A , Auerbach SH , Volicer L , Chui H , et al.   Head injury and the risk of Alzheimer disease in the MIRAGE study . Neurology . 2000;54(6):1316–1323
  7. Farrer LA , Cupples LA , Haines JL , Hyman B , Kukull WA , Mayeux R , et al.   Effects of age, sex and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease (a meta-analysis) . JAMA . 1997;278(16):1349–1356
  8. Sano M , Ernesto C , Thomas RG , Klauber MR , Schafer K , Grundman M , et al.   A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer’s disease . N Engl J Med . 1997;336(17):1216–1222
  9. Tang M-X , Jacobs D , Stern Y , Marder K , Schofield P , Gurland B , et al.   Effect of oestrogen during menopause on risk and age at onset of Alzheimer’s disease . Lancet . 1996;348:429–432
  10. Kawas C , Resnick S , Morrison A . A prospective study of estrogen replacement therapy and the risk of developing Alzheimer’s disease (The Baltimore Longitudinal Study of Aging) . Neurology . 1997;48:1517–1521
  11. McGeer PL , Schulzer M , McGeer EG . Arthritis and anti-inflammatory agents as possible protective factors for Alzheimer’s disease (a review of 17 epidemiologic studies) . Neurology . 1996;47(2):425–432
  12. Grundy SM , Balady GJ , Criqui MH , Fletcher G , Greenland P , Hiratzka LF , et al.   When to start cholesterol-lowering therapy in patients with coronary heart disease (A statement for healthcare professionals from the American Heart Association Task Force on Risk Reduction) . Circulation . 1997;95:1683–1685
  13. LaRosa JC , He J , Vupputuri S . Effect of statins on risk of coronary disease (a meta-analysis of randomized controlled trials) . JAMA . 1999;282:2340–2346
  14. Pignone M , Phillips C , Mulrow C . Use of lipid lowering drugs for primary prevention of coronary heart disease (meta-analysis of randomised trials) . Br Med J . 2000;321:983–986
  15. Byington RP , Davis BR , Plehn JF , White HD , Baker J , Cobbe SM , et al.   Reduction of stroke events with pravastatin (the prospective pravastatin pooling (PPP) project) . Circulation . 2001;103:387–392
  16. Jick H , Zornberg GL , Jick SS , Seshadri S , Drachman DA . Statins and the risk of dementia . Lancet . 2000;356:1627–1631
  17. Wolozin B , Kellman W , Ruosseau P , Celesia GG , Siegel G . Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3methyglutaryl coenzyme A reductase inhibitors . Arch Neurol . 2000;57:1439–1443
  18. Hajjar I , Schumpert J , Hirth V , Wieland D , Eleazer GP . The impact of the use of statins on the prevalence of dementia and the progression of cognitive impairment . J Geront . 2002;57A:M414–M418
  19. Rockwood K , Kirkland S , Hogan DB , MacKnight C , Merry H , Verreault R , et al.   Use of lipid-lowering agents, indication bias, and the risk of dementia in community-dwelling elderly people . Arch Neurol . 2002;59:223–227
  20. Zamrini E , McGwin G , Roseman JM . Association between statin use and Alzheimer’s Disease . Neuroepidemiology . 2004;23:94–98
  21. Li G , Higdon R , Kukull WA , Peskind E , Van Valen Moore K , Tsuang D , et al.   Statin therapy and risk of dementia in the elderly (a community based cohort study) . Neurology . 2004;63:1624–1628
  22. Zandi PP , Sparks DL , Khachaturian AS , Tschanz JT , Norton M , Steinberg M , et al.   Do statins reduce risk of incident dementia and Alzheimer Disease?. The Cache County Study . Arch Gen Psychiatry . 2005;62:217–224
  23. Rea TD , Breitner JC , Psaty BM , Fitzpatrick AL , Lopez OL , Newman AB , et al.   Statin use and the risk of incident dementia (The Cardiovascular Health Study) . Arch Neurology . 2005;62:1047–1051
  24. Farrer LA , Cupples LA , Blackburn S , Kiely D , Auerbach S , Growdon J , et al.   Interrater agreement for diagnosis of Alzheimer disease (the MIRAGE study) . Neurology . 1994;44:652–656
  25. Demissie S , Green RC , Mucci L , Tziavas S , Martelli K , Bang K , et al.   Reliability of information collected by proxy in family studies of Alzheimer disease . Neuroepidemiology . 2001;20(2):105–111
  26. McKhann GM , Drachman D , Folstein MF , Katzman R , Price D , Stadlan EM . Clinical diagnosis of Alzheimer’s disease (report of the NINCDS-ADRDA work group) . Neurology . 1984;34:939–944
  27. Brandt J , Spencer M , Folstein M . The telephone interview for cognitive status . Neuropsychiatry Neuropsychol Behav Neurol . 1988;1(2):111–117
  28. Welsh KA , Breitner JCS , Magruder-Habib KM . Detection of dementia in the elderly using telephone screening of cognitive status . Neuropsychiatry Neuropsychol Behav Neurol . 1993;6:103–110
  29. Khachaturian ZS . Diagnosis of Alzheimer’s disease . Arch Neurol . 1985;42:1097–1105
  30. Markesbery WR . Neuropathological criteria for the diagnosis of Alzheimer’s disease . Neurobiol Aging . 1997;18(S4):S13–S19
  31. Heart Protection Study Collaborative Group . MRC/BHF heart protection study of cholesterol lowering with simvastatin in 20536 high-risk individuals (a randomised placebo-controlled trial) . Lancet . 2002;360:7–22
  32. Shepherd J , Blauw GJ , Murphy MB , Bollen ELEM , Buckley BM , Cobbe SM , et al.   Pravastatin in elderly individuals at risk of vascular disease (PROSPER) (a randomised controlled trial) . Lancet . 2002;360(9346):1623–1630
  33. Sparks DL , Sabbagh MN , Connor DJ , Lopez J , Launer LJ , Browne P , et al.   Atorvastatin for the treatment of mild to moderate Alzheimer Disease (preliminary results) . Arch Neurol . 2005;62:753–757
  34. Bodovitz S , Klein WL . Cholesterol modulates alpha-secretase cleavage of amyloid precursor protein . J Biol Chem . 1996;271:4436–4440
  35. Racchi M , Baetta R , Salvietti N , Ianna P , Franceschini G , Pacletti R , et al.   Secretory processing of amyloid precursor protein in inhibited by increase in cellular cholesterol content . Biochem J . 1997;322:893–898
  36. Urmoneit B , Turner J , Dyrks T . Cationic lipids (lipofectamine) and disturbance of cellular cholesterol and sphinglmyelin distribution modulates gamma-secretase activity within amyloid precursor protein in vitro . Prostoglandins Other Lipid Metiat . 1998;55:343–391
  37. Sambamurti K , Duff K , Pappolla MA . Hypercholesterolemia accelerates the Alzheimer’s amyloid pathology in a transgenic mouse model . Neurobiol Dis . 2000;7:321–331
  38. Simons M , Keller P , De Strooper B , Beyreuther K , Dotti CG , Simons K . Cholesterol depletion inhibits the generation of β-amyloid in hippocampal neurons . Proc Natl Acad Sci U S A . 1998;95:6460–6464
  39. Fassbender K , Simons M , Bergmann C , Stoick M , Lütjohann D , Keller P , et al.   Simvastatin strongly reduces levels of Alzheimer’s disease β-amyloid peptides Aβ42 and Aβ41 in vitro and in vivo . PNAS . 2001;98:5856–5861
  40. Friedhoff LT , Cullen EI , Geoghagaen NSM , Buxbaum JD . Treatment with controlled-release lovastatin decreases serum concentrations of human β-amyloid (Aβ) peptide . Int J Neuropsychopharm . 2001;4:127–130
  41. Buxbaum JD , Geoghagen NSM , Friedhoff LT . Cholesterol depletion with physiological concentrations of a statin decreases the formation of the Alzheimer amyloid Aβ peptide . J Alzheimer Dis . 2001;3:221–229
  42. Sparks DL , Liu H , Gross DR , Scheff SW . Increased density of cortical Apolipoprotein E immunoreactive neurons in rabbit brain after dietary administration of cholesterol . Neurosci Lett . 1995;187:142–144
  43. Sparks DL . Intraneuronal β-amyloid immunoreactivity in the CNS . Neurobiol Aging . 1996;17:291–299
  44. Streit WJ , Sparks DL . Activation of microglia in the brains of humans with heart disease and hypercholesterolemic rabbits . J Mol Med . 1997;75:130–138
  45. Durham RA , Parker CA , Emmerling MR , Bisgaier CL , Walker LC . Effect of age and diet on the expression of beta-amyloid 1-40 and 1-42 in the brains of apolipoprotein-E-deficient mice . Neurobiol Aging . 1998;19:S281
  46. Refolo LM , Pappolla MA , Malester B , LaFrancois J , Bryant-Thomas T , Wang R , et al.   Hypercholesterolemia accelerates the Alzheimer’s amyloid pathology in a transgenic mouse model . Neurobiol Dis . 2000;7:321–331
  47. Mahley RW . Apolipoprotein E (Cholesterol transport protein with expanding role in cell biology) . Science . 1988;240:622–630
  48. Beisiegel U , Weber W , Ihrke G , Herz J , Stanley KK . The LDL-receptor-related protein, LRP, is an apolipoprotein E-binding protein . Nature . 1989;341:162–164
  49. Utermann G , Hees M , Steinmetz A . Polymorphism of apolipoprotein E and occurrence of dysbetalipoproteinaemia in man . Nature . 1977;269:604–607
  50. Cumming AM , Robertson FW . Polymorphism at the apolipoprotein E locus in relation to risk of coronary disease . Clin Genet . 1984;25:310–313
  51. Sing CF , Davignon J . Role of the apolipoprotein E polymorphism in determining normal plasma lipid and lipoprotein variation . Am J Hum Genet . 1985;37:268–285
  52. Lenzen HJ , Assmann G , Buchwalsky R , Schulte H . Association of apolipoprotein E polymorphism, low-density lipoprotein cholesterol and coronary artery disease . Clin Chem . 1986;32:778–781
  53. Davignon J , Gregg RE , Sing CF . Apolipoprotein polymorphism and atherosclerosis . Arteriosclerosis . 1988;8:1–21
  54. Kussi T , Nieminen MS , Ehnholm C , et al.   Apolipoprotein E polymorphism and coronary artery disease (increased prevalence of apolipoprotein E-4 in angiographically defined coronary patients) . Arteriosclerosis . 1989;9:237–241
  55. Eichner JE , Kuller LH , Orchard TJ , Grandits GA , McCallum LM , Ferrell RE , et al.   Relation of apolipoprotein E phenotype to myocardial infarction and mortality from coronary artery disease . Am J Cardiol . 1993;71:160–165
  56. Luc G , Bard JM , Arveiler D , Evans A , Cambou J-P , Bingham A , et al.   Impact of apolipoprotein E polymorphism on lipoproteins and risk of myocardial infarction (the ECTIM Study) . Arterioscler Thromb . 1994;14:1412–1419
  57. Wilson PWF , Myers RH , Larson MG , Ordovas JM , Wolf PA , Schaefer EJ . Apolipoprotein E alleles, dyslipidemia, and coronary heart disease. The Framingham offspring study . JAMA . 1994;272:1666–1671
  58. Stengård JH , Zerba KE , Pekkanen J , Ehnholm C , Nissinen A , Sing CF . Apolipoprotein E polymorphism predicts death from coronary heart disease in a longitudinal study of elderly Finnish men . Circulation . 1995;91:265–269
  59. Jarvik GP , Wijsman EM , Kukull WA , Schellenberg GD , Yu C , Larson EB . Interactions of apolipoprotein E genotype, total cholesterol level, age, and sex in prediction of Alzheimer’s disease (a case-control study) . Neurology . 1995;45:1092–1096
  60. Hofman A , Ott A , Breteler MMB , Bots ML , Slooter AJC , van Harskamp F , et al.   Atherosclerosis, apolipoprotein E, and prevalence of dementia and Alzheimer’s disease in the Rotterdam Study . Lancet . 1997;349:151–154
  61. Notkola I-L , Raimo S , Pekkanen J , Erkinjuntti T , Ehnholm C , Kivinen P , et al.   Serum total cholesterol, Apolipoprotein E e4 allele, and Alzheimer’s disease . Neuroepidemiology . 1998;17:14–20
  62. Evans RM , Emsley CL , Gao S , Sahota A , Hall KS , Farlow MR , et al.   Serum cholesterol, APOE genotype, and the risk of Alzheimer’s disease (a population-based study of African Americans) . Neurology . 2000;54:240–242
  63. Moroney JT , Tang M-X , Berglund L , Merchant C , Bell K , Stern Y , et al.   Low-density lipoprotein cholesterol and the risk of dementia with stroke . JAMA . 1999;282:254–260
  64. Romas S , Tang M-X , Berglund L , Mayeux R . APOE genotype, plasma lipids, lipoproteins, and AD in the community elderly . Neurology . 1999;53:517–521
  65. Sparks DL , Hunsaker JC , Scheff SW , Kryscio RF , Henson JL , Markesbery WR . Cortical senile plaques in coronary artery disease, aging and Alzheimer’s disease . Neurbiol Aging . 1990;11:601–608
  66. Sparks DL , Liu H , Scheff SW , Cyne CM , Hunsaker JC . Cortical senile plaques in coronary artery disease, aging and Alzheimer’s disease . J Neuropath Exp Neurol . 1993;52:135–142
  67. Sparks DL , Scheff W , Liu H , et al.   Increased incidence of neurofibrillary tangles (NFT) in non-demented individuals with hypertension . J Neurol Sci . 1995;131:162–169
  68. Soneira CF , Scott TM . Severe cardiovascular disease and Alzheimer’s disease (senile plaque formation in cortical areas) . Clin Anat . 1996;9:118–127
  69. Davignon J , Laaksonen R . Low-density lipoprotein-independent effects of statins . Curr Opin Lipidol . 1999;10:543–559
  70. März W , Wieland H . HMG-CoA reductase inhibition (anti-inflammatory effects beyond lipid lowering) . Herz . 2000;25:117–125
  71. Ridker PM , Rifai N , Clearfield M , Downs JR , Weis SE , Miles JS , et al.   Measurement of C-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary events . N Engl J Med . 2001;344:1959–1965
  72. Cucchiara B , Kasner SE . Use of statins in CNS disorders . J Neurol Sci . 2001;187:81–89
  73. Paris D , Townsend KP , Humphrey J , Obregon DF , Yokota K , Mullan M . Statins inhibit Aβ-neurotoxicity in vitro and Aβ-induced vasoconstriction and inflammation in rat aortae . Atherosclerosis . 2002;161:293–299
  74. Launer LJ , White LR , Petrovitch H , Ross GW , Curb JD . Cholesterol and neuropathologic markers of AD (a population-based study) . Neurology . 2001;57:1447–1452
  75. Koudinov AR , Berezov TT , Koudinova NV . The levels of soluble amyloid beta in different high density lipoprotein subfractions distinguish Alzheimer’s and normal aging cerebrospinal fluid (implications for brain cholesterol pathology?) . Neurosci Lett . 2001;314:115–118

PII: S1552-5260(06)00043-4

doi: 10.1016/j.jalz.2006.02.003

Alzheimer's & Dementia: The Journal of the Alzheimer's Association
Volume 2, Issue 2 , Pages 96-103 , April 2006

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