CNS Drugs

, Volume 22, Issue 11, pp 887–902

Preventing Alzheimer’s Disease

Separating Fact From Fiction
Leading Article

Abstract

Alzheimer’s disease is an ever-increasing health concern among the aging population, and as we research new and existing treatments for this disease we begin to uncover possibilities for its prevention. Observational studies and animal models have provided promising findings and generated excitement, but placebo-controlled clinical trials are required to demonstrate true efficacy for these treatments.

In the past two decades, clinical trials have led to the approval of symptomatic treatments for Alzheimer’s disease, including cholinesterase inhibitors and, more recently, an NMDA receptor antagonist. Clinical trials have also examined antioxidants, NSAIDs, hormone replacement, nutritional supplements and non-pharmacological interventions for the treatment and prevention of Alzheimer’s disease. While the results of many of these trials have been disappointing, new mechanisms targeting the hallmark pathology of Alzheimer’s disease are currently under investigation, including immunotherapy and secretase modulation, targeted at reducing the amyloid burden, for which we await the results. We review the evidence from completed trials, support for ongoing studies and propose directions for future research.

References

  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(9): 1337–42PubMedCrossRefGoogle Scholar
  2. 2.
    Winblad B, Wimo A, Jonsson L. Public health impact [abstract]. Alzheimers Dement 2007; 3(3): S165CrossRefGoogle Scholar
  3. 3.
    Howard J, Taylor JA, Ganikos ML, et al. An overview of prevention research: issues, answers, and agendas. Pub Health Rep 1988; 103: 674–83Google Scholar
  4. 4.
    Froom P. Benbassat J. Inconsistencies in the classification of preventive interventions. Prev Med 2000; 31: 153–8Google Scholar
  5. 5.
    Petersen RC, Thomas RG, Grundman M, et al. Vitamin E and donepezil for the treatment of mild cognitive impairment. N Engl J Med 2005 Jun 9; 352(23): 2379–88PubMedCrossRefGoogle Scholar
  6. 6.
    Cummings JL, Doody R, Clark C. Disease-modifying therapies for Alzheimer disease: challenges to early intervention. Neurology 2007; 69(16): 1622–34PubMedCrossRefGoogle Scholar
  7. 7.
    Courtney C, Farrell D, Gray R, et al. Long-term donepezil treatment in 565 patients with Alzheimer’s disease (AD2000): randomized double-blind trial. Lancet 2004; 363: 2105–15PubMedCrossRefGoogle Scholar
  8. 8.
    Racchi M, Govoni S. The pharmacology of amyloid precursor protein processing. Exp Gerontol 2003; 38(1-2): 145–57PubMedCrossRefGoogle Scholar
  9. 9.
    Nitsch RM, Slack BE, Wurtman RJ, et al. Release of Alzheimer amyloid precursor derivatives stimulated by activation of mus-carinic acetylcholine receptors. Science 1992; 258: 304–7PubMedCrossRefGoogle Scholar
  10. 10.
    Van Dam D, De Deyn PP. Cognitive evaluation of disease-modifying efficacy of galantamine and memantine in the APP23 model. Eur Neuropsychopharmacol 2006 Jan; 16(1): 59–69PubMedCrossRefGoogle Scholar
  11. 11.
    Clarke NA, Soininen H, Gustafson L, et al. Tacrine may alter APP-like protein levels in the lumbar CSF of Alzheimer patients. Int J Geriatr Psychiatry 2001 Nov; 16(11): 1104–6PubMedCrossRefGoogle Scholar
  12. 12.
    Parnetti L, Amici S, Lanari A, et al. Cerebrospinal fluid levels of biomarkers and activity of acetylcholinesterase (AChE) and butyrylcholinesterase in AD patients before and after treatment with different AChE inhibitors. Neurol Sci 2002 Sep; 23Suppl. 2: S95–6PubMedCrossRefGoogle Scholar
  13. 13.
    Li L, Sengupta A, Haque N, et al. Memantine inhibits and reverses the Alzheimer type abnormal hyperphosphorylation of tau and associated neurodegeneration. FEBS Lett 2004 May 21; 566(1-3): 261–9PubMedCrossRefGoogle Scholar
  14. 14.
    Peskind ER, Potkin SG, Pomara N, et al. Memantine treatment in mild to moderate Alzheimer disease: a 24-week randomized controlled trial. Am J Geriatr Psychiatry 2006; 14: 704–15PubMedCrossRefGoogle Scholar
  15. 15.
    Scharf S, Mander A, Ugoni A, et al. A double-blind, placebo-controlled trial of diclofenac/misoprostol in Alzheimer’s disease. Neurology 1999; 53(1): 197–201PubMedCrossRefGoogle Scholar
  16. 16.
    Aisen PS, Schafer KA, Grundman M, et al. Effects of rofecoxib or naproxen vs placebo on Alzheimer disease progression: a randomized controlled trial. JAMA 2003; 289(21): 2819–26PubMedCrossRefGoogle Scholar
  17. 17.
    Thal LJ, Ferris SH, Kirby L, et al. A randomized, double-blind, study of rofecoxib in patients with mild cognitive impairment. Neuropsychopharmacology 2005 Jun; 30(6): 1204–15PubMedCrossRefGoogle Scholar
  18. 18.
    Steering Committee. Statement from the steering committee of the Alzheimer’s Disease Anti-inflammatory Prevention Trial (ADAPT). Statement for the FDA Joint Advisory Committee; 2005 Feb 18 [online]. Available from URL: http://www.jhucct.com/adapt/pdf%20documents/FDA%20-ADAPT%20STATEMENT_web%20posting.pdf [Accessed 2008 Oct 6]
  19. 19.
    US Department of Health and Human Services. NIH halts use of COX-2 inhibitor in large cancer prevention trial. NIH News, 2004 Dec 17 [online]. Available from URL: http://www.nih.gov/news/pr/dec2004/od-17URL.htm [Accessed 2004 Dec 21]
  20. 20.
    US FDA. FDA statement on naproxen, 2004 Dec 20 [online]. Available from URL: http://www.fda.gov/bbs/topics/news/2004/NEW01148.html [Accessed 2008 Aug 13]
  21. 21.
    Wang PN, Liao SQ, Liu RS, et al. Effects of estrogen on cognition, mood, and cerebral blood flow in AD: a controlled study. Neurology 2000; 54: 2061–6PubMedCrossRefGoogle Scholar
  22. 22.
    Mulnard RA, Cotman CW, Kawas C, et al. Estrogen replacement therapy for treatment of mild to moderate Alzheimer disease. JAMA 2000; 283: 1007–15PubMedCrossRefGoogle Scholar
  23. 23.
    Henderson VW, Paganini-Hill A, Miller BL, et al. Estrogen for Alzheimer’s disease in women: randomized, double-blind, placebo-controlled trial. Neurology 2000; 54: 295–301PubMedCrossRefGoogle Scholar
  24. 24.
    Tierney, M. Estradiol and norethindrone for the prevention of decline in verbal memory in older women at risk for cognitive impairment: a randomized controlled trial [abstract no. 02-04-05]. 11th International Conference on Alzheimer’s Disease; 2008 Jul 26–31; Chicago (IL)Google Scholar
  25. 25.
    Shumaker SA, Legault C, Rapp SR, et al. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women. The Women’s Health Initiative Memory Study: a randomized controlled trial. JAMA 2003 May 28; 289(20): 2651–62Google Scholar
  26. 26.
    Shumaker SA, Legault C, Kuller L, et al. Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women. The Women’s Health Initiative Memory Study. JAMA 2004 Jun 23; 291(24): 2947–58Google Scholar
  27. 27.
    Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002; 288(3): 321–33PubMedCrossRefGoogle Scholar
  28. 28.
    Sano M, Ernesto C, Thomas RG, et al. A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer’s disease. The Alzheimer’s Disease Cooperative Study. N Engl J Med 1997; 336(17): 1216–22Google Scholar
  29. 29.
    Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002; 360(9326): 23–33CrossRefGoogle Scholar
  30. 30.
    Onofrj M, Thomas A, Luciano AL, et al. Donepezil versus vitamin E in Alzheimer’s disease: part 2. Mild versus moderate-severe Alzheimer’s disease. Clin Neuropharmacol 2002 Jul–Aug; 25(4): 207–15Google Scholar
  31. 31.
    Lonn E, Bosch J, Yusuf S, et al. Effects of long-term vitamin E supplementation on cardiovascular events and cancer: a randomized controlled trial. JAMA 2005; 293: 1338–47PubMedCrossRefGoogle Scholar
  32. 32.
    Sparks DL, Sabbagh M, Connor DJ, et al. Atorvastatin for the treatment of mild to moderate Alzheimer’s disease. Arch Neurol 2005; 62: 753–7PubMedCrossRefGoogle Scholar
  33. 33.
    PROSPER study group. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomized controlled trial. Lancet 2002; 360: 1623–30CrossRefGoogle Scholar
  34. 34.
    Collins R, Armitage J, Parish S, et al. Effects of cholesterol-lowering with simvastatin on stroke and other major vascular events in 20,536 people with cerebrovascular disease or other high-risk conditions. Lancet 2004; 363(9411): 757–67PubMedCrossRefGoogle Scholar
  35. 35.
    Bodovitz S, Klein WL. Cholesterol modulates alpha-secretase cleavage of amyloid precursor protein. J Biol Chem 1996 Feb 23; 271(8): 4436–40PubMedCrossRefGoogle Scholar
  36. 36.
    Sparks DL, Scheff SW, Hunsaker III JC, et al. Induction of Alzheimer-like beta-amyloid immunoreactivity in the brains of rabbits with dietary cholesterol. Exp Neurol 1994 Mar; 126(1): 88–94PubMedCrossRefGoogle Scholar
  37. 37.
    Sparks DL, Liu H, Gross DR, et al. Increased density of cortical apolipoprotein E immunoreactive neurons in rabbit brain after dietary administration of cholesterol. Neurosci Lett 1995 Mar 3; 187(2): 142–4PubMedCrossRefGoogle Scholar
  38. 38.
    Streit WJ, Sparks DL. Activation of microglia in the brains of humans with heart disease and hypercholesterolemic rabbits. J Mol Med 1997 Feb; 75(2): 130–8PubMedCrossRefGoogle Scholar
  39. 39.
    Shie FS, Jin LW, Cook DG, et al. Diet-induced hypercholester-olemia enhances brain A beta accumulation in transgenic mice. Neuroreport 2002 Mar 25; 13(4): 455–9PubMedCrossRefGoogle Scholar
  40. 40.
    Fishman CE, White SL, DeLong CA, et al. High fat diet potentiates β-amyloid deposition in the APP V717F transgenic mouse model of Alzheimer’s Disease. Soc Neurosci 1999; 25: 1859Google Scholar
  41. 41.
    Wolozin B, Kellman W, Ruosseau P, et al. Decreased prevalence of Alzheimer’s disease associated with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. Arch Neurol 2000; 57: 1439–43PubMedCrossRefGoogle Scholar
  42. 42.
    Jick H, Zornberg GL, Jick SS, et al. Statins and the risk of dementia. Lancet 2000; 356: 1627–31PubMedCrossRefGoogle Scholar
  43. 43.
    Zamrini E, McGwinn G, Roseman JM. Association between statin use and Alzheimer’s disease. Neuroepidemiology 2004; 23: 94–8PubMedCrossRefGoogle Scholar
  44. 44.
    Dufoil C, Richard F, Fievet N, et al. APOE genotype, cholesterol level, lipid-lowering treatment and dementia. Neurology 2005; 65: 1531–8CrossRefGoogle Scholar
  45. 45.
    Rockwood K, Kirkland S, Hogan DB, et al. Use of lipid-lowering agents, indication bias and the risk of dementia in community-dwelling elderly people. Arch Neurol 2002; 59: 223–7PubMedCrossRefGoogle Scholar
  46. 46.
    Rockwood K, Kirkland S, Fisk J, et al. Use of lipid lowering agents and the risk of cognitive impairment, not dementia, in relation to apolipoprotein E status [abstract]. Neurobiol Aging 2004; 25Suppl. 2: S27CrossRefGoogle Scholar
  47. 47.
    Yaffe K, Barrett-Connor E, Lin F, et al. Serum lipoprotein levels, statin use and cognitive function in older women. Arch Neurol 2002; 59: 378–84PubMedCrossRefGoogle Scholar
  48. 48.
    Bernick C, Katz R, Smith NL, et al. Statins and cognitive function in the elderly. Neurology 2005; 65: 1388–94PubMedCrossRefGoogle Scholar
  49. 49.
    Masse I, Bordet R, Deplanque D, et al. Lipid lowering agents are associated with a slower cognitive decline in Alzheimer’s disease. J Neurol Neurosurg Psych 2005; 76: 1624–9CrossRefGoogle Scholar
  50. 50.
    Doraiswamy PM, Steffens DC, McQuoid DR. Statin use and hippocampal volumes in elderly subjects at risk for Alzheimer’s disease: a pilot observational study. Am J Alzheimers Dis Other Demen 2004; 19: 275–8PubMedCrossRefGoogle Scholar
  51. 51.
    Rodriguez EG, Dodge HH, Birzescu MA, et al. Use of lipid-lowering drugs in older adults with and without dementia: a community based epidemiological study. J Am Geriatr Soc 2002; 50: 1852–6PubMedCrossRefGoogle Scholar
  52. 52.
    Reitz C, Tang MX, Luchsinger J, et al. Relation of plasma lipids to Alzheimer’s disease and vascular dementia. Arch Neurol 2004; 61: 705–14PubMedCrossRefGoogle Scholar
  53. 53.
    Zandi PP, Sparks DL, Khachaturian AS, et al. Do statins reduce risk of incident dementia and Alzheimer Disease? Arch Gen Psychiatry 2005; 62: 217–24PubMedCrossRefGoogle Scholar
  54. 54.
    Li G, Higdon R, Kukull WA, et al. Statin therapy and the risk of dementia in the elderly. Neurology 2004; 63: 1624–8PubMedCrossRefGoogle Scholar
  55. 55.
    Rea TD, Breitner JC, Psaty BM, et al. Statin use and the risk of incident dementia. Arch Neurol 2005; 62: 1047–51PubMedCrossRefGoogle Scholar
  56. 56.
    Hajjar I, Schumpert J, Hirth V, et al. The impact of the use of statins on the prevalence of dementia and progression of cognitive impairment. J Gerontol A Biol Sci Med Sci 2002; 57: M414–8PubMedCrossRefGoogle Scholar
  57. 57.
    Dufoil C, Richard F, Fievet N, et al. APOE genotype, cholesterol level, lipid-lowering treatment and dementia. Neurology 2005; 65: 1531–8CrossRefGoogle Scholar
  58. 58.
    Rockwood K, Kirkland S, Hogan DB, et al. Use of lipid-lowering agents, indication bias and the risk of dementia in community dwellng elderly people. Arch Neurol 2002; 59: 223–7PubMedCrossRefGoogle Scholar
  59. 59.
    Rockwood K, Kirkland S, Fisk J, et al. Use of lipid lowering agents and the risk of cognitive impairment, not dementia, in relation to apolipoprotein E status [abstract]. Neurobiol Aging 2004; 25Suppl. 2: S27CrossRefGoogle Scholar
  60. 60.
    Zandi PP, Sparks DL, Khachaturian AS, et al. Do statins reduce risk of incident dementia and Alzheimer Disease? Arch Gen Psychiatry 2005; 62: 217–24PubMedCrossRefGoogle Scholar
  61. 61.
    Rea TD, Breitner JC, Psaty BM, et al. Statin use and the risk of incident dementia. Arch Neurol 2005; 62: 1047–51PubMedCrossRefGoogle Scholar
  62. 62.
    Gibellato MG, Moore JL, Selby K, et al. Effects of lovastatin and pravastatin on cognitive function in military aircrew. Aviat Space Environ Med 2001; 72: 805–12PubMedGoogle Scholar
  63. 63.
    Kostis JB, Rosen RC, Wilson AC. Central nervous system effects of HMG-CoA reductase inhibitors: lovastatin and pravastatin on sleep and cognitive performance in patients with hypercholesterolemia. J Clin Pharmacol 1994; 34: 989–96PubMedGoogle Scholar
  64. 64.
    Harrison RW, Ashton CH. Do cholesterol-lowering agents affect brain activity? A comparison of simvastatin, pravastatin or placebo in healthy volunteers. Br J Clin Pharmacol 1994; 37: 231–6PubMedCrossRefGoogle Scholar
  65. 65.
    Cutler N, Sramke J, Veroff A, et al. Effects of treatment with simvastatin and pravastatin on cognitive function in patients with hypercholesterolemia. Br J Clin Pharmacol 1995; 39: 333–6PubMedCrossRefGoogle Scholar
  66. 66.
    Heart Protection Study Collaborative Group. MRC/BHF heart protection study of cholesterol lowering with simvastatin in 20536 high-risk individuals. Lancet 2002; 360: 7–22CrossRefGoogle Scholar
  67. 67.
    Simons M, Schwarzler F, Luthjohann D, et al. Treatment with simvastatin in normocholesterolemic patients with Alzheimer’s disease: a 26-week, randomized, placebo-controlled double-blind trial. Ann Neurol 2002; 52: 346–50PubMedCrossRefGoogle Scholar
  68. 68.
    Aisen PS, Saumier D, Briand R, et al. A phase II study targeting amyloid-beta with 3APS in mild-to-moderate Alzheimer disease. Neurology 2006 Nov 28; 67(10): 1757–63PubMedCrossRefGoogle Scholar
  69. 69.
    Neurochem announces results from tramiprosate (Alzhemed™) North American phase III clinical trial [press release]. Laval (QC): Neurochem, 2007 Aug 26 [online]. Available from URL: http://72.232.136.18/~neurochem/getpage.php [Accessed 2008 Aug 19]
  70. 70.
    Neurochem announces important initiatives to provide medical and health benefits to patients [press release]. Laval (QC): Neurochem, 2007 Nov 8 [online]. Available from URL: http://72.232.136.18/~neurochem/getpage.php [Accessed 2008 Aug19]
  71. 71.
    Schenk D, Barbour R, Dunn W, et al. Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 1999 Jul 8; 400(6740): 173–7PubMedCrossRefGoogle Scholar
  72. 72.
    Orgogozo JM, Gilman S, Dartigues JF, et al. Subacute meningoencephalitis in a subset of patients with AD after Abeta42 immunization. Neurology 2003 Jul 8; 61(1): 46–54PubMedCrossRefGoogle Scholar
  73. 73.
    Nicoll JA, Wilkinson D, Holmes C, et al. Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: a case report. Nat Med 2003 Apr; 9(4): 448–52PubMedCrossRefGoogle Scholar
  74. 74.
    Holmes C, Boche D, Wilkinson D, et al. Long-term effects of Abeta42 immunisation in Alzheimer’s disease: follow-up of a randomised, placebo-controlled, phase I trial. Lancet 2008; 372(9634): 216–23PubMedCrossRefGoogle Scholar
  75. 75.
    Gilman S, Koller M, Black RS, et al. Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial. Neurology 2005; 64(9): 1553–62PubMedCrossRefGoogle Scholar
  76. 76.
    Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975; 12: 189–98PubMedCrossRefGoogle Scholar
  77. 77.
    Rosen WG, Mohs RC, Davis KL. A new rating scale for Alzheimer’s disease. Am J Psychiatry 1984; 141: 1356–64PubMedGoogle Scholar
  78. 78.
    Fox NC, Black RS, Gilman S, et al. Effects of Abeta immunization (AN1792) on MRI measures of cerebral volume in Alzheimer disease. Neurology 2005 May 10; 64(9): 1563–72PubMedCrossRefGoogle Scholar
  79. 79.
    Gupta RK, Rost BE. Aluminum compounds as vaccine adjuvants. In: O’Hagan DT, editor. Vaccine adjuvants. Totowa (NJ): Humana Press, 2000: 65–89CrossRefGoogle Scholar
  80. 80.
    Hilbich C, Kisters-Woike B, Reed J, et al. Substitutions of hydrophobic amino acids reduce the amyloidenicity of Alzheimer’s disease Abeta 4 peptides. J Mol Biol 1992; 228: 1–14CrossRefGoogle Scholar
  81. 81.
    Dodel RC, Du Y, Depboylu C, et al. Intravenous immunoglobulins containing antibodies against beta-amyloid for the treatment of Alzheimer’s disease. J Neurol Neurosurg Psychiatry 2004 Oct; 75(10): 1472–4PubMedCrossRefGoogle Scholar
  82. 82.
    Relkin NR, Szabo P, Adamiak B, et al. 18-Month study of intravenous immunoglobulin for treatment of mild Alzheimer disease. Neurobiol Aging. Epub 2008 Feb 20Google Scholar
  83. 83.
    Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics [published erratum appears in Science 2002 Sep 27; 297(5590): 2209]. Science 2002 Jul 19; 297(5580): 353–6PubMedCrossRefGoogle Scholar
  84. 84.
    Chang W, Koelsch G, Down D, et al. Memapsin 2 (Beta-Secretase, BACE) immunizations as therapy for Alzheimer’s disease [abstract no. 01-06-03]. International Conference on Alzheimer’s Disease; 2006 Jul 15–20; MadridGoogle Scholar
  85. 85.
    May PC, Boggs LN, Yang Z, et al. Bace inhibitor in vivo proof-of-concept studies in PDAPP mice [abstract no. P4-271]. International Conference on Alzheimer’s Disease; 2006 Jul 15–20; MadridGoogle Scholar
  86. 86.
    Arbel M, Sivan G, Idan R, et al. Inhibition of amyloid precursor protein processing by beta-secretase via site directed antibodies [abstract no. 02-05-02]. International Conference on Alzheimer’s Disease; 2006 Jul 15–20; MadridGoogle Scholar
  87. 87.
    Xiu H, Sweeney D, Wang R, et al. Generation of Alzheimer beta-amyloid protein in the trans-Golgi network in the apparent absence of vesicle formation. Proc Natl Acad Sci U S A 1997; 94: 3748–52CrossRefGoogle Scholar
  88. 88.
    Launer LJ. Demonstrating the case that AD is a vascular disease: epidemiologic evidence. Ageing Res Rev 2002; 1: 61–77PubMedCrossRefGoogle Scholar
  89. 89.
    de La Torre JC. Is Alzheimer’s disease a neurodegenerative or vascular disorder? Data, dogma and dialectics. Lancet Neurol 2004; 3: 184–90PubMedCrossRefGoogle Scholar
  90. 90.
    Morris MC, Scherr PA, Hebert LE, et al. Association of incident Alzheimer disease and blood pressure measured from 13 years before to 2 years after diagnosis in a large community study. Arch Neurol 2001; 58: 1640–6PubMedCrossRefGoogle Scholar
  91. 91.
    Glynn RJ, Beckett LA, Hebert LE, et al. Current and remote blood pressure and cognitive decline. JAMA 1999; 281: 438–45PubMedCrossRefGoogle Scholar
  92. 92.
    Scherr PA, Hebert LE, Smith LA, et al. Relation of blood pressure to cognitive function in the elderly. Am J Epidemiol 1991; 134: 1303–131PubMedGoogle Scholar
  93. 93.
    Lindsay J, Laurin D, Verreault R, et al. Risk factors for Alzheimer’s disease: a prospective analysis from the Canadian Study of Health and Aging. Am J Epidemiol 2002; 156: 445–53PubMedCrossRefGoogle Scholar
  94. 94.
    Andre-Peterson L, Hagberg B, Janzon L, et al. A comparison of cognitive ability in normotensive and hypertensive 68-year-old men: results from population study ‘Men born in 1914’ in Malmo, Sweden. Exp Aging Res 2001; 27: 319–40CrossRefGoogle Scholar
  95. 95.
    Hajjar I, Catoe H, Sixta S, et al. Cross-sectional and longitudinal association between antihypertensive medications and cognitive impairment in an elderly population. J Gerontol A Biol Sci Med Sci 2005; 60: 76–3CrossRefGoogle Scholar
  96. 96.
    Tzourio C, Dufouil C, Ducimetiere P, et al. Cognitive decline in individuals with high blood pressure: a longitudinal study in the elderly-EVA study group. Epidemiology of vascular aging. Neurology 1999; 53: 1948–52Google Scholar
  97. 97.
    Kilander L, Nyman H, Boberg M, et al. Hypertension is related to cognitive impairment: a 20 year follow-up of 999 men. Hypertension 1998; 31: 780–6PubMedCrossRefGoogle Scholar
  98. 98.
    Elias MF, Wolf PA, D’Agostino RB, et al. Untreated blood pressure level is inversely related to cognitive functioning: the Framingham study. Am J Epidemiol 1993; 6: 353–64Google Scholar
  99. 99.
    Launer LJ, Ross GW, Petrovitch H, et al. Midlife blood pressure and dementia: the Honolulu-Asia aging study. Neurobiol Aging 2000; 21: 49–55PubMedCrossRefGoogle Scholar
  100. 100.
    in’t Veld BA, Ruitenberg A, Hofman A, et al. Antihypertensive drugs and incidence of dementia: the Rotterdam study. Neurobiol Aging 2001; 22: 407–12PubMedCrossRefGoogle Scholar
  101. 101.
    Cacciatore F, Abete P, Ferrara N, et al. The role of blood pressure in cognitive impairment in an elderly population. J Hypertens 1997; 15: 135–42PubMedCrossRefGoogle Scholar
  102. 102.
    Farmer ME, Kittner SJ, Abbott RD, et al. Longitudinally measured blood pressure, antihypertensive medication use and cognitive performance: the Framingham study. J Clin Epidemiol 1990; 43: 475–80PubMedCrossRefGoogle Scholar
  103. 103.
    Waldstein SR, Giggey PP, Thayer JF, et al. Nonlinear relations of blood pressure to cognitive function. The Baltimore Longitudinal Study of Aging. Hypertension 2005; 45: 374–9Google Scholar
  104. 104.
    Murray MD, Lane KA, Gao S, et al. Preservation of cognitive function with antihypertensive medications. Arch Intern Med 2002; 162: 2090–6PubMedCrossRefGoogle Scholar
  105. 105.
    Lithell H, Hansson L, Skoog I, et al. The study on cognition and prognosis in the elderly (SCOPE): principal results of a randomized double-blind intervention trial. J Hypertens 2003; 21: 875–86PubMedCrossRefGoogle Scholar
  106. 106.
    Skoog I, Lithell H, Hansson L, et al. Effect of baseline cognitive function and antihypertensive treatment on cognitive and cardiovascular outcomes. Study on Cognition and Prognosis in the Elderly (SCOPE). Am J Hypertens 2005; 18: 1052–9PubMedGoogle Scholar
  107. 107.
    Prince MJ, Bird AS, Blizard RA, et al. Is the cognitive function of older patients affected by antihypertensive treatment? Results from 54 months of the Medical Research Council’s treatment trial of hypertension in older adults. BMJ 1996; 312: 801–5PubMedCrossRefGoogle Scholar
  108. 108.
    Cervilla JA, Prince M, Joels S, et al. Long-term predictors of cognitive outcome in a cohort of older people with hypertension. Br J Psychiatry 2000; 177: 66–71PubMedCrossRefGoogle Scholar
  109. 109.
    PROGRESS Collaborative Group. Effects of blood pressure lowering with perindopril and indapamide therapy on dementia and cognitive decline in patients with cerebrovascular disease. Arch Intern Med 2003; 163: 1069–75CrossRefGoogle Scholar
  110. 110.
    Geschwind DH. Tau phosphorylation, tangles, and neurodegen-eration: the chicken or the egg? Neuron 2003; 40: 457–60PubMedCrossRefGoogle Scholar
  111. 111.
    Engel T, Hernandez F, Avila J, et al. Full reversal of Alzheimer’s disease-like phenotype in a mouse model with conditional overexpression of glycogen synthase kinase-3. J Neurosci 2006; 26: 5083–90PubMedCrossRefGoogle Scholar
  112. 112.
    Noble W, Olm V, Takata K. et al. Cdk5 is a key factor in tau aggregation and tangle formation in vivo. Neuron 2003; 38(4): 555–65Google Scholar
  113. 113.
    Butler D, Bendiske J, Michaelis ML, et al. Microtubule-stabilizing agent prevents protein accumulation-induced loss of synaptic markers. Eur J Pharmacol 2007 May 7; 562(1-2): 20–7PubMedCrossRefGoogle Scholar
  114. 114.
    Nakashima H, Ishihara T, Suguimoto P, et al. Chronic lithium treatment decreases tau lesions by promoting ubiquitination in a mouse model of tauopathies. Acta Neuropathol (Berl) 2005; 110: 547–56CrossRefGoogle Scholar
  115. 115.
    McEwen BS, Alves SE, Bulloch K, et al. Ovarian steroids and the brain: implications for cognition and aging. Neurology 1997; 48Suppl. 7: S8–15PubMedCrossRefGoogle Scholar
  116. 116.
    Wen Y, Yang S, Liu R, et al. Estrogen attenuates nuclear factor-kappa B activation induced by transient cerebral ischemia. Brain Res 2004; 1008(2): 147–54PubMedCrossRefGoogle Scholar
  117. 117.
    Dodel RC, Du Y, Bales KR, et al. Sodium salicylate and 17beta-estradiol attenuate nuclear transcription factor NF-kappaB translocation in cultured rat astroglial cultures following exposure to amyloid A beta(1-40) and lipopolysaccharides. J Neurochem 1999; 73: 1453–60PubMedCrossRefGoogle Scholar
  118. 118.
    Simpkins JW, Yang SH, Wen Y, et al. Estrogens, progestins, menopause and neurodegeneration: basic and clinical studies. Cell Mol Life Sci 2005; 62: 271–80PubMedCrossRefGoogle Scholar
  119. 119.
    Yue X, Lu M, Lancaster T, et al. Brain estrogen deficiency accelerates Abeta plaque formation in an Alzheimer’s disease animal model. Proc Natl Acad Sci U S A 2005 Dec 27; 102(52): 19198–203PubMedCrossRefGoogle Scholar
  120. 120.
    Engelhart MJ, Geerlings MI, Ruitenberg A, et al. Dietary intake of antioxidants and risk of Alzheimer disease. JAMA 2002; 287(24): 3223–9PubMedCrossRefGoogle Scholar
  121. 121.
    Morris MC, Evans DA, Bienias JL, et al. Dietary intake of antioxidant nutrients and the risk of incident Alzheimer disease in a biracial community study. JAMA 2002; 287(24): 3230–7PubMedCrossRefGoogle Scholar
  122. 122.
    Thomas A, Iacono D, Bonanni L, et al. Donepezil, rivastigmine, and vitamin E in Alzheimer disease: a combined P300 eventrelated potentials/neuropsychologic evaluation over 6 months. Clin Neuropharmacol 2001 Jan–Feb; 24(1): 31–42PubMedCrossRefGoogle Scholar
  123. 123.
    Thal LJ, Grundman M, Berg J, et al. Idebenone treatment fails to slow cognitive decline in Alzheimer’s disease. Neurology 2003 Dec 9; 61(11): 1498–502PubMedCrossRefGoogle Scholar
  124. 124.
    Gutzmann H, Kuhl KP, Hadler D, et al. Safety and efficacy of idebenone versus tacrine in patients with Alzheimer’s disease: results of a randomized, double-blind, parallel-group multicenter study. Pharmacopsychiatry 2002 Jan; 35(1): 12–8PubMedCrossRefGoogle Scholar
  125. 125.
    Adair JC, Knoefel JE, Morgan N. Controlled trial of N-acetylcysteine for patients with probable Alzheimer’s disease. Neurology 2001; 57: 1515–7PubMedCrossRefGoogle Scholar
  126. 126.
    Miller III ER, Pastor-Barriuso R, Dalai D, et al. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med 2005; 142(1): 37–46PubMedGoogle Scholar
  127. 127.
    Bales KR, Verina T, Dodel RC, et al. Lack of apolipoprotein E dramatically reduces amyloid beta-peptide deposition. Nat Genet 1997; 17(3): 263–4PubMedCrossRefGoogle Scholar
  128. 128.
    Nilsson LN, Bales KR, DiCarlo G, et al. Alpha-1-antichymotrypsin promotes beta-sheet amyloid plaque deposition in a transgenic mouse model of Alzheimer’s disease. J Neurosci 2001; 21(5): 1444–51PubMedGoogle Scholar
  129. 129.
    Eikelenboom P, van Gool WA. Neuroinflammatory perspectives on the two faces of Alzheimer’s disease. J Neural Transm 2004; 111(3): 281–94PubMedCrossRefGoogle Scholar
  130. 130.
    Reines SA, Block GA, Morris JC, et al. Rofecoxib: no effect on Alzheimer’s disease in a 1-year, randomized, blinded, controlled study. Neurology 2004; 62(1): 66–71PubMedCrossRefGoogle Scholar
  131. 131.
    Wilcock GK. Flurizan in AD: efficacy and safety in a 24-month study. Lancet Neurol 2008 Jun; 7(6); 483–93PubMedCrossRefGoogle Scholar
  132. 132.
    Green R. 18-Month phase III trial results for tarenflurbil (Flurizan) [abstract no. 03-04-01]. 11th International Conference on Alzheimer’s Disease; 2008 Jul 26–31; Chicago (IL)Google Scholar
  133. 133.
    Kanowski S, Herrmann WM, Stephan K, et al. Proof of efficacy of the Ginkgo biloba special extract EGb 761 in outpatients suffering from mild to moderate primary degenerative dementia of the Alzheimer type or multi-infarct dementia. Pharmacopsychiatry 1996; 29: 47–56PubMedCrossRefGoogle Scholar
  134. 134.
    van Dongen M, van Rossum E, Kessels A, et al. Ginkgo for elderly people with dementia and age-associated memory impairment: a randomized clinical trial. J Clin Epidemiol 2003; 56(4): 367–76PubMedCrossRefGoogle Scholar
  135. 135.
    Solomon PR, Adams F, Silver A, et al. Ginkgo for memory enhancement: a randomized controlled trial. JAMA 2002; 288(7): 835–40PubMedCrossRefGoogle Scholar
  136. 136.
    Blasko I, Kemmler G, Krampla W, et al. Plasma amyloid beta protein 42 in non-demented persons aged 75 years: effects of concomitant medication and medial temporal lobe atrophy. Neurobiol Aging 2005 Aug–Sep; 26(8): 1135–43PubMedCrossRefGoogle Scholar
  137. 137.
    Oken BS, Storzbach DM, Kaye JA. The efficacy of Ginkgo biloba on cognitive function in Alzheimer disease. Arch Neurol 1998 Nov; 55(11): 1409–15PubMedCrossRefGoogle Scholar
  138. 138.
    Birks J, Grimley Evans J. Ginkgo biloba for cognitive impairment and dementia. Cochrane Database Syst Rev 2007; (2): CD003120Google Scholar
  139. 139.
    DeKosky ST, Fitzpatrick A, Ives DG, et al. The Ginkgo Evaluation of Memory (GEM) study: design and baseline data of a randomized trial of Ginkgo biloba extract in prevention of dementia. Contemp Clin Trials 2006 Jun; 27(3): 238–53CrossRefGoogle Scholar
  140. 140.
    Akhondzadeh S, Noroozian M, Mohammadi M, et al. Salvia officinalis extract in the treatment of patients with mild to moderate Alzheimer’s disease: a double blind, randomized and placebo-controlled trial. J Clin Pharm Ther 2003 Feb; 28(1): 53–9PubMedCrossRefGoogle Scholar
  141. 141.
    Akhondzadeh S, Noroozian M, Mohammadi M, et al. Melissa officinalis extract in the treatment of patients with mild to moderate Alzheimer’s disease: a double blind, randomised, placebo controlled trial. J Neurol Neurosurg Psychiatry 2003 Jul; 74(7): 863–6PubMedCrossRefGoogle Scholar
  142. 142.
    Mimori Y, Katsuoka H, Nakamura S. Thiamine therapy in Alzheimer’s disease. Metab Brain Dis 1996 Mar; 11(1): 89–94PubMedCrossRefGoogle Scholar
  143. 143.
    Bryan J, Calvaresi E, Hughes D. Short-term folate, vitamin B-12 or vitamin B-6 supplementation slightly affects memory performance but not mood in women of various ages. J Nutr 2002 Jun; 132(6): 1345–56PubMedGoogle Scholar
  144. 144.
    Sommer BR, Hoff AL, Costa M, et al. Folic acid supplementation in dementia: a preliminary report. Proceedings of the 1 lth Annual Meeting of the American Association for Geriatric Psychiatry; 1998 Mar 8–11; San Diego (CA)Google Scholar
  145. 145.
    Barnes DE, Yaffe K, Satariano WA, et al. A longitudinal study of cardiorespiratory fitness and cognitive function in healthy older adults. J Am Geriatr Soc 2003 Apr; 51(4): 459–65PubMedCrossRefGoogle Scholar
  146. 146.
    Lytle ME, Vander Bilt J, Pandav RS, et al. Exercise level and cognitive decline: the MoVIES project. Alzheimer Dis Assoc Disord 2004 Apr–Jun; 18(2): 57–64PubMedCrossRefGoogle Scholar
  147. 147.
    Heyn P, Abreu BC, Ottenbacher KJ. The effects of exercise training on elderly persons with cognitive impairment and dementia: a meta-analysis. Arch Phys Med Rehabil 2004 Oct; 85(10): 1694–704PubMedCrossRefGoogle Scholar
  148. 148.
    Olazaran J, Muniz R, Reisberg B, et al. Benefits of cognitive-motor intervention in MCI and mild to moderate Alzheimer disease. Neurology 2004; 63(12): 2348–53PubMedCrossRefGoogle Scholar
  149. 149.
    Wilson RS, Bennett DA, Bienias JL, et al. Cognitive activity and cognitive decline in a biracial community population. Neurology 2003 Sep 23; 61(6): 812–6PubMedCrossRefGoogle Scholar
  150. 150.
    Verghese J, Lipton RB, Katz MJ, et al. Leisure activities and the risk of dementia in the elderly. N Engl J Med 2003 Jun 19; 348(25): 2508–16PubMedCrossRefGoogle Scholar
  151. 151.
    Chapman SB, Weiner MF, Rackley A, et al. Effects of cognitive-communication stimulation for Alzheimer’s disease patients treated with donepezil. J Speech Lang Hear Res 2004 Oct; 47(5): 1149–63PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2008

Authors and Affiliations

  • Mary Sano
    • 1
    • 2
  • Hillel Grossman
    • 1
    • 2
  • Kathleen Van Dyk
    • 1
    • 2
  1. 1.The Alzheimer Disease Research Center of Mount Sinai School of MedicineNew YorkUSA
  2. 2.James J Peters Veterans Affairs Medical CenterBronxUSA
  3. 3.Mount Sinai School of Medicine and the James J Peters VAMCBronxUSA

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