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Alzheimer's Disease, Cerebrovascular Disease, and the β-amyloid Cascade

Published online by Cambridge University Press:  02 December 2014

Kie Honjo ,
Sandra E. Black  and
Nicolaas P. L. G. Verhoeff
Kie Honjo*
Affiliation:
Rotman Research Institute, University of Toronto, Toronto, Ontario, Canada Department of Neurology, Hiroshima University Hospital, Hiroshima, Japan
Sandra E. Black
Affiliation:
Rotman Research Institute, University of Toronto, Toronto, Ontario, Canada
Nicolaas P. L. G. Verhoeff
Affiliation:
Kunin-Lunenfeld Applied Research Unit, Baycrest, Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada
*
1-2-3 Kasumi, Minami-ku, Hiroshima, Hiroshima, Japan 734-8551. Email: kiehon@hotmail.com
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Abstract

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Alzheimer's disease (AD), considered the commonest neurodegenerative cause of dementia, is associated with hallmark pathologies including extracellular amyloid-β protein (Aβ) deposition in extracellular senile plaques and vessels, and intraneuronal tau deposition as neurofibrillary tangles. Although AD is usually categorized as neurodegeneration distinct from cerebrovascular disease (CVD), studies have shown strong links between AD and CVD. There is evidence that vascular risk factors and CVD may accelerate Aβ 40-42 production/ aggregation/deposition and contribute to the pathology and symptomatology of AD. Aβ deposited along vessels also causes cerebral amyloid angiopathy. Amyloid imaging allows in vivo detection of AD pathology, opening the way for prevention and early treatment, if disease-modifying therapies in the pipeline show safety and efficacy. In this review, we review the role of vascular factors and Aβ, underlining that vascular risk factor management may be important for AD prevention and treatment.

Résumé

RÉSUMÉ

La maladie d'Alzheimer (MA), considérée comme la cause neurodégénérative de démence la plus fréquente, est associée à des pathologies caractéristiques dont le dépôt extracellulaire de protéine 13-amyloïde (A13) dans les plaques séniles extracellulaires et les vaisseaux et le dépôt intraneuronal de la protéine tau sous forme d'amas neurofibrillaires. Bien que la MA soit habituellement classifiée comme une neurodégénérescence distincte de la maladie cérébrovasculaire (MCV), des études ont montré des liens étroits entre la MA et la MCV. Il existe des données selon lesquelles les facteurs de risque vasculaire et la MCV peuvent accélérer la production/l'agrégation/le dépôt de l'Af3 40-42 et contribuer à la pathologie et à la symptomatologie de la MA. Le dépôt de l'Af3 le long des vaisseaux cause également l'angiopathie amyloïde cérébrale. L'imagerie de l'amyloïde permet la détection in vivo de la pathologie de la MA, ouvrant ainsi la voie à la prévention et au traitement précoces, si des traitements modificateurs de la maladie actuellement en développement s'avèrent sûrs et efficaces. Nous revoyons ici le rôle des facteurs de risque vasculaire et de l'A13, tout en soulignant que le contrôle des facteurs de risque vasculaire peut être important dans la prévention et le traitement de la MA.

Type
Review Article
Information
Canadian Journal of Neurological Sciences , Volume 39 , Issue 6 , November 2012 , pp. 712 - 728
Copyright
Copyright © The Canadian Journal of Neurological 2012

References

1. Alzheimer’s Disease International[homepage on the Internet]. London, UK: World Alzheimer report 2011. The benefits of early diagnosis and intervention. [updated 2011 Sep; cited 2012 Jun 17]. Available from: http://www.alz.co.uk/research/world-report-2011/ Google Scholar
2. Alzheimer Society of Canada[homepage on the Internet]. Toronto, Canada: Rising tide: The impact of dementia on Canadian society. [updated 2012 Apr 19; cited 2012 Apr 23]. Available from: http://www.alzheimer.ca/en/Get-involved/Raise-your-voice/Rising-Tide Google Scholar
3. Alzheimer’s Association. Alzheimer’s disease facts and figures. Alzheimers Dement. 2010;6:158–94.Google Scholar
4. Hebert, LE, Scherr, PA, Bienias, JL, Bennett, DA, Evans, DA. Alzheimer disease in the US population: prevalence estimates using the 2000 census. Arch Neurol. 2003;60:1119–22.Google Scholar
5. RTI International[homepage on the Internet]. Economic studies program: Disease-Specific estimates of direct and indirect costs and NIH support. Fiscal Year 2000 Update. [updated 2007 Jul 25; cited 2012 Jun 17]. Available from: http://ospp.od.nih.gov/ecostudies/COIreportweb.htm Google Scholar
6. Roth, M. The natural history of mental disorder in old age. J Ment Sci. 1955;101:281–301.Google Scholar
7. de la Torre, JC. Alzheimer disease as a vascular disorder: nosological evidence. Stroke. 2002;33:1152–62.Google Scholar
8. Gorelick, PB. Risk factors for vascular dementia and Alzheimer disease. Stroke. 2004;35:2620–2.Google Scholar
9. Kalaria, RN. The role of cerebral ischemia in Alzheimer’s disease. Neurobiol Aging. 2000;21:321–30.CrossRefGoogle ScholarPubMed
10. Esiri, MM, Nagy, Z, Smith, MZ, Barnetson, L, Smith, AD. Cerebrovascular disease and threshold for dementia in the early stages of Alzheimer’s disease. Lancet. 1999;354:919–20.CrossRefGoogle ScholarPubMed
11. Petrovitch, H, Ross, GW, Steinhorn, SC, et al. AD lesions and infarcts in demented and non-demented Japanese-American men. Ann Neurol. 2005;57:98–103.CrossRefGoogle ScholarPubMed
12. Snowdon, DA, Greiner, LH, Mortimer, JA, Riley, KP, Greiner, PA, Markesbery, WR. Brain infarction and the clinical expression of Alzheimer disease. The Nun Study. JAMA. 1997;277:813–17.CrossRefGoogle ScholarPubMed
13. Kalaria, RN, Bhatti, SU, Lust, WD, Perry, G. The amyloid precursor protein in ischemic brain injury and chronic hypoperfusion. Ann N Y Acad Sci. 1993;695:190–3.CrossRefGoogle ScholarPubMed
14. Nihashi, T, Inao, S, Kajita, Y, et al. Expression and distribution of beta amyloid precursor protein and beta amyloid peptide in reactive astrocytes after transient middle cerebral artery occlusion. Acta Neurochir (Wien). 2001;143:287–95.Google Scholar
15. Honjo, K, van Reekum, R, Verhoeff, NP. Alzheimer’s disease and infection: do infectious agents contribute to progression of Alzheimer’s disease? Alzheimers Dement. 2009;5:348–60.CrossRefGoogle ScholarPubMed
16. Braak, H, Braak, E. Frequency of stages of Alzheimer-related lesions in different age categories. Neurobiol Aging. 1997;18:351–7.Google Scholar
17. Walsh, DM, Hartley, DM, Kusumoto, Y, et al. Amyloid beta-protein fibrillogenesis. Structure and biological activity of protofibrillar intermediates. J Biol Chem. 1999;274:25945–52.Google Scholar
18. Walsh, DM, Klyubin, I, Fadeeva, JV, et al. Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature. 2002;416:535–9.Google Scholar
19. Klein, WL, Krafft, GA, Finch, CE. Targeting small Abeta oligomers: the solution to an Alzheimer’s disease conundrum? Trends Neurosci. 2001;24:219–24.CrossRefGoogle Scholar
20. McKhann, GM, Knopman, DS, Chertkow, H, et al. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging and the Alzheimer’s Association workgroup. Alzheimers Dement. 2011;7:263–9.Google Scholar
21. Chertkow, H, Black, S. Imaging biomarkers and their role in dementia clinical trials. Can J Neurol Sci. 2007;34:S77–83.Google Scholar
22. Drzezga, A. Amyloid-plaque imaging in early and differential diagnosis of dementia. Ann Nucl Med. 2010;24:55–66.Google Scholar
23. Herholz, K, Ebmeier, K. Clinical amyloid imaging in Alzheimer’s disease. Lancet Neurol. 2011;10:667–70.CrossRefGoogle ScholarPubMed
24. Klunk, WE, Engler, H, Nordberg, A, et al. Imaging brain amyloid in Alzheimer’s disease with Pittsburgh Compound-B. Ann Neurol. 2004;55:306–19.Google Scholar
25. Shoghi-Jadid, K, Small, GW, Agdeppa, ED, et al. Localization of neurofibrillary tangles and beta-amyloid plaques in the brains of living patients with Alzheimer disease. Am J Geriatr Psychiatry. 2002;10:24–35.Google Scholar
26. Verhoeff, NP, Wilson, AA, Takeshita, S, et al. In-vivo imaging of Alzheimer disease beta-amyloid with [11C]SB-13 PET. Am J Geriatr Psychiatry. 2004;12:584–95.Google Scholar
27. Bell, RD, Zlokovic, BV. Neurovascular mechanisms and blood-brain barrier disorder in Alzheimer’s disease. Acta Neuropathol. 2009;118:103–13.Google Scholar
28. American Psychiatric Association; Diagnostic and statistical manual of mental disorders. 4th ed. Text revision. Washington, D.C.: 2000. p. 135–80.Google Scholar
29. Roman, GC, Tatemichi, TK, Erkinjuntti, T, et al. Vascular dementia: diagnostic criteria for research studies. Report of the NINDS-AIREN International Workshop. Neurology. 1993;43:250–60.Google Scholar
30. Neuropathology, Group. Medical Research Council Cognitive Function and Aging Study. Pathological correlates of late-onset dementia in a multicentre, community-based population in England and Wales. Neuropathology Group of the Medical Research Council Cognitive Function and Ageing Study (MRC CFAS). Lancet. 2001;357:169–75.Google Scholar
31. Selkoe, DJ. Toward a comprehensive theory for Alzheimer’s disease. Hypothesis: Alzheimer’s disease is caused by the cerebral accumulation and cytotoxicity of amyloid beta-protein. Ann N Y Acad Sci. 2000;924:17–25.Google Scholar
32. Mawuenyega, KG, Sigurdson, W, Ovod, V, et al. Decreased clearance of CNS beta-amyloid in Alzheimer’s disease. Science. 2010;330:1774.CrossRefGoogle ScholarPubMed
33. de la Torre, JC. Critically attained threshold of cerebral hypoperfusion: the CATCH hypothesis of Alzheimer’s pathogenesis. Neurobiol Aging. 2000;21:331–42.CrossRefGoogle ScholarPubMed
34. Canadian study of health and aging: study methods and prevalence of dementia. CMAJ 1994;150:899–913.Google Scholar
35. Breteler, MM. Vascular risk factors for Alzheimer’s disease: an epidemiologic perspective. Neurobiol Aging. 2000;21:153–60.Google Scholar
36. Jorm, AF, Korten, AE, Henderson, AS. The prevalence of dementia: a quantitative integration of the literature. Acta Psychiatr Scand. 1987;76:465–79.Google Scholar
37. Rogaeva, E, Meng, Y, Lee, JH, et al. The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease. Nat Genet. 2007;39:168–77.Google Scholar
38. Morgan, K. Commentary: the three new pathways leading to Alzheimer’s disease. Neuropathol Appl Neurobiol. 2011;37:353–7.Google Scholar
39. Menzel, HJ, Kladetzky, RG, Assmann, G. Apolipoprotein E polymorphism and coronary artery disease. Arteriosclerosis. 1983;3:310–15.Google Scholar
40. De Strooper B. Loss-of-function presenilin mutations in Alzheimer disease. Talking point on the role of presenilin mutations in Alzheimer disease. EMBO Rep. 2007;8:141–6.Google Scholar
41. Revesz, T, Holton, JL, Lashley, T, et al. Genetics and molecular pathogenesis of sporadic and hereditary cerebral amyloid angiopathies. Acta Neuropathol. 2009;118:115–30.CrossRefGoogle ScholarPubMed
42. Black, S, Iadecola, C. Vascular cognitive impairment: small vessels, big toll: introduction. Stroke. 2009;40:S38–9.Google Scholar
43. Slooter, AJ, van Duijn, CM. Genetic epidemiology of Alzheimer disease. Epidemiol Rev. 1997;19:107–19.Google Scholar
44. Farrer, LA, Cupples, LA, Haines, JL, et al. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA. 1997;278:1349–56.Google Scholar
45. Aggarwal, NT, Wilson, RS, Beck, TL, Bienias, JL, Berry-Kravis, E, Bennett, DA. The apolipoprotein E epsilon4 allele and incident Alzheimer’s disease in persons with mild cognitive impairment. Neurocase. 2005;11:3–7.Google Scholar
46. Farlow, MR, He, Y, Tekin, S, Xu, J, Lane, R, Charles, HC. Impact of APOE in mild cognitive impairment. Neurology. 2004;63: 1898–901.Google Scholar
47. Hsiung, GY, Sadovnick, AD, Feldman, H. Apolipoprotein E epsilon4 genotype as a risk factor for cognitive decline and dementia: data from the Canadian Study of Health and Aging. CMAJ. 2004; 171:863–7.Google Scholar
48. Small, BJ, Rosnick, CB, Fratiglioni, L, Backman, L. Apolipoprotein E and cognitive performance: a meta-analysis. Psychol Aging. 2004;19:592–600.CrossRefGoogle ScholarPubMed
49. Strittmatter, WJ, Weisgraber, KH, Huang, DY, et al. Binding of human apolipoprotein E to synthetic amyloid beta peptide: isoform-specific effects and implications for late-onset Alzheimer disease. Proc Natl Acad Sci USA. 1993;90:8098–102.Google Scholar
50. Blass, JP, Poirier, J. Pathophysiology of the Alzheimer syndrome. In: Gauthier, S, editor. Clinical diagnosis and management of Alzheimer’s disease. London: Martin Dunitz; 1996. p. 17–31.Google Scholar
51. van der Flier, WM, Pijnenburg, YA, Fox, NC, Scheltens, P. Early-onset versus late-onset Alzheimer’s disease: the case of the missing APOE varepsilon4 allele. Lancet Neurol. 2010;10: 280–8.Google Scholar
52. Premkumar, DR, Cohen, DL, Hedera, P, Friedland, RP, Kalaria, RN. Apolipoprotein E-epsilon4 alleles in cerebral amyloid angiopathy and cerebrovascular pathology associated with Alzheimer’s disease. Am J Pathol. 1996;148:2083–95.Google ScholarPubMed
53. Greenberg, SM, Briggs, ME, Hyman, BT, et al. Apolipoprotein E epsilon 4 is associated with the presence and earlier onset of hemorrhage in cerebral amyloid angiopathy. Stroke. 1996;27: 1333–7.Google Scholar
54. O’Donnell, HC, Rosand, J, Knudsen, KA, et al. Apolipoprotein E genotype and the risk of recurrent lobar intracerebral hemorrhage. N Engl J Med. 2000;342:240–5.Google Scholar
55. Corder, EH, Saunders, AM, Risch, NJ, et al. Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease. Nat Genet. 1994;7:180–4.Google Scholar
56. Rensink, AA, de Waal, RM, Kremer, B, Verbeek, MM. Pathogenesis of cerebral amyloid angiopathy. Brain Res Brain Res Rev. 2003; 43:207–23.Google Scholar
57. McCarron, MO, Nicoll, JA, Ironside, JW, Love, S, Alberts, MJ, Bone, I. Cerebral amyloid angiopathy-related hemorrhage. Interaction of APOE epsilon2 with putative clinical risk factors. Stroke. 1999;30:1643–6.Google Scholar
58. 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;45:1092–6.CrossRefGoogle ScholarPubMed
59. Burns, M, Duff, K. Use of in vivo models to study the role of cholesterol in the etiology of Alzheimer’s disease. Neurochem Res. 2003;28:979–86.Google Scholar
60. Kim, J, Basak, JM, Holtzman, DM. The role of apolipoprotein E in Alzheimer’s disease. Neuron. 2009;63:287–303.Google Scholar
61. Breteler, MM. Vascular involvement in cognitive decline and dementia. Epidemiologic evidence from the Rotterdam Study and the Rotterdam Scan Study. Ann, NY Acad Sci. 2000;903: 457–65.Google Scholar
62. Kivipelto, M, Helkala, EL, Laakso, MP, et al. Midlife vascular risk factors and Alzheimer’s disease in later life: longitudinal, population based study. BMJ. 2001;322:1447–51.Google Scholar
63. Pappolla, MA, Bryant-Thomas, TK, Herbert, D, et al. Mild hypercholesterolemia is an early risk factor for the development of Alzheimer amyloid pathology. Neurology. 2003;61:199–205.Google Scholar
64. Simons, M, Keller, P, De Strooper, B, Beyreuther, K, Dotti, CG, Simons, K. Cholesterol depletion inhibits the generation of beta-amyloid in hippocampal neurons. Proc Natl Acad Sci USA. 1998;95:6460–4.Google Scholar
65. Refolo, LM, Malester, B, LaFrancois, J, et al. Hypercholesterolemia accelerates the Alzheimer’s amyloid pathology in a transgenic mouse model. Neurobiol Dis. 2000;7:321–31.Google Scholar
66. Li, L, Cao, D, Garber, DW, Kim, H, Fukuchi, K. Association of aortic atherosclerosis with cerebral beta-amyloidosis and learning deficits in a mouse model of Alzheimer’s disease. Am J Pathol. 2003;163:2155–64.Google Scholar
67. Hirsch-Reinshagen, V, Maia, LF, Burgess, BL, et al. The absence of ABCA1 decreases soluble ApoE levels but does not diminish amyloid deposition in two murine models of Alzheimer disease. J Biol Chem. 2005;280:43243–56.Google Scholar
68. 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;59:223–7.Google Scholar
69. Yaffe, K, Barrett-Connor, E, Lin, F, Grady, D. Serum lipoprotein levels, statin use, and cognitive function in older women. Arch Neurol. 2002;59:378–84.CrossRefGoogle ScholarPubMed
70. Wolozin, B, Wang, SW, Li, NC, Lee, A, Lee, TA, Kazis, LE. Simvastatin is associated with a reduced incidence of dementia and Parkinson’s disease. BMC Med. 2007;5:20.Google Scholar
71. Fassbender, K, Simons, M, Bergmann, C, et al. Simvastatin strongly reduces levels of Alzheimer’s disease beta -amyloid peptides Abeta 42 and Abeta 40 in vitro and in vivo. Proc Natl Acad Sci USA. 2001;98:5856–61.Google Scholar
72. Paris, D, Townsend, KP, Obregon, DF, Humphrey, J, Mullan, M, Yokota, K. Pro-inflammatory effect of freshly solubilized beta-amyloid peptides in the brain. Prostaglandins Other Lipid Mediat. 2002;70:1–12.Google Scholar
73. Wolozin, B, Manger, J, Bryant, R, Cordy, J, Green, RC, McKee, A. Re-assessing the relationship between cholesterol, statins and Alzheimer’s disease. Acta Neurol Scand Suppl. 2006;185:63–70.Google Scholar
74. Solomon, A, Sippola, R, Soininen, H, et al. Lipid-lowering treatment is related to decreased risk of dementia: a population-based study (FINRISK). Neurodegener Dis. 2010;7:180–2.Google Scholar
75. Sparks, DL, Connor, DJ, Sabbagh, MN, Petersen, RB, Lopez, J, Browne, P. 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.Google Scholar
76. Feldman, HH, Doody, RS, Kivipelto, M, et al. Randomized controlled trial of atorvastatin in mild to moderate Alzheimer disease: LEADe. Neurology. 2010;74:956–64.CrossRefGoogle ScholarPubMed
77. Sano, M. Multi-center, randomized, double-blind, placebo-controlled trial of simvastatin to slow the progression of Alzheimer’s disease. Alzheimers Dement. 2008;4(Suppl 4): T200.Google Scholar
78. Amarenco, P, Bogousslavsky, J, Callahan, A, 3rd, et al. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med. 2006;355:549–59.Google Scholar
79. Shobab, LA, Hsiung, GY, Feldman, HH. Cholesterol in Alzheimer’s disease. Lancet Neurol. 2005;4:841–52.Google Scholar
80. Elias, MF, Wolf, PA, D’Agostino, RB, Cobb, J, White, LR. Untreated blood pressure level is inversely related to cognitive functioning: the Framingham Study. Am J Epidemiol. 1993;138:353–64.Google Scholar
81. Launer, LJ, Masaki, K, Petrovitch, H, Foley, D, Havlik, RJ. The association between midlife blood pressure levels and late-life cognitive function. The Honolulu-Asia Aging Study. JAMA. 1995;274:1846–51.Google Scholar
82. Sparks, DL, Scheff, SW, Liu, H, Landers, TM, Coyne, CM, Hunsaker, JC, 3rd. Increased incidence of neurofibrillary tangles (NFT) in non-demented individuals with hypertension. J Neurol Sci. 1995;131:162–9.Google Scholar
83. Skoog, I. Status of risk factors for vascular dementia. Neuroepidemiology. 1998;17:2–9.Google Scholar
84. Launer, LJ, Ross, GW, Petrovitch, H, et al. Midlife blood pressure and dementia: the Honolulu-Asia aging study. Neurobiol Aging. 2000;21:49–55.CrossRefGoogle ScholarPubMed
85. Petrovitch, H, White, LR, Izmirilian, G, et al. Midlife blood pressure and neuritic plaques, neurofibrillary tangles, and brain weight at death: the HAAS. Honolulu-Asia aging Study. Neurobiol Aging. 2000;21:57–62.Google Scholar
86. Forette, F, Seux, ML, Staessen, JA, et al. Prevention of dementia in randomised double-blind placebo-controlled Systolic Hypertension in Europe (Syst-Eur) trial. Lancet. 1998;352: 1347–51.CrossRefGoogle ScholarPubMed
87. Ohrui, T, Tomita, N, Sato-Nakagawa, T, et al. Effects of brain-penetrating ACE inhibitors on Alzheimer disease progression. Neurology. 2004;63:1324–5.Google Scholar
88. Birkenhager, WH, Forette, F, Staessen, JA. Dementia and antihypertensive treatment. Curr Opin Nephrol Hypertens. 2004; 13:225–30.Google Scholar
89. Hemming, ML, Selkoe, DJ. Amyloid beta-protein is degraded by cellular angiotensin-converting enzyme (ACE) and elevated by an ACE inhibitor. J Biol Chem. 2005;280:37644–50.Google Scholar
90. Kilander, L, Nyman, H, Boberg, M, Hansson, L, Lithell, H. Hypertension is related to cognitive impairment: a 20-year follow-up of 999 men. Hypertension. 1998;31:780–6.Google Scholar
91. Li, NC, Lee, A, Whitmer, RA, et al. Use of angiotensin receptor blockers and risk of dementia in a predominantly male population: prospective cohort analysis. BMJ. 2010;340:b5465.Google Scholar
92. Fournier, A, Oprisiu-Fournier, R, Serot, JM, et al. Prevention of dementia by antihypertensive drugs: how AT1-receptor-blockers and dihydropyridines better prevent dementia in hypertensive patients than thiazides and ACE-inhibitors. Expert Rev Neurother. 2009;9:1413–31.Google Scholar
93. Oprisiu-Fournier, R, Serot, JM, Achard, JM, Messerli, FH, Black, SE, Fournier, A. AT1 receptor blockers for cognition decline after cardiac surgery? Stroke. 2006;37:2666.Google Scholar
94. Leibson, CL, Rocca, WA, Hanson, VA, et al. Risk of dementia among persons with diabetes mellitus: a population-based cohort study. Am J Epidemiol. 1997;145:301–8.Google Scholar
95. Yoshitake, T, Kiyohara, Y, Kato, I, et al. Incidence and risk factors of vascular dementia and Alzheimer’s disease in a defined elderly Japanese population: the Hisayama Study. Neurology. 1995;45: 1161–8.Google Scholar
96. 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.Google Scholar
97. Ott, A, Stolk, RP, van Harskamp, F, Pols, HA, Hofman, A, Breteler, MM. Diabetes mellitus and the risk of dementia: The Rotterdam Study. Neurology. 1999;53:1937–42.Google Scholar
98. Xu, WL, von Strauss, E, Qiu, CX, Winblad, B, Fratiglioni, L. Uncontrolled diabetes increases the risk of Alzheimer’s disease: a population-based cohort study. Diabetologia. 2009;52:1031–9.Google Scholar
99. Craft, S. Insulin resistance syndrome and Alzheimer’s disease: age- and obesity-related effects on memory, amyloid, and inflammation. Neurobiol Aging. 2005;26:65–9.Google Scholar
100. Watson, GS, Peskind, ER, Asthana, S, et al. Insulin increases CSF Abeta42 levels in normal older adults. Neurology. 2003;60: 1899–903.Google Scholar
101. Gasparini, L, Gouras, GK, Wang, R, et al. Stimulation of beta-amyloid precursor protein trafficking by insulin reduces intraneuronal beta-amyloid and requires mitogen-activated protein kinase signaling. J Neurosci. 2001;21:2561–70.Google Scholar
102. Fishel, MA, Watson, GS, Montine, TJ, et al. Hyperinsulinemia provokes synchronous increases in central inflammation and beta-amyloid in normal adults. Arch Neurol. 2005;62:1539–44.Google Scholar
103. Gustafson, D, Rothenberg, E, Blennow, K, Steen, B, Skoog, I. An 18-year follow-up of overweight and risk of Alzheimer disease. Arch Intern Med. 2003;163:1524–8.Google Scholar
104. Hayden, KM, Zandi, PP, Lyketsos, CG, et al. Vascular risk factors for incident Alzheimer disease and vascular dementia: the Cache County study. Alzheimer Dis Assoc Disord. 2006;20:93–100.Google Scholar
105. Expert Panel on Detection E, and Treatment of High Blood Cholesterol in Adults. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA. 2001; 285:2486–97s.Google Scholar
106. Alexander, CM, Landsman, PB, Teutsch, SM, Haffner, SM. NCEP-defined metabolic syndrome, diabetes, and prevalence of coronary heart disease among NHANES III participants age 50 years and older. Diabetes. 2003;52:1210–14.Google Scholar
107. Razay, G, Vreugdenhil, A, Wilcock, G. The metabolic syndrome and Alzheimer disease. Arch Neurol. 2007;64:93–6.CrossRefGoogle ScholarPubMed
108. Bostom, AG, Silbershatz, H, Rosenberg, IH, et al. Nonfasting plasma total homocysteine levels and all-cause and cardiovascular disease mortality in elderly Framingham men and women. Arch Intern Med. 1999;159:1077–80.Google Scholar
109. Garcia, A. Cobalamin and homocysteine in older adults: do we need to test for serum levels in the work-up of dementia? Alzheimers Dement. 2007;3:318–24.Google Scholar
110. Bostom, AG, Rosenberg, IH, Silbershatz, H, et al. Nonfasting plasma total homocysteine levels and stroke incidence in elderly persons: the Framingham Study. Ann Intern Med. 1999;131: 352–5.Google Scholar
111. Seshadri, S, Beiser, A, Selhub, J, et al. Plasma homocysteine as a risk factor for dementia and Alzheimer’s disease. N Engl J Med. 2002;346:476–83.Google Scholar
112. Clarke, R, Smith, AD, Jobst, KA, Refsum, H, Sutton, L, Ueland, PM. Folate, vitamin B12, and serum total homocysteine levels in confirmed Alzheimer disease. Arch Neurol. 1998;55:1449–55.CrossRefGoogle ScholarPubMed
113. Garcia, A, Haron, Y, Pulman, K, Hua, L, Freedman, M. Increases in homocysteine are related to worsening of stroop scores in healthy elderly persons: a prospective follow-up study. J Gerontol A Biol Sci Med Sci. 2004;59:1323–7.Google Scholar
114. Garcia, A, Zanibbi, K. Homocysteine and cognitive function in elderly people. CMAJ. 2004;171:897–904.CrossRefGoogle ScholarPubMed
115. Lee, PN. Smoking and Alzheimer’s disease: a review of the epidemiological evidence. Neuroepidemiology. 1994;13:131–44.Google Scholar
116. Aggarwal, NT, Bienias, JL, Bennett, DA, et al. The relation of cigarette smoking to incident Alzheimer’s disease in a biracial urban community population. Neuroepidemiology. 2006;26: 140–6.Google Scholar
117. Sacco, KA, Bannon, KL, George, TP. Nicotinic receptor mechanisms and cognition in normal states and neuropsychiatric disorders. J Psychopharmacol. 2004;18:457–74.Google Scholar
118. Hellstrom-Lindahl, E, Mousavi, M, Ravid, R, Nordberg, A. Reduced levels of Abeta 40 and Abeta 42 in brains of smoking controls and Alzheimer’s patients. Neurobiol Dis. 2004;15:351–60.Google Scholar
119. Verhoeff, NP. Acetylcholinergic neurotransmission and the beta-amyloid cascade: implications for Alzheimer’s disease. Expert Rev Neurother. 2005;5:277–84.Google Scholar
120. Black, SE, Patterson, C, Feightner, J. Preventing dementia. Can J Neurol Sci. 2001;28 Suppl 1:S56–66.Google Scholar
121. Patterson, C, Feightner, J, Garcia, A, MacKnight, C. General risk factors for dementia: a systematic evidence review. Alzheimers Dement. 2007;3:341–7.Google Scholar
122. Patterson, C, Feightner, JW, Garcia, A, Hsiung, GY, MacKnight, C, Sadovnick, AD. Diagnosis and treatment of dementia: 1. Risk assessment and primary prevention of Alzheimer disease. CMAJ. 2008;178:548–56.CrossRefGoogle ScholarPubMed
123. Roher, AE, Esh, C, Kokjohn, TA, et al. Circle of Willis atherosclerosis is a risk factor for sporadic Alzheimer’s disease. Arterioscler Thromb Vasc Biol. 2003;23:2055–62.Google Scholar
124. Roher, AE, Esh, C, Rahman, A, Kokjohn, TA, Beach, TG. Atherosclerosis of cerebral arteries in Alzheimer disease. Stroke. 2004;35:2623–7.Google Scholar
125. Honig, LS, Kukull, W, Mayeux, R. Atherosclerosis and AD: analysis of data from the US National Alzheimer’s Coordinating Center. Neurology. 2005;64:494–500.Google Scholar
126. Hofman, A, Ott, A, Breteler, MM, et al. Atherosclerosis, apolipoprotein E, and prevalence of dementia and Alzheimer’s disease in the Rotterdam Study. Lancet. 1997;349:151–4.Google Scholar
127. Belohlavek, M, Jiamsripong, P, Calleja, AM, et al. Patients with Alzheimer disease have altered transmitral flow: echocardiographic analysis of the vortex formation time. J Ultrasound Med. 2009;28:1493–500.Google Scholar
128. Pettersen, JA, Gao, FQ, Black, SE. Carotid artery bifurcation tortuosity as a possible contributor to substantia innominata atrophy and executive dysfunction in Alzheimer disease. Stroke. 2008;39:682–3.Google Scholar
129. Holland, CM, Smith, EE, Csapo, I, et al. Spatial distribution of white-matter hyperintensities in Alzheimer disease, cerebral amyloid angiopathy, and healthy aging. Stroke. 2008;39:1127–33.Google Scholar
130. Roher, AE, Kuo, YM, Esh, C, et al. Cortical and leptomeningeal cerebrovascular amyloid and white matter pathology in Alzheimer’s disease. Mol Med 2003;9:112–22.Google Scholar
131. Black, S, Gao, F, Bilbao, J. Understanding white matter disease: imaging-pathological correlations in vascular cognitive impairment. Stroke. 2009;40:S48–52.Google Scholar
132. Moody, DM, Brown, WR, Challa, VR, Anderson, RL. Periventricular venous collagenosis: association with leukoaraiosis. Radiology. 1995;194:469–76.Google Scholar
133. Heyman, A, Fillenbaum, GG, Welsh-Bohmer, KA, et al. Cerebral infarcts in patients with autopsy-proven Alzheimer’s disease: CERAD, part XVIII. Consortium to Establish a Registry for Alzheimer’s Disease. Neurology. 1998;51:159–62.Google Scholar
134. Zekry, D, Duyckaerts, C, Belmin, J, Geoffre, C, Moulias, R, Hauw, JJ. Cerebral amyloid angiopathy in the elderly: vessel walls changes and relationship with dementia. Acta Neuropathol (Berl). 2003; 106:367–73.Google Scholar
135. Koistinaho, M, Koistinaho, J. Interactions between Alzheimer’s disease and cerebral ischemia-focus on inflammation. Brain Res Brain Res Rev. 2005;48:240–50.Google Scholar
136. Whitehead, SN, Hachinski, VC, Cechetto, DF. Interaction between a rat model of cerebral ischemia and beta-amyloid toxicity: inflammatory responses. Stroke. 2005;36:107–12.Google Scholar
137. Pluta, R, Barcikowska, M, Misicka, A, Lipkowski, AW, Spisacka, S, Januszewski, S. Ischemic rats as a model in the study of the neurobiological role of human beta-amyloid peptide. Time-dependent disappearing diffuse amyloid plaques in brain. Neuroreport. 1999;10:3615–19.Google Scholar
138. Pratico, D. Peripheral biomarkers of oxidative damage in Alzheimer’s disease: the road ahead. Neurobiol Aging. 2005;26: 581–3.Google Scholar
139. Crack, PJ, Taylor, JM. Reactive oxygen species and the modulation of stroke. Free Radic Biol Med. 2005;38:1433–44.Google Scholar
140. Migliore, L, Fontana, I, Trippi, F, et al. Oxidative DNA damage in peripheral leukocytes of mild cognitive impairment and AD patients. Neurobiol Aging. 2005;26:567–73.Google Scholar
141. Iadecola, C, Zhang, F, Niwa, K, et al. SOD1 rescues cerebral endothelial dysfunction in mice overexpressing amyloid precursor protein. Nat Neurosci. 1999;2:157–61.Google Scholar
142. Banati, RB, Gehrmann, J, Wiessner, C, Hossmann, KA, Kreutzberg, GW. Glial expression of the beta-amyloid precursor protein (APP) in global ischemia. J Cereb Blood Flow Metab. 1995;15: 647–54.Google Scholar
143. Yokota, M, Saido, TC, Tani, E, Yamaura, I, Minami, N. Cytotoxic fragment of amyloid precursor protein accumulates in hippocampus after global forebrain ischemia. J Cereb Blood Flow Metab. 1996;16:1219–23.Google Scholar
144. DeKosky, ST, Ikonomovic, MD, Wang, X, et al. Plasma and cerebrospinal fluid alpha1-antichymotrypsin levels in Alzheimer’s disease: correlation with cognitive impairment. Ann Neurol. 2003;53:81–90.Google Scholar
145. Townsend, KP, Pratico, D. Novel therapeutic opportunities for Alzheimer’s disease: focus on nonsteroidal anti-inflammatory drugs. Faseb J. 2005;19:1592–601.Google Scholar
146. Arvanitakis, Z, Grodstein, F, Bienias, JL, et al. Relation of NSAIDs to incident AD, change in cognitive function, and AD pathology. Neurology. 2008;70:2219–25.Google Scholar
147. Breitner, JC, Haneuse, SJ, Walker, R, et al. Risk of dementia and AD with prior exposure to NSAIDs in an elderly community-based cohort. Neurology. 2009;72:1899–905.Google Scholar
148. Sonnen, JA, Larson, EB, Walker, RL, et al. Nonsteroidal anti-inflammatory drugs are associated with increased neuritic plaques. Neurology. 2010;75:1203–10.Google Scholar
149. Bateman, RJ, Munsell, LY, Morris, JC, Swarm, R, Yarasheski, KE, Holtzman, DM. Human amyloid-beta synthesis and clearance rates as measured in cerebrospinal fluid in vivo. Nat Med. 2006; 12:856–61.CrossRefGoogle Scholar
150. Claassen, JA, Jansen, RW. Cholinergically mediated augmentation of cerebral perfusion in Alzheimer’s disease and related cognitive disorders: the cholinergic-vascular hypothesis. J Gerontol A Biol Sci Med Sci. 2006;61:267–71.Google Scholar
151. Aucoin, JS, Jiang, P, Aznavour, N, et al. Selective cholinergic denervation, independent from oxidative stress, in a mouse model of Alzheimer’s disease. Neuroscience. 2005;132:73–86.Google Scholar
152. Minoshima, S, Giordani, B, Berent, S, Frey, KA, Foster, NL, Kuhl, DE. Metabolic reduction in the posterior cingulate cortex in very early Alzheimer’s disease. Ann Neurol. 1997;42:85–94.Google Scholar
153. Nagata, K, Sato, M, Satoh, Y, et al. Hemodynamic aspects of Alzheimer’s disease. Ann N Y Acad Sci. 2002;977:391–402.Google Scholar
154. Serpell, LC. Alzheimer’s amyloid fibrils: structure and assembly. Biochim Biophys Acta. 2000;1502:16–30.Google Scholar
155. Qi-Takahara, Y, Morishima-Kawashima, M, Tanimura, Y, et al. Longer forms of amyloid beta protein: implications for the mechanism of intramembrane cleavage by gamma-secretase. J Neurosci. 2005;25:436–45.Google Scholar
156. Hardy, J. Amyloid, the presenilins and Alzheimer’s disease. Trends Neurosci. 1997;20:154–9.Google Scholar
157. Hyman, BT, West, HL, Rebeck, GW, Lai, F, Mann, DM. Neuropathological changes in Down’s syndrome hippocampal formation. Effect of age and apolipoprotein E genotype. Arch Neurol. 1995;52:373–8.Google Scholar
158. De Strooper, B, Saftig, P, Craessaerts, K, et al. Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature. 1998;391:387–90.Google Scholar
159. Lue, LF, Kuo, YM, Roher, AE, et al. Soluble amyloid beta peptide concentration as a predictor of synaptic change in Alzheimer’s disease. Am J Pathol. 1999;155:853–62.Google Scholar
160. Berg, L, McKeel, DW Jr, Miller, JP, et al. Clinicopathologic studies in cognitively healthy aging and Alzheimer’s disease: relation of histologic markers to dementia severity, age, sex, and apolipoprotein E genotype. Arch Neurol. 1998;55:326–35.Google Scholar
161. Klein, WL, Stine, WB Jr, Teplow, DB. Small assemblies of unmodified amyloid beta-protein are the proximate neurotoxin in Alzheimer’s disease. Neurobiol Aging. 2004;25:569–80.Google Scholar
162. Walsh, DM, Lomakin, A, Benedek, GB, Condron, MM, Teplow, DB. Amyloid beta-protein fibrillogenesis. Detection of a protofibrillar intermediate. J Biol Chem. 1997;272:22364–72.Google Scholar
163. Bitan, G, Kirkitadze, MD, Lomakin, A, Vollers, SS, Benedek, GB, Teplow, DB. Amyloid beta -protein (Abeta) assembly: Abeta 40 and Abeta 42 oligomerize through distinct pathways. Proc Natl Acad Sci USA. 2003;100:330–5.Google Scholar
164. Gorman, PM, Yip, CM, Fraser, PE, Chakrabartty, A. Alternate aggregation pathways of the Alzheimer beta-amyloid peptide: Abeta association kinetics at endosomal pH. J Mol Biol. 2003; 325:743–57.Google Scholar
165. Huang, TH, Yang, DS, Fraser, PE, Chakrabartty, A. Alternate aggregation pathways of the Alzheimer beta-amyloid peptide. An in vitro model of preamyloid. J Biol Chem. 2000;275: 36436–40.Google Scholar
166. Petersen, RC, Parisi, JE, Dickson, DW, et al. Neuropathologic features of amnestic mild cognitive impairment. Arch Neurol. 2006;63:665–72.Google Scholar
167. Hartley, DM, Walsh, DM, Ye, CP, et al. Protofibrillar intermediates of amyloid beta-protein induce acute electrophysiological changes and progressive neurotoxicity in cortical neurons. J Neurosci. 1999;19:8876–84.Google Scholar
168. Cleary, JP, Walsh, DM, Hofmeister, JJ, et al. Natural oligomers of the amyloid-beta protein specifically disrupt cognitive function. Nat Neurosci. 2005;8:79–84.Google Scholar
169. Morimoto, A, Irie, K, Murakami, K, et al. Aggregation and neurotoxicity of mutant amyloid beta (A beta) peptides with proline replacement: importance of turn formation at positions 22 and 23. Biochem Biophys Res Commun. 2002;295:306–11.Google Scholar
170. Weller, RO, Boche, D, Nicoll, JA. Microvasculature changes and cerebral amyloid angiopathy in Alzheimer’s disease and their potential impact on therapy. Acta Neuropathol. 2009;118: 87–102.Google Scholar
171. Herzig, MC, Winkler, DT, Burgermeister, P, et al. Abeta is targeted to the vasculature in a mouse model of hereditary cerebral hemorrhage with amyloidosis. Nat Neurosci. 2004;7:954–60.Google Scholar
172. Fryer, JD, Simmons, K, Parsadanian, M, et al. Human apolipoprotein E4 alters the amyloid-beta 40:42 ratio and promotes the formation of cerebral amyloid angiopathy in an amyloid precursor protein transgenic model. J Neurosci. 2005;25: 2803–10.Google Scholar
173. Thal, DR, Griffin, WS, de Vos, RA, Ghebremedhin, E. Cerebral amyloid angiopathy and its relationship to Alzheimer’s disease. Acta Neuropathol. 2008;115:599–609.Google Scholar
174. Pettersen, JA, Sathiyamoorthy, G, Gao, FQ, et al. Microbleed topography, leukoaraiosis, and cognition in probable Alzheimer disease from the Sunnybrook dementia study. Arch Neurol. 2008;65:790–5.Google Scholar
175. Johnson, KA, Gregas, M, Becker, JA, et al. Imaging of amyloid burden and distribution in cerebral amyloid angiopathy. Ann Neurol. 2007;62:229–34.Google Scholar
176. Greenberg, SM, Vernooij, MW, Cordonnier, C, et al. Cerebral microbleeds: a guide to detection and interpretation. Lancet Neurol. 2009;8:165–74.Google Scholar
177. Kalaria, RN. The blood-brain barrier and cerebrovascular pathology in Alzheimer’s disease. Ann N Y Acad Sci. 1999;893:113–25.Google Scholar
178. Nalivaevaa, NN, Fisk, L, Kochkina, EG, et al. Effect of hypoxia/ischemia and hypoxic preconditioning/reperfusion on expression of some amyloid-degrading enzymes. Ann NY Acad Sci. 2004;1035:21–33.Google Scholar
179. Smith, EE, Greenberg, SM. Beta-amyloid, blood vessels, and brain function. Stroke. 2009;40:2601–6.Google Scholar
180. Nicoll, JA, Yamada, M, Frackowiak, J, Mazur-Kolecka, B, Weller, RO. Cerebral amyloid angiopathy plays a direct role in the pathogenesis of Alzheimer’s disease. Pro-CAA position statement. Neurobiol Aging. 2004;25:589–97.Google Scholar
181. Attems, J, Jellinger, KA. Only cerebral capillary amyloid angiopathy correlates with Alzheimer pathology-a pilot study. Acta Neuropathol (Berl). 2004;107:83–90.Google Scholar
182. Christie, R, Yamada, M, Moskowitz, M, Hyman, B. Structural and functional disruption of vascular smooth muscle cells in a transgenic mouse model of amyloid angiopathy. Am J Pathol. 2001;158:1065–71.Google Scholar
183. Chen, K, Ayutyanont, N, Langbaum, JB, et al. Characterizing Alzheimer’s disease using a hypometabolic convergence index. Neuroimage. 2011;56:52–60.Google Scholar
184. Jagust, W, Reed, B, Mungas, D, Ellis, W, Decarli, C. What does fluorodeoxyglucose PET imaging add to a clinical diagnosis of dementia? Neurology. 2007;69:871–7.Google Scholar
185. Agdeppa, ED, Kepe, V, Liu, J, et al. 2-Dialkylamino-6-acylmalononitrile substituted naphthalenes (DDNP analogs): novel diagnostic and therapeutic tools in Alzheimer’s disease. Mol Imaging Biol. 2003;5:404–17.Google Scholar
186. Verhoeff, NPLG. Amyloid imaging in vivo: implications for Alzheimer’s disease management. Expert Opinion on Medical Diagnostics. 2007;1:337–49.Google Scholar
187. Vandenberghe, R, Van Laere, K, Ivanoiu, A, et al. 18F-flutemetamol amyloid imaging in Alzheimer disease and mild cognitive impairment: a phase 2 trial. Ann Neurol. 2010;68:319–29.Google Scholar
188. Barthel, H, Gertz, HJ, Dresel, S, et al. Cerebral amyloid-beta PET with florbetaben (18F) in patients with Alzheimer’s disease and healthy controls: a multicentre phase 2 diagnostic study. Lancet Neurol. 2011;10:424–35.Google Scholar
189. Clark, CM, Schneider, JA, Bedell, BJ, et al. Use of florbetapir-PET for imaging beta-amyloid pathology. JAMA. 2011;305:275–83.Google Scholar
190. Choi, SR, Schneider, JA, Bennett, DA, et al. Correlation of amyloid PET ligand florbetapir F 18 binding with Abeta aggregation and neuritic plaque deposition in postmortem brain tissue. Alzheimer Dis Assoc Disord. 2012;26:8–16.Google Scholar
191. FDA Approves 18F-Florbetapir PET Agent. J Nucl Med. 2012; 53:15N.Google Scholar
192. Wengenack, TM, Jack, CR Jr, Garwood, M, Poduslo, JF. MR microimaging of amyloid plaques in Alzheimer’s disease transgenic mice. Eur J Nucl Med Mol Imaging. 2008;35 Suppl 1:S82–8.Google Scholar
193. Nakada, T, Matsuzawa, H, Igarashi, H, Fujii, Y, Kwee, IL. In vivo visualization of senile-plaque-like pathology in Alzheimer’s disease patients by MR microscopy on a 7T system. J Neuroimaging. 2008;18:125–9.Google Scholar
194. Braak, H, Braak, E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol (Berl). 1991;82:239–59.Google Scholar
195. Thal, DR, Rub, U, Schultz, C, et al. Sequence of Abeta-protein deposition in the human medial temporal lobe. J Neuropathol Exp Neurol. 2000;59:733–48.Google Scholar
196. Thal, DR, Rub, U, Orantes, M, Braak, H. Phases of A beta-deposition in the human brain and its relevance for the development of AD. Neurology. 2002;58:1791–800.Google Scholar
197. McGowan, E, Sanders, S, Iwatsubo, T, et al. Amyloid phenotype characterization of transgenic mice overexpressing both mutant amyloid precursor protein and mutant presenilin 1 transgenes. Neurobiol Dis. 1999;6:231–44.Google Scholar
198. Price, JC, Klunk, WE, Lopresti, BJ, et al. Kinetic modeling of amyloid binding in humans using PET imaging and Pittsburgh Compound-B. J Cereb Blood Flow Metab. 2005;25:1528–47.Google Scholar
199. Jack, CR Jr, Lowe, VJ, Weigand, SD, et al. Serial PIB and MRI in normal, mild cognitive impairment and Alzheimer’s disease: implications for sequence of pathological events in Alzheimer’s disease. Brain. 2009;132:1355–65.Google Scholar
200. Jack, CR Jr, Wiste, HJ, Vemuri, P, et al. Brain beta-amyloid measures and magnetic resonance imaging atrophy both predict time-to-progression from mild cognitive impairment to Alzheimer’s disease. Brain. 2010;133:3336–48.Google Scholar
201. Rowe, CC, Villemagne, VL. Brain amyloid imaging. J Nucl Med. 2011;52:1733–40.Google Scholar
202. Villain, N, Chetelat, G, Grassiot, B, et al. Regional dynamics of amyloid-beta deposition in healthy elderly, mild cognitive impairment and Alzheimer’s disease: a voxelwise PiB-PET longitudinal study. Brain. 2012 (Epub ahead of print).Google Scholar
203. Rinne, JO, Brooks, DJ, Rossor, MN, et al. 11C-PiB PET assessment of change in fibrillar amyloid-beta load in patients with Alzheimer’s disease treated with bapineuzumab: a phase 2, double-blind, placebo-controlled, ascending-dose study. Lancet Neurol. 2010;9:363–72.Google Scholar
204. Viswanathan, A, Chabriat, H. Cerebral microhemorrhage. Stroke. 2006;37:550–5.Google Scholar
205. Vardy, ER, Hussain, I, Hooper, NM. Emerging therapeutics for Alzheimer’s disease. Expert Rev Neurother. 2006;6:695–704.Google Scholar
206. Townsend, M. When will Alzheimer’s Disease be cured? A pharmaceutical perspective. J Alzheimers Dis. 2011;24:43–52.Google Scholar
207. Wilcock, GK, Black, SE, Hendrix, SB, Zavitz, KH, Swabb, EA, Laughlin, MA. Efficacy and safety of tarenflurbil in mild to moderate Alzheimer’s disease: a randomised phase II trial. Lancet Neurol. 2008;7:483–93.Google Scholar
208. Green, RC, Schneider, LS, Amato, DA, et al. Effect of tarenflurbil on cognitive decline and activities of daily living in patients with mild Alzheimer disease: a randomized controlled trial. JAMA. 2009;302:2557–64.Google Scholar
209. Geerts, H. NC-531 (Neurochem). Curr Opin Investig Drugs. 2004;5: 95–100.Google Scholar
210. McLaurin, J, Kierstead, ME, Brown, ME, et al. Cyclohexanehexol inhibitors of Abeta aggregation prevent and reverse Alzheimer phenotype in a mouse model. Nat Med. 2006;12:801–8.Google Scholar
211. Janus, C, Pearson, J, McLaurin, J, et al. A beta peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer’s disease. Nature. 2000;408:979–82.Google Scholar
212. Schenk, D, Barbour, R, Dunn, W, et al. Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature. 1999;400:173–7.Google Scholar
213. Pfeifer, M, Boncristiano, S, Bondolfi, L, et al. Cerebral hemorrhage after passive anti-Abeta immunotherapy. Science. 2002;298: 1379.Google Scholar
214. Nicoll, JA, Wilkinson, D, Holmes, C, Steart, P, Markham, H, Weller, RO. Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: a case report. Nat Med. 2003;9:448–52.Google Scholar
215. Orgogozo, JM, Gilman, S, Dartigues, JF, et al. Subacute meningoencephalitis in a subset of patients with AD after Abeta42 immunization. Neurology. 2003;61:46–54.Google Scholar
216. 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: 216–23.Google Scholar
217. Delrieu, J, Ousset, PJ, Caillaud, C, Vellas, B. ‘Clinical trials in Alzheimer’s disease’: immunotherapy approaches. J Neurochem. 2012;120 Suppl 1:186–93.Google Scholar
218. Sperling, RA, Aisen, PS, Beckett, LA, et al. Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7:280–92.Google Scholar