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Risk Profiles of Alzheimer Disease

Published online by Cambridge University Press:  02 December 2014

Melanie Bilbul  and
Hyman M. Schipper
Melanie Bilbul
Affiliation:
Centre for Neurotranslational Research, Lady Davis Institute for Medical Research, Jewish General Hospital, Department of Neurology & Neurosurgery, McGill University, Montreal, Quebec, Canada
Hyman M. Schipper*
Affiliation:
Centre for Neurotranslational Research, Lady Davis Institute for Medical Research, Jewish General Hospital, Department of Neurology & Neurosurgery, McGill University, Montreal, Quebec, Canada
*
Lady Davis Institute Jewish General Hospital, 3755 Cote St. Catherine Road, Montreal, Quebec, H3T 1E2, Canada
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Abstract

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Alzheimer disease (AD) is a dementing, neurodegenerative disorder that affects approximately 500,000 Canadians and its prevalence is expected to double over the next 30 years. Although several medications may temporarily augment cognitive abilities in AD, there presently exists no proven method to avoid the inevitable clinical deterioration in this devastating condition. The delineation of risk factors for the development of AD offers hope for the advent of effective prevention or interventions that might retard the onset of symptoms. In this article, we provide a comprehensive review of midlife risk factors implicated in the etiopathogenesis of sporadic AD. Although some risk factors are heritable and largely beyond our control, others are determined by lifestyle or environment and are potentially modifiable. In a companion paper, we introduce the concept of an Alzheimer Risk Assessment Clinic for ascertainment and mitigation of these and other putative dementia risk factors in middle-aged adults.

Type
Review Article
Information
Canadian Journal of Neurological Sciences , Volume 38 , Issue 4 , July 2011 , pp. 580 - 592
Copyright
Copyright © The Canadian Journal of Neurological 2011

References

1.Selkoe, DJ.The molecular pathology of Alzheimer’s disease. Neuron. 1991;6(4):487–98.CrossRefGoogle ScholarPubMed
2.Rising tide: The impact of dementia on Canadian society: Alzheimer Society of Canada, 2010. http://www.alzheimer.caGoogle Scholar
3.Khachaturian, ZS.A roadmap for the prevention of dementia II: Leon Thal Symposium 2008. Alzheimer Dement. 2009;5(2):85–92.CrossRefGoogle ScholarPubMed
4.Khachaturian, ZS, Khachaturian, AS.Prevent Alzheimer’s disease by 2020: a national strategic goal. Alzheimer Dement. 2009; 5(2):81–4.Google Scholar
5.Schipper, HM, Liberman, A, Kelner, N, et al.ARAC - The Montreal Jewish General Hospital Alzheimer Risk Assessment Clinic. Can J Neurol Sci. 2011;38(4):600–11.Google Scholar
6.Farrer, LA, O’Sullivan, DM, Cupples, LA, Growdon, JH, Myers, RH.Assessment of genetic risk for Alzheimer’s disease among firstdegree relatives. Ann Neurol. 2004;25(5):485–93.Google Scholar
7.Gatz, M, Pedersen, NL, Berg, S, et al.Heritability for Alzheimer’s disease: the study of dementia in Swedish twins. J Gerontol. 1997;52A(2):M117–25.Google Scholar
8.Mann, DMA.Alzheimer’s disease and Down’s syndrome. Histopathology. 1983;13:125–37.Google Scholar
9.Lott, IT, Osann, K, Doran, E, Nelson, L.Down syndrome and Alzheimer disease: response to donepezil. Arch Neurol. 2002; 59(7):1133–6.Google Scholar
10.Rogaev, EI, Sherrington, R, Rogaeva, EA, et al.Familial Alzheimer’s disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer’s disease type 3 gene. Nature. 1995;376(6543):775–8.Google Scholar
11.Rogaeva, E, Tandon, A, George-Hyslop, PHS.Genetic markers in the diagnosis of Alzheimer’s disease. J Alzheimers Dis. 2001;3 (3):293.CrossRefGoogle ScholarPubMed
12.Li, WH, Tanimura, M, Luo, CC, Datta, S, Chan, L.The apolipoprotein multigene family: biosynthesis, structure, structure-function relationships, and evolution. J Lipid Res. 1988;29(3):245–71.Google Scholar
13.Zhong, N, Weisgraber, KH.Understanding the association of Apolipoprotein E4 with Alzheimer disease: clues from its structure. J Biol Chem. 2009;284:6027–31.Google Scholar
14.Weisgraber, K.Apolipoprotein E distribution among human plasma lipoproteins: role of the cysteine-arginine interchange at residue 112. J Lipid Res. 1990;31:1503–11.CrossRefGoogle ScholarPubMed
15.Weisgraber, KH, Shinto, LH.Identification of the disulfide-linked homodimer of apolipoprotein E3 in plasma. Impact on receptor binding activity. J Biol Chem. 1991;266:12029–34.Google ScholarPubMed
16.Hsiung, G-YR, Sadovnick, AD.Genetics and dementia: risk factors, diagnosis, and management. Alzheimers Dementia. 2007;3(4): 418–27.Google Scholar
17.Schipper, HM.Apolipoprotein E: Implications for AD neurobiology, epidemiology and risk assessment. Neurobiol Aging. doi:10. 1016/j.neurobiolaging.2009.04.021Google Scholar
18.Corder, EH, Saunders, AM, Strittmatter, WJ, et al.Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science. 1993;261(5123):921–3.Google Scholar
19.Fleisher, A, Grundman, M, Clifford, RJ, et al.Sex, apolipoprotein E {varepsilon}4 status, and hippocampal volume in mild cognitive impairment. Arch Neurol. 2005;62(6):953–7.Google Scholar
20.Mortensen, EL, Høgh, P.A gender difference in the association between APOE genotype and age-related cognitive decline. Neurology. 2001;57:89–95.CrossRefGoogle ScholarPubMed
21.Harris, FM, Brecht, WJ, Xu, Q, et al.Carboxyl-terminal-truncated apolipoprotein E4 causes Alzheimer’s disease-like neurodegeneration and behavioral deficits in transgenic mice. Proc Natl Acad Sci. 2003;100(19):10966–71.CrossRefGoogle ScholarPubMed
22.Bennett, DA, Wilson, RS, Schneider, JA, et al.Apolipoprotein E {epsilon} 4 allele, AD pathology, and the clinical expression of Alzheimer’s disease. Neurology. 2003;60(2):246–52.Google Scholar
23.Acharya, P, Segall, ML, Zaiou, M, et al.Comparison of the stabilities and unfolding pathways of human apolipoprotein E isoforms by differential scanning calorimetry and circular dichroism. Biochim Biophys Acta. 2002;1584(1):9–19.Google Scholar
24.Raber, J, Huang, Y, Ashford, J.ApoE genotype accounts for a vast majority of AD risk and AD pathology. Neurobiol Aging. 2004; 25:641–50.Google Scholar
25.Moreira, P, Honda, K, Liu, Q, et al.Oxidative stress: the old enemy in Alzheimer’s disease pathophysiology. Curr Alzheimer Res. 2005;2(4):403–8.Google Scholar
26.Schipper, HM.Brain iron deposition and the free radical-mitochondrial theory of ageing. Ageing Res Rev. 2004;3: 265–301.Google Scholar
27.Tchaikovskaya, T, Fraifeld, V, Urphanishvili, T, Andorfer, JH, Davies, P, Listowsky, I.Glutathione S-transferase hGSTM3 and ageing-associated neurodegeneration: relationship to Alzheimer’s disease. Mech Ageing Dev. 2005;126(2):309–15.Google Scholar
28.Maes, OC, Schipper, HM, Chong, G, Chertkow, HM, Wang, E.A GSTM3 polymorphism associated with an etiopathogenetic mechanism in Alzheimer disease. Neurobiol Aging. 2010;31(1): 34–45.CrossRefGoogle ScholarPubMed
29.Moalem, S, Percy, ME, Andrews, DF, et al.Are hereditary hemochromatosis mutations involved in Alzheimer disease? Am J Medical Genet. 2000;93(1):58–86.Google Scholar
30.Sampietro, M, Caputo, L, Casatta, A, et al.The hemochromatosis gene affects the age of onset of sporadic Alzheimer’s disease. Neurobiol Aging. 2001;22(4):563–8.CrossRefGoogle ScholarPubMed
31.Pulliam, JF, Jennings, CD, Kryscio, RJ, et al.Association of HFE mutations with neurodegeneration and oxidative stress in Alzheimer’s disease and correlation with APOE. Am J Medical Genet. 2003;119B(1):48–53.CrossRefGoogle ScholarPubMed
32.Berlin, D, Chong, G, Chertkow, H, Bergman, H, Phillips, NA, Schipper, HM.Evaluation of HFE (hemochromatosis) mutations as genetic modifiers in sporadic AD and MCI. Neurobiol Aging. 2004;25(4):465–74.Google Scholar
33.Zatta, P, Messori, L, Mauri, P, et al.The C2 variant of human serum transferrin retains the iron binding properties of the native protein. Biochim Biophys Acta. 2005;1741(3):264–70.Google Scholar
34.Zambenedetti, P, Bellis, GD, Biunno, I, Musicco, M, Zattac, P.Transferrin C2 variant does confer a risk for Alzheimer’s disease in caucasians. J Alzheimers Dis. 2003; 5(6):423–7.Google Scholar
35.Van Rensburg, SJ, Potocnik, FCV, Villiers, JNPd, Kotze, MJ, Taljaard, JJF.Earlier age of onset of Alzheimer’s disease in patients with both the transferrin C2 and apolipoprotein Epsilon 4 alleles. Ann NY Acad. Sci. 2000;903:200–3.Google Scholar
36.Katzov, H, Chalmers, K, Palmgren, J, et al.Genetic variants of ABCA1 modify Alzheimer disease risk and quantitative traits related to beta-amyloid metabolism. Hum Mutat. 2004;23(4): 358–67.Google Scholar
37.Mace, S, Cousin, E, Ricard, S, et al.ABCA2 is a strong genetic risk factor for early-onset Alzheimer’s disease. Neurobiol Dis. 2005; 18(1):119–25.Google Scholar
38.Li, Y, Nowotny, P, Holmans, P, et al.Association of late-onset Alzheimer’s disease with genetic variation in multiple members of the GAPD gene family. Proc Natl Acad Sci USA. 2004;101 (44):15688–93.CrossRefGoogle ScholarPubMed
39.Lio, D, Licastro, F, Scola, L, et al.Interleukin-10 promoter polymorphism in sporadic Alzheimer’s disease. Genes Immun. 2003;4(3):234–8.Google Scholar
40.Feher, A, Juhasz, A, Rimanoczy, A, Kalman, J, Janka, Z.Association between BDNF Val66Met polymorphism andAlzheimer disease, dementia with Lewy bodies, and Pick disease. Alzheimer Dis Assoc Disord. 2009;23(3):224–8.Google Scholar
41.Ertekin-Taner, N, Allen, M, Fadale, D, et al.Genetic variants in a haplotype block spanning IDE are significantly associated with plasma Abeta42 levels and risk for Alzheimer disease. Hum Mutat. 2004;23(4):334–42.CrossRefGoogle Scholar
42.Roses, AD, Lutz, MW, Amrine-Madsen, H, et al.A TOMM40 variable-length polymorphism predicts the age of late-onset Alzheimer’s disease. Pharmacogenomics J. 2009.Google Scholar
43.Harold, D, Abraham, R, Hollingworth, P, et al.Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer’s disease. Nat Genet. 2009;41(10): 1088–93.Google Scholar
44.Kivipelto, M, Ngandu, T, Laatikainen, T, Winblad, B, Soininen, H, Tuomilehto, J.Risk score for the prediction of dementia risk in 20 years among middle aged people: a longitudinal, population-based study. Lancet Neurol. 2006;5(9):735–41.Google Scholar
45.Kivipelto, M, Helkala, EL, Laakso, MP, et al.Midlife vascular risk factors and Alzheimer’s disease in later life: longitudinal, population based study. Brit Med J. 2001;322:1447–51.Google Scholar
46.Vermeer, S, Koudstaal, P, Oudkerk, M, Hofman, A, Breteler, M.Prevalence and risk factors of silent brain infarcts in the population-based Rotterdam Scan Study. Stroke. 2002;33: 1179–80.Google Scholar
47.Waldstein, SR, Siegel, EL, Lefkowitz, D, et al.Stress-induced blood pressure reactivity and silent cerebrovascular disease. Stroke. 2004;(35):1294–8.Google Scholar
48.Petrovitch, H, White, LR, Izmiriliand, G, et al.Midlife blood pressure and neuritic plaques, neurofibrillary tangles, and brain weight at death: the HAAS. Neurobiol Aging. 2000;21(1):57–62.Google Scholar
49.Tzourio, C, Anderson, C, Chapman, N, et al.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(9):1069–75.Google Scholar
50.Whitmer, RA, Sidney, S, Selby, J, Johnston, SC, Yaffe, K.Midlife cardiovascular risk factors and risk of dementia in late life. Neurology. 2005;64(2):277–81.Google Scholar
51.Kalaria, RN.The role of cerebral ischemia in Alzheimer’s disease. Neurobiol Aging. 2000;21:321–30.Google Scholar
52.Kadotani, H, Kadotani, T, Young, T, et al.Association between apolipoprotein E {epsilon}4 and sleep-disordered breathing in adults. J Am Med Assoc. 2001;285(22):2888–90.Google Scholar
53.Guo, X, Waern, M, Sjögren, K, et al.Midlife respiratory function and incidence of Alzheimer’s disease: A 29-year longitudinal study in women. Neurobiol Aging. 2007;28(3):343–50.Google Scholar
54.Cosentino, FII, Bosco, P, Drago, V, et al.The APOE [epsilon]4 allele increases the risk of impaired spatial working memory in obstructive sleep apnea. Sleep Medicine. 2008;9(8):831–9.Google Scholar
55.Gottlieb, DJ, DeStefano, AL, Foley, DJ, et al.APOE ε4 is associated with obstructive sleep apnea/hypopnea. Neurology. 2004;63(4): 664–8.CrossRefGoogle ScholarPubMed
56.Gozal, D, Capdevila, OS, Kheirandish-Gozal, L, Crabtree, VM.APOE ε4 allele, cognitive dysfunction, and obstructive sleep apnea in children. Neurology. 2007;69(3):243–9.CrossRefGoogle ScholarPubMed
57.O’Hara, R, Luzon, A, Hubbard, J, Zeitzer, JM.Sleep apnea, apolipoprotein epsilon 4 allele, and TBI: mechanism for cognitive dysfunction and development of dementia. J Rehabil Res Dev. 2009;46(6):837–50.Google Scholar
58.Sun, X, He, G, Qing, H, et al.Hypoxia facilitates Alzheimer’s disease pathogenesis by up-regulating BACE1 gene expression. Proc Natl Acad Sci. 2006;103(49):18727–32.Google Scholar
59.Andel, R, Crowe, M, Pedersen, NL, Fratiglioni, L, Johansson, B, Gatz, M.Physical exercise at midlife and risk of dementia three decades later: A population-based study of Swedish twins. J Gerontol. 2008;63(A):62–6.Google Scholar
60.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(5):445–53.Google Scholar
61.Verghese, J, Lipton, RB, Katz, MJ, et al.Leisure activities and the risk of dementia in the elderly. N Engl J Med. 2003;348(25):2508–16.Google Scholar
62.Rovio, S, Kareholt, I, Helkala, E, et al.Leisure-time physical activity at midlife and the risk of dementia and Alzheimer’s disease. Lancet Neurology. 2005;4(11):705–11.Google Scholar
63.Mahley, RW, Rall, SC. Jr.Apolipoprotein E: far more than a lipid transport protein. Annu Rev Genomics Hum Gen. 2000;1: 507–37.Google Scholar
64.Rolland, Y, Abellan van Kan, G, Vellas, B.Physical activity and Alzheimer’s disease: from prevention to therapeutic perspectives. J Am Medical Direc Assoc. 2008;9(6):390–405.Google Scholar
65.Rovio, S, Kåreholt, I, Helkala, E-L, et al.Leisure-time physical activity at midlife and the risk of dementia and Alzheimer’s disease. Lancet Neurol. 2005;4(11):705–11.Google Scholar
66.Ott, A, Stolk, RP, Hofman, A, van Harskamp, F, Grobbee, DE, Breteler, MMB.Association of diabetes mellitus and dementia: the Rotterdam Study. Diabetologia. 1996;39(11):1392–7.Google Scholar
67.Curb, JD, Rodriguez, BL, Abbott, RD, et al.Longitudinal association of vascular and Alzheimer’s dementias, diabetes, and glucose tolerance. Neurology. 1999;52(5):971–5.Google Scholar
68.Xu, W, Qiu, C, Gatz, M, Pedersen, NL, Johansson, B, Fratiglioni, L.Mid- and late-life diabetes in relation to the risk of dementia. Diabetes. 2009;58(1):71–7.Google Scholar
69.Martins, IJ, Hone, E, Foster, JK, et al.Apolipoprotein E, cholesterol metabolism, diabetes, and the convergence of risk factors for Alzheimer’s disease and cardiovascular disease. Mol Psychiatry. 2006;11(8):721–36.Google Scholar
70.Ronnemaa, E, Zethelius, B, Sundelof, J, et al.Impaired insulin secretion increases the risk of Alzheimer disease. Neurology. 2008;71(14): 1065–71.Google Scholar
71.Knopman, DS.Go to the head of the class to avoid vascular dementia and skip diabetes and obesity. Neurology. 2008;71(14): 1046–7.Google Scholar
72.Craft, S, Watson, G.Insulin and neurodegenerative disease: shared and specific mechanisms. Lancet Neurol. 2004;3:169–78.CrossRefGoogle ScholarPubMed
73.Peila, R, Rodriguez, BL, Launer, LJ.Type 2 Diabetes, APOE gene, and the risk for dementia and related pathologies. Diabetes. 2002;51(4):1256–62.Google Scholar
74.Jarvik, GP, Wijsman, EM, Kukull, WA, et al.Interactions of apolipoprotein E genotype, total cholesterol level, age, and sex in prediction of Alzheimer’s disease: A case-control study. Neurology. 1995;45(6):1092–6.Google Scholar
75.Kivipelto, M, Helkala, EL, Laakso, MP, et al.Apolipoprotein E ε4 allele, elevated midlife total cholesterol level, and high midlife systolic blood pressure are independent risk factors for late-life Alzheimer disease. Ann Int Med. 2002;137(3):149–55.Google Scholar
76.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 Neurology. 2002;59:223–7.CrossRefGoogle ScholarPubMed
77.Feldman, HH, Doody, RS, Kivipelto, M, et al.Randomized controlled trial of atorvastatin in mild to moderate Alzheimer disease. Neurology. 2010;74(12):956–64.Google Scholar
78.Zandi, PP, Sparks, DL, Khachaturian, AS, et al.Do statins reduce risk of incident dementia and Alzheimer disease? Arch Gen Psychiatry. 2005;62:217–24.Google Scholar
79.Li, G, Higdon, R, Kukull, WA, et al.Statin therapy and risk of dementia in the elderly: a community-based prospective cohort study. Neurology. 2004;63:1624–8.CrossRefGoogle ScholarPubMed
80.Milionis, H, Florentin, M, Giannopoulos, S.Metabolic syndrome and Alzheimer’s disease: a link to a vascular hypothesis? CNS Spectr. 2008;13(7):606–13.CrossRefGoogle ScholarPubMed
81.Vanhanen, M, Koivisto, K, Moilanen, L, et al.Association of metabolic syndrome with Alzheimer disease: a population-based study. Neurology. 2006;67(5):843–7.Google Scholar
82.Yaffe, K, Sawaya, G, Lieberburg, I, Grady, D.Estrogen therapy in postmenopausal women: effects on cognitive function and dementia. J Am Med Assoc. 1998;279:688–95.Google Scholar
83.Kawas, C.A prospective study of estrogen replacement therapy and the risk of developing Alzheimer’s disease: the Baltimore Longitudinal Study of Aging. Obstet Gynecol Surv. 1997;52 (11):694.Google Scholar
84.Tang, MX.Effect of oestrogen during menopause on risk and age at onset of Alzheimer’s disease. Obstet Gynecol Surv. 1997;52 (1):37.Google Scholar
85.Shumaker, SA, Legault, C, Kuller, L, et al.Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Women’s Health Initiative Memory Study. J Am Med Assoc. 2004;291 (24):2947–58.Google Scholar
86.Sherwin, BB.Estrogen and memory in women: how can we reconcile the findings? Horm Behav. 2005;47(3):371–5.Google Scholar
87.Yaffe, K, Haan, M, Byers, A, Tangen, C, Kuller, L.Estrogen use, APOE, and cognitive decline: evidence of gene-environment interaction. Neurology. 2000;54(10):1949–54.Google Scholar
88.Patterson, C, Feightner, J, Garcia, A, MacKnight, C.Primary prevention of dementia. Alzheimer’s Dementia. 2007;3(4): 348–54.Google Scholar
89.Moffat, SD, Zonderman, AB, Metter, EJ, et al.Free testosterone and risk for Alzheimer disease in older men. Neurology. 2004;62(2): 188–93.Google Scholar
90.Balldin, J, Gottfries, CG, Karlsson, I, Lindstedt, G, Langstrom, G, Walinder, J.Dexamethasone suppression test and serum prolactin in dementia disorders. Br J Psychiatry. 1983;143:277–81.Google Scholar
91.Sapolsky, RM.Is this relevant to the human? In: Sapolsky, RM, editor. Stress, the aging brain, and the mechanisms of neuron death. Cambridge: MIT Press; 1992. p. 305–39.Google Scholar
92.Souza-Talarico, JN, Chaves, EC, Lupien, SJ, Nitrini, R, Caramelli, P.Relationship between cortisol levels and memory performance may be modulated by the presence or absence of cognitive impairment: evidence from healthy elderly, mild cognitive impairment and Alzheimer’s disease subjects. J Alzheimers Dis. 2009;19(3):839–48.Google Scholar
93.Spar, JE, Gerner, R.Does the dexamethasone suppression test distinguish dementia from depression? Am J Psychiatry. 1982;139(2):238–40.Google Scholar
94.Green, KN, Billings, LM, Roozendaal, B, McGaugh, JL, LaFerla, FM.Glucocorticoids increase amyloid-β and tau pathology in a mouse model of Alzheimer’s disease. J Neurosci. 2006;26(35): 9047–56.Google Scholar
95.van Osch, LADM, Hogervorst, E, Combrinck, M, Smith, AD.Low thyroid-stimulating hormone as an independent risk factor for Alzheimer Disease. Neurology. 2004;62:1967–71.Google Scholar
96.Reiter, RJ, Carneiro, RC, Oh, CS.Melatonin in relation to cellular antioxidative defense mechanisms. Horm Metab Res. 1997;29 (8):363–72.Google Scholar
97.Cheng, Y, Feng, Z, Zhang, Q-Z, Zhang, J-T.Beneficial effects of melatonin in experimental models of Alzheimer disease. Acta Pharmacol Sin. 2006;27 (2):129–39.Google Scholar
98.Wang, J, Wang, Z.Role of melatonin in Alzheimer-like neurodegeneration. Acta Pharmacol Sin. 2006;27(1):41–9.Google Scholar
99.Verdoux, H, Lagnaoui, R, Begaud, B.Is benzodiazepine use a risk factor for cognitive decline and dementia? a literature review of epidemiological studies. Psychol Med. 2005;35:307–15.Google Scholar
100.Tyas, SL, Manfreda, J, Strain, LA, Montgomery, PR.Risk factors for Alzheimer’s disease: a population-based, longitudinal study in Manitoba, Canada. Int J Epidemiol. 2001;30:590–7.Google Scholar
101.Verreault, R, Laurin, D, Lindsay, J, De Serres, G.Past exposure to vaccines and subsequent risk of Alzheimer’s disease. Can Med Assoc J. 2001;165(11):1495–8.Google ScholarPubMed
102.Ernst, T, Chang, L, Leonido-Yee, M, Speck, O.Evidence for long-term neurotoxicity associated with methamphetamine abuse: A 1H MRS study. Neurology. 2000;54:1344–9.Google Scholar
103.Shih, RA, Glass, TA, Bandeen-Roche, K, et al.Environmental lead exposure and cognitive function in community-dwelling older adults. Neurology. 2006;67:1556–62.Google Scholar
104.Flaten, TP.Aluminium as a risk factor in Alzheimer’s disease, with emphasis on drinking water. Brain Res Bull. 2001;55(2):187–96.Google Scholar
105.Mutter, J, Naumann, J, Sadaghiani, C, Schneider, R, Walach, H.Alzheimer Disease: mercury as pathogenetic factor and apolipoprotein E as a moderator. Neuroendocrinol Lett. 2004; 25(5):331–9.Google Scholar
106.Bush, AI.Metal complexing agents as therapies for Alzheimer’s disease. Neurobiol Aging. 2002;23:1031–8.Google Scholar
107.Baldi, I, Lebailly, P, Mohammed-Brahim, B, Letenneur, L, Dartigues, J-F, Brochard, P.Neurodegenerative diseases and exposure to pesticides in the elderly Am J Epidemiol. 2003;157:409–14.Google Scholar
108.Gauthier, E, Fortier, I, Courchesne, F, Pepin, P, Mortimer, J, Gauvreau, D.Environmental pesticide exposure as a risk factor for Alzheimer’s disease: a case-control study. Environ Res. 2001;86 (1):37–45.Google Scholar
109.Finch, C, Morgan, T.Systemic inflammation, infection, APOE alleles, and Alzheimer disease: a position paper. Curr Alzheimer Res. 2007;4(2):185–9.Google Scholar
110.McGeer, E, McGeer, P.The importance of inflammatory mechanisms in Alzheimer’s disease. Exp Gerontol. 1998;33(5):371–8.CrossRefGoogle Scholar
111.Breteler, MMB.Vascular risk factors for Alzheimer’s disease: An epidemiologic perspective. Neurobiol Aging. 2000;21(2):153–60.Google Scholar
112.Mi, W, Pawlik, M, Sastre, M, et al.Cystatin C inhibits amyloid-beta deposition in Alzheimer’s disease mouse models. Nature Gen. 2007;39:1440–2.Google Scholar
113.Sundelöf, J, Årnlöv, J, Ingelsson, E, et al.Serum cystatin C and the risk of Alzheimer disease in elderly men. Neurology. 2008;71:1072–9.Google Scholar
114.Maes, OC, Kravitz, S, Mawal, Y, et al.Characterization of alpha(1)-antitrypsin as a heme oxygenase-1 suppressor in Alzheimer plasma. Neurobiol Dis. 2006;24:89–100.Google Scholar
115.Etminan, M, Gill, S, Samii, A.Effect of non-steroidal anti-inflammatory drugs on risk of Alzheimer’s disease: systematic review and metaanalysis of observational studies. Brit Med J. 2003;327(7404):128.Google Scholar
116.Szekely, CA, Thorne, JE, Zandi, PP, et al.Nonsteroidal anti-inflammatory drugs for the prevention of Alzheimer’s disease: a systematic review. Neuroepidemiol. 2004;23:159–69.CrossRefGoogle ScholarPubMed
117.Klegeris, A, McGeer, P.Non-steroidal anti-inflammatory drugs (NSAIDs) and other antiinflammatory agents in the treatment of neurodegenerative disease. CurrAlzheimer Res. 2005;2:355–65.Google Scholar
118.Lyketsos, CG, Breintner, JC, Green, RC, et al.Naproxen and celcoxiben do not prevent AD in early results from a randomized clinical trial. Neurology. 2007;68(21):1800–8.Google Scholar
119.Sonnen, JA, Larson, EB, Walker, RL, et al.Nonsteroidal anti-inflammatory drugs are associated with increased neuritic plaques. Neurology. 2010;75(13):1203–10.Google Scholar
120.Breitner, J.NSAIDs and Alzheimer’s disease: how far to generalize from trials? Lancet Neurol. 2003;2:527.CrossRefGoogle ScholarPubMed
121.Sofi, F, Cesari, F, Abbate, R, Gensini, GF, Casini, A.Adherence to Mediterranean diet and health status: meta-analysis. BMJ. 2008 Sep 11;337:a1344.doi:10.1136/bmj.a1344.Google Scholar
122.Trichopoulou, A, Costacou, T, Bamia, C, Trichopoulos, D.Adherence to a Mediterranean diet and survival in a Greek population. N Engl J Med. 2003;348(26):2599–608.Google Scholar
123.Feart, C, Samieri, C, Barberger-Gateau, P.Mediterranean diet and cognitive function in older adults. Curr Opin Clin Nutr Metab Care. 2010;13(1):14–8.Google Scholar
124.Scarmeas, N, Stern, Y, Tang, MX, Mayeux, R, Luchsinger, JA.Mediterranean diet and risk for Alzheimer’s disease. Ann Neurol. 2006;59(6):912–21.Google Scholar
125.Scarmeas, N, Stern, Y, Mayeux, R, Manly, JJ, Schupf, N, Luchsinger, JA.Mediterranean diet and mild cognitive impairment. Arch Neurol. 2009;66(2):216–25.Google Scholar
126.Moreira, PI, Honda, K, Liu, Q, et al.Oxidative stress: the old enemy in Alzheimer’s disease pathophysiology. Curr Alzheimer Res. 2005;2(4):403–8.Google Scholar
127.Zandi, PP, Anthony, JC, Khachaturian, AS, et al.Reduced risk of Alzheimer disease in users of antioxidant vitamin supplements: the Cache County Study. Arch Neurol. 2004;61(1):82–8.Google Scholar
128.Engelhart, MJ, Geerlings, MI, Ruitenberg, A, et al.Dietary Intake of Antioxidants and Risk of Alzheimer Disease. J Am Med Assoc. 2002;287(24):3223–9.Google Scholar
129.Sano, M, Ernesto, C, Thomas, R, et al.A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer’s disease. N Engl J Med. 1997;336(17):1216–22.Google Scholar
130.Laurin, D, Masaki, KH, Foley, DJ, White, LR, Launer, LJ.Midlife dietary intake of antioxidants and risk of late-life incident dementia: The Honolulu-Asia Aging Study. Am J Epidemiol. 2004;159(10):959–67.Google Scholar
131.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. J Am Med Assoc. 2002;287(24): 3230–7.Google Scholar
132.Petersen, RC, Thomas, RG, Grundman, M, et al.Donepezil and vitamin E in the treatment of mild cognitive impairment. N Engl J Med. 2005;352:2379–88.Google Scholar
133.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(11):1449–55.Google Scholar
134.Wang, H-X, Wahlin, A, Basun, H, Fastbom, J, Winblad, B, Fratiglioni, L.Vitamin B12 and folate in relation to the development of Alzheimer’s disease. Neurology. 2001;56(9):1188–94.Google Scholar
135.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
136.Hooshmand, B, Solomon, A, Kareholt, I, et al.Homocysteine and holotranscobalamin and the risk of Alzheimer disease: A longitudinal study. Neurology. 2010;75(16):1408–14.Google Scholar
137.Wald, DS, Bishop, L, Wald, NJ, et al.Randomized trial of folic acid supplementation and serum homocysteine levels. Arch Intern Med. 2001;161(5):695–700.Google Scholar
138.McMahon, JA, Green, TJ, Skeaff, CM, Knight, RG, Mann, JI, Williams, SM.A controlled trial of homocysteine lowering and cognitive performance. N Engl J Med. 2006;354(26):2764–72.Google Scholar
139.Tucker, KL, Olson, B, Bakun, P, Dallal, GE, Selhub, J, Rosenberg, IH.Breakfast cereal fortified with folic acid, vitamin B-6, and vitamin B-12 increases vitamin concentrations and reduces homocysteine concentrations: a randomized trial. Am J Clin Nutr. 2004;79(5):805–11.Google Scholar
140.Smith, AD, Smith, SM, de Jager, CA, et al.Homocysteine-lowering by B vitamins slows the rate of accelerated brain atrophy in mild cognitive impairment: a randomized controlled trial. PLoS1. 2010;5(9):e12244.Google Scholar
141.Durga, J, van Boxtel, MPJ, Schouten, EG, et al.Effect of 3-year folic acid supplementation on cognitive function in older adults in the FACIT trial: a randomised, double blind, controlled trial. Lancet. 2007;369(9557):208–16.Google Scholar
142.Ford, AH, Flicker, L, Alfonso, H, et al.Vitamins B(12), B(6), and folic acid for cognition in older men. Neurology. 2010;75(17):1540–7.CrossRefGoogle Scholar
143.Malouf, M, Grimley, EJ, Areosa, SA.Folic acid with or without vitamin B12 for cognition and dementia. Cochrane Database Syst Rev. 2003(4):CD004514.Google Scholar
144.Kang, JH, Cook, N, Manson, J, Buring, JE, Albert, CM, Grodstein, F.A trial of B vitamins and cognitive function among women at high risk of cardiovascular disease. Amer J Clin Nutr. 2008;88(6):1602–10.Google Scholar
145.Yang, Q, Botto, LD, Erickson, JD, et al.Improvement in stroke mortality in Canada and the United States, 1990 to 2002. Circulation. 2006;113(10):1335–43.CrossRefGoogle ScholarPubMed
146.Blass, JP, Gleason, P, Brush, D, DiPonte, P, Thaler, H.Thiamine and Alzheimer’s disease: a pilot study. Arch Neurol. 1988;45(8): 833–5.Google Scholar
147.Gehlert, DR, Morey, WA, Wamsley, JK.Alterations in muscarinic cholinergic receptor densities induced by thiamine deficiency: Autoradiographic detection of changes in high- and low-affinity agonist binding. J Neurosci Res. 1985;13(3):443–52.Google Scholar
148.Kril, JJ.Neuropathology of thiamine deficiency disorders. Metabol Brain Dis 1996;11(1):9–17.Google Scholar
149.Mimori, Y, Katsuoka, H, Nakamura, S.Thiamine therapy in Alzheimer’s disease. Metabol Brain Dis. 1996;11(1):89–94.Google Scholar
150.Nolan, KA, Black, RS, Sheu, KFR, Langberg, J, Blass, JP.A trial of thiamine in Alzheimer’s disease. Arch Neurol. 1991;48(1):81–3.Google Scholar
151.Meador, K, Loring, D, Nichols, M, et al.Preliminary findings of high-dose thiamine in dementia of Alzheimer’s type. J Geriatr Psychiatry Neurol. 1993;6(4):222–9.Google Scholar
152.Hageman, GJ, Stierum, RH.Niacin, poly(ADP-ribose) polymerase-1 and genomic stability. Mutat Res Fund Molec Mech Mutag. 2001;475(1-2):45–56.Google Scholar
153.Melo, SS, Arantes, MR, Meirelles, MS, Jordáo, AA Jr, Vannucchi, H.Lipid peroxidation in nicotinamide-deficient and nicotinamide-supplemented rats with streptozotocin-induced diabetes. Acta Diabetol. 2000;37(1):33–9.Google Scholar
154.Morris, MC, Evans, DA, Bienias, JL, et al.Dietary niacin and the risk of incident Alzheimer’s disease and of cognitive decline. J Neurol Neurosurg Psychiatry. 2004;75(8):1093–9.Google Scholar
155.Bourre, JM.Dietary omega-3 Fatty acids and Psychiatry: mood, behaviour, stress, depression, dementia and aging. J Nutr Health Aging. 2005;9(1):31–8.Google Scholar
156.Bourre, JM.Effects of nutrients (in food) on the structure and function of the nervous system: update on dietary requirements for brain. Part 2: macronutrients. J Nutr Health Aging. 2006;10 (5):386–99.Google Scholar
157.Conquer, JA, Tierney, MC, Zecevic, J, Bettger, WJ, Fisher, RH.Fatty acid analysis of blood plasma of patients with Alzheimer’s disease, other types of dementia, and cognitive impairment. Lipids. 2000;35(12):1305–12.Google Scholar
158.Maia, L, dev Mendonça, A.Does caffeine intake protect from Alzheimer’s disease? Eur J Neurol. 2002;9:377–82.Google Scholar
159.Quintana, JLB, Allam, MF, Del Castillo, AS, Navajas, RF-C.Alzheimer’s disease and coffee: a quantitative review. Neurol Res. 2007;29(1):91–5(5).Google Scholar
160.Eskelinena, MH, Ngandua, T, Tuomilehto, J, Soininen, H, Kivipelto, M.Midlife coffee and tea drinking and the risk of late-life dementia: a population-based CAIDE study. J Alzheimers Dis. 2009;16:85–91.Google Scholar
161.Larrieu, S, Letenneur, L, Helmer, C, Dartigues, JF, Barberger-Gateau, P.Nutritional factors and risk of incident dementia in the PAQUID longitudinal cohort. J Nutr Health Aging. 2004;8(3): 150–4.Google Scholar
162.Mortimer, J.Brain reserve and the clinical expression of Alzheimer’s disease. Geriatrics. 1997;52(Suppl 2):S50–53.Google Scholar
163.Stern, Y, Gurland, B, Tatemichi, TK, Tang, MX, Wilder, D, Mayeux, R.Influence of education and occupation on the incidence of Alzheimer’s disease. J Am Med Assoc. 1994;271(13):1004–10.Google Scholar
164.Crowe, M, Andel, R, Pedersen, NL, Johansson, B, Gatz, M.Does participation in leisure activities lead to reduced risk of Alzheimer’s disease? a prospective study of Swedish twins. J Gerontol. 2003;58(5):P249–55.Google Scholar
165.Scarmeas, N, Levy, G, Tang, MX, Manly, J, Stern, Y.Influence of leisure activity on the incidence of Alzheimer’s disease. Neurology. 2001;57(12):2236–42.Google Scholar
166.Valenzuela, MJ, Sachdev, P.Brain reserve and dementia: a systematic review. Psychol Med. 2006;36(04):441–54.Google Scholar
167.Stern, C, Munn, Z.Cognitive leisure activities and their role in preventing dementia: a systematic review. Int J Evid Based Healthc. 2010;8(1):2–17.Google Scholar
168.Ball, K, Berch, DB, Helmers, KF, et al., for the ASG. Effects of Cognitive Training Interventions With Older Adults. J Am Med Assoc. 2002;288(18):2271–81.Google Scholar
169.Valenzuela, M, Sachdev, P.Can cognitive exercise prevent the onset of dementia? Systematic review of randomized clinical trials with longitudinal follow-up. Am J Geriat Psychiatry. 2009;17(3):179–87.Google Scholar
170.Neely, AS, Bäckman, L.Effects of multifactorial memory training in old age: generalizability across tasks and individuals. J Gerontol. 1995;50B(3):P134–40.Google Scholar
171.Verhaeghen, P, Marcoen, A, Goossens, L.Improving memory performance in the aged through mnemonic training: a meta-analytic study. Psychol Aging. 1992;7(2):242–51.Google Scholar
172.Mahncke, HW, Connor, BB, Appelman, J, et al.Memory enhancement in healthy older adults using a brain plasticity-based training program: A randomized, controlled study. Proc Natl Acad Sci. 2006;103(33):12523–8.Google Scholar
173.Optale, G, Urgesi, C, Busato, V, et al.Controlling memory impairment in elderly adults using virtual reality memory training: A randomized controlled pilot study. Neurorehabil Neural Repair 2010;24(4):348–57.Google Scholar
174.Wilson, RS, Krueger, KR, Arnold, SE, et al.Loneliness and risk of Alzheimer disease. Arch Gen Psychiatry. 2007;64(2):234–40.Google Scholar
175.Helmer, C, Damon, D, Letenneur, L, et al.Marital status and risk of Alzheimer’s disease: a French population-based cohort study. Neurology. 1999;53(9):1953–8.Google Scholar
176.Guo, Z, Cupples, LA, Kurz, A, et al.Head injury and the risk of AD in the MIRAGE study. Neurology. 2000;54(6):1316–23.Google Scholar
177.Jordan, BD, Relkin, NR, Ravdin, LD, Jacobs, AR, Bennett, A, Gandy, S.Apolipoprotein E epsilon4 associated with chronic traumatic brain injury in boxing. J Am Med Assoc. 1997;278(2):136–40.Google Scholar
178.Mayeux, R, Ottman, R, Maestre, G, et al.Synergistic effects of traumatic head injury and apolipoprotein-epsilon 4 in patients with Alzheimer’s disease. Neurology. 1995;45(3 Pt 1):555–7.Google Scholar
179.Plassman, BL, Havlik, RJ, Steffens, DC, et al.Documented head injury in early adulthood and risk of Alzheimer’s disease and other dementias. Neurology. 2000;55(8):1158–66.Google Scholar
180.Szczygielski, J, Mautes, A, Steudel, WI, Falkai, P, Bayer, TA, Wirths, O.Traumatic brain injury: cause or risk of Alzheimer’s disease? A review of experimental studies. J Neural Transm. 2005;112(11):1547–64.Google Scholar
181.Wilson, M, Montgomery, H.Impact of genetic factors on outcome from brain injury. Br J Anaesth. 2007;99(1):43–8.Google Scholar
182.McCrory, P, Zazryn, T, Cameron, P.The evidence for chronic traumatic encephalopathy in boxing. Sports Med. 2007;37(6):467–76.Google Scholar
183.Rabadi, MH, Jordan, BD.The cumulative effect of repetitive concussion in sports. Clin J Sport Med. 2001;11(3):194–8.Google Scholar
184.Hoehn, MM, Yahr, MD.Parkinsonism: onset, progression and mortality. Neurology. 1967;17:427–42.Google Scholar
185.Marder, K, Tang, M-X, Cote, L, Stern, Y, Mayeux, R.The frequency and associated risk factors for dementia in patients with Parkinson’s disease. Arch Neurol. 1995;52(7):695–701.Google Scholar
186.Breteler, MMB, Groot, RFM, Romunde, LKJ, Hofman, A.Risk of dementia in patients with Parkinson’s disease, epilepsy, and severe head trauma: a register-based follow-up study. Am J Epidemiol. 1995;142(12).Google Scholar
187.Kempster, PA, O’Sullivan, SS, Holton, JL, Revesz, T, Lees, AJ.Relationships between age and late progression of Parkinson’s disease: a clinico-pathological study. Brain. 2010;133(6):1755–62.Google Scholar
188.Schipper, HM.The role of biologic markers in the diagnosis of Alzheimer’s disease Alzheimers Dementia. 2007;3:325–32.Google Scholar
189.Tsuboi, Y, Josephs, KA, Cookson, N, Dickson, aDW.APOE E4 is a determinant for Alzheimer type pathology in progressive supranuclear palsy. Neurology. 2003;60:240–5.Google Scholar
190.Mackenzie, IRA, Miller, LA.Senile plaques in temporal lobe epilepsy. Acta Neuropathol. 1994;87:504–10.Google Scholar
191.Griffin, WST, Mrak, RE.Interleukin-1 in the genesis and progression of and risk for development of neuronal degeneration in Alzheimer’s disease. J Leukocyte Biol. 2002;72:233–8.Google Scholar
192.Sheng, J, Boop, F, Mrak, R, Griffin, W.Increased neuronal beta-amyloid precursor protein expression in human temporal lobe epilepsy: association with IL-1 alpha immunoreactivity. J Neurochem. 1994;63:1872–9.Google Scholar
193.Gouras, GK, Relkin, NR, Sweeney, D, Munoz, DG, Mackenzie, IR, Gandy, SE.Increased apolipoprotein E epsilon 4 in epilepsy with senile plaques. Ann Neurol. 1997 Mar;41(3):402–4.Google Scholar
194.Alisky, JM.The coming problem of HIV-associated Alzheimer’s disease. Med Hypoth. 2007;69(5):1140–3.Google Scholar
195.Guillemin, GJ, Brew, BJ.Chronic HIV infection leads to an Alzheimer’s disease like illness: involvement of the kynurenine pathway. Internat Cong Ser. 2007;1304:324–34.Google Scholar
196.Clifford, DB, Fagan, AM, Holtzman, DM, et al.CSF biomarkers of Alzheimer disease in HIV-associated neurologic disease. J Neurol. 2009;73(23):1982–7.Google Scholar
197.Butters, MA, Young, JB, Lopez, O, et al.Pathways linking late-life depression to persistent cognitive impairment and dementia. Dialog Clin Neurosci 2008;10:345–57.Google Scholar
198.Ownby, RL, Crocco, E, Acevedo, A, John, V, Loewenstein, D.Depression and risk for Alzheimer disease: systematic review, meta-analysis, and metaregression analysis. Arch Gen Psychiatry. 2006;63(5):530–8.Google Scholar
199.Chen, P, Ganguli, M, Mulsant, B, DeKosky, S.The temporal relationship between depressive symptoms and dementia: a community-based prospective study. Arch Gen Psychiatry. 1999; 56(3):261–6.Google Scholar
200.Zalsman, G, Aizenberg, D, Sigler, M, Nahshony, E, Karp, L, Weizman, A.Increased risk for dementia in elderly psychiatric inpatients with late-onset major depression. J Nerv Mental Dis. 2000;188 (4):242–3.Google Scholar
201.Baldessarini, R, Hegarty, J, Bird, E, Benes, F.Meta-analysis of postmortem studies of Alzheimer’s disease-like neuropathology in schizophrenia. Am J Psychiatry. 1997;154:861–3.Google Scholar
202.Harrison, P, Weinberger, D.Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Mol Psychiatry. 2005;10:40–68.Google Scholar
203.Jellinger, KA, Gabriel, E.No increased incidence of Alzheimer’s disease in elderly schizophrenics. Acta Neuropathol. 1999;97:165–9.Google Scholar
204.Thibaut, F, Coron, B, Hannequin, D, et al.No association of apolipoprotein epsilon 4 allele with schizophrenia even in cognitively impaired patients. Schizophr Res. 1998;30(2): 149–53.Google Scholar
205.Digman, JM.Personality structure: Emergence of the five-factor model. Ann Rev Psychiatry. 1990;41(1):417–40.Google Scholar
206.Wilson, RS, Evans, DA, Bienias, JL, Mendes de Leon, CF, Schneider, JA, Bennett, DA.Proneness to psychological distress is associated with risk of Alzheimer’s disease. Neurology. 2003;61:1479–85.Google Scholar
207.Wilson, RS, Schneider, JA, Arnold, SE, Bienias, JL, Bennett, DA.Conscientiousness and the incidence of Alzheimer disease and mild cognitive impairment. Arch Gen Psychiatry. 2007;64(10): 1204–12.Google Scholar
208.Dominick, K, Ahern, F, Gold, C, Heller, D.Relationship of health-related quality of life to health care utilization and mortality among older adults. Aging Clin Exp Res. 2002 Dec;14(6):499–508.Google Scholar
209.Koenig, H, Cohen, H, George, L, Hays, J, Larson, D, Blazer, D.Attendance at religious services, interleukin-6, and other biological parameters of immune function in older adults. Int J Psychiatry Med. 1997;27(3):233–50.Google Scholar
210.Koenig, H, Cohen, H, Blazer, D, et al.Religious coping and depression among elderly, hospitalized medically ill men. Am J Psychiatry. 1992;149:1693–700.Google Scholar
211.Idler, E, Kasl, S.Religion among disabled and nondisabled persons II: attendance at religious services as a predictor of the course of disability. J Gerontol. 1997;52B(6):S306–16.Google Scholar
212.Kaufman, Y, Anaki, D, Binns, M, Freedman, M.Cognitive decline in Alzheimer disease: Impact of spirituality, religiosity, and QOL. Neurology. 2007;68:1509–14.Google Scholar
213.Schipper, HM.Presymptomatic apolipoprotein E genotyping for AD risk assessment and prevention. Alzheimer Dement, 2011, [in press].Google Scholar
214.Beaudet, A.message from the president. Annual Meeting of Chairs and Scientific Officers. Ottawa, ON, Canada: Canadian Institutes for Health Research, 2010.Google Scholar