Pathology supported genetic testing and treatment of cardiovascular disease in middle age for prevention of alzheimer's disease

Metabolic Brain Disease

Volumn 27, Issue 3, 2012, Pages 255-266

  Kotze, Maritha J ^a   Rensburg, Susan J Van ^b  

^a STELLENBOSCH UNIVERSITY   (South Africa)

^b STELLENBOSCH UNIVERSITY   (South Africa)

Author keywords

Alzheimer's disease; Biochemistry; Cvd; Genetics; Personalised medicine; PSGT

Indexed keywords

APOLIPOPROTEIN E; CYANOCOBALAMIN; FOLIC ACID; LOW DENSITY LIPOPROTEIN RECEPTOR; PYRIDOXINE; RIBOFLAVIN; THIAMINE;

ALZHEIMER DISEASE; ARTICLE; BODY MASS; CARDIAC PATIENT; CARDIOVASCULAR DISEASE; CHOLESTEROL BLOOD LEVEL; FAMILIAL HYPERCHOLESTEROLEMIA; GENETIC SCREENING; HEART INFARCTION; HEMOCHROMATOSIS; HUMAN; HYPERCHOLESTEROLEMIA; HYPERTENSION; IRON METABOLISM; MIDDLE AGED; NEUROFIBRILLARY TANGLE; PATHOLOGY; SINGLE NUCLEOTIDE POLYMORPHISM;

EID: 84864759869     PISSN: 08857490     EISSN: 15737365     Source Type: Journal    
DOI: 10.1007/s11011-012-9296-8     Document Type: Article

References (89)

1. Aisen PS, Schneider LS, Sano M, Diaz-Arrastia R, van Dyck CH, Weiner MF, Bottiglieri T, Jin S, Stokes KT, Thomas RG, Thal LJ, Alzheimer Disease Cooperative Study (2008) High-dose B vitamin supplementation and cognitive decline in Alzheimer disease: a randomized controlled trial. JAMA 300:1774-1783
2. Almén MS, Jacobsson JA, Moschonis G, Benedict C, Chrousos GP, Fredriksson R, Schiöth HB (2012) Genome wide analysis reveals association of a FTO gene variant with epigenetic changes. Genomics Jan 2 [Epub ahead of print]
3. Anttila T, Helkala EL, Viitanen M, Kåreholt I, Fratiglioni L, Winblad B, Soininen H, Tuomilehto J, Nissinen A, Kivipelto M (2004) Alcohol drinking in middle age and subsequent risk of mild cognitive impairment and dementia in old age: a prospective population based study. Br Med J 329:539
4. Artinian NT, Fletcher GF, Mozaffarian D, Kris-Etherton P, Van Horn L, Lichtenstein AH, Kumanyika S, Kraus WE, Fleg JL, Redeker NS, Meininger JC, Banks J, Stuart-Shor EM, Fletcher BJ, Miller TD, Hughes S, Braun LT, Kopin LA, Berra K, Hayman LL, Ewing LJ, Ades PA, Durstine JL, Houston-Miller N, Burke LE, American Heart Association Prevention Committee of the Council on Cardiovascular Nursing (2010) Interventions to promote physical activity and dietary lifestyle changes for cardiovascular risk factor reduction in adults: a scientific statement from the American Heart Association. Circulation 122:406-441
5. Bader Lange ML, St Clair D, Markesbery WR, Studzinski CM, Murphy MP, Butterfield DA (2010) Age-related loss of phospholipid asymmetry in APP(NLh)/APP(NLh) x PS-1(p264L0/PS-1(P264L) human double mutant knock-in mice: relevance to Alzheimer's disease. Neurobiol Dis 38:104-115
6. Barberger-Gateau P, Raffaitin C, Letenneur L, Berr C, Tzourio C, Dartiques JF, Alpérovitch A (2007) Dietary patterns and risk of dementia: the Three-City cohort study. Neurology 69:1921-1930
7. Bartzokis G, Lu PH, Tishler TA, Peters DG, Kosenko A, Barrall KA, Finn JP, Villablanca P, Laub G, Altshuler LL, Geschwind DH, Mintz J, Neely E, Connor JR (2010) Prevalent iron metabolism gene variants associated with increased brain ferritin iron in healthy older men. J Alzheimer's Dis 20:333-341
8. Bartzokis G, Lu PH, Tingus K, Peters DG, Amar CP, Tishler TA, Finn JP, Villablanca P, Altshuler LL, Mintz J, Neely E, Connor JR (2011) Gender and iron genes may modify associations between brain iron and memory in healthy aging. Neuropsychopharmacology 36:1375-1384
9. Benedict C, Jacobsson JA, Rönnemaa E, Sällman-Almén M, Brooks S, Schultes B, Fredriksson R, Lannfelt L, Kilander L, Schiöth HB (2011) The fat mass and obesity gene is linked to reduced verbal fluency in overweight and obese elderly men. Neurobiol Aging 32:1159.e1-5
10. Bertram L, Heekeren H (2010) Obesity and the brain: a possible genetic link. Alz Res Ther 2:27
11. Berulava T, Horsthemke B (2010) The obesity-associated SNPs in intron 1 of the FTO gene affect primary transcript levels. Eur J Hum Genet 18:1054-1056
12. Bjorkhem I (2006) Crossing the barrier: oxysterols as cholesterol transporters and metabolic modulators in the brain. J Intern Med 260:493-508
13. Bowman GL, Dodge H, Frei B et al (2009) Ascorbic acid and rates of cognitive decline in Alzheimer's disease. J Alzheimer's Dis 16:93-98
14. Bowman GL, Silbert LC, Howieson D, Dodge HH, Traber MG, Frei B, Kaye JA, Shannon J, Quinn JF (2012) Nutrient biomarker patterns, cognitive function, and MRI measures of brain aging. Neurology 78:241-249
15. Brown AA, Hu FB (2001) Dietary modulation of endothelial function: implications for cardiovascular disease. Am J Clin Nutr 73:673-686
16. Cacabelos R (2003) The application of functional genomics to Alzheimer's disease. Pharmacogenomics 4:597-621
17. Cacabelos R (2008) Pharmacogenomics and therapeutic prospects in dementia. Eur Arch Psychiatry Clin Neurosci 258(Suppl 1):28-47
18. Coppedè F, Tannorella P, Pezzini I, Migheli F, Ricci G, Lenco EC, Piaceri I, Polini A, Nacmias B, Monzani F, Sorbi S, Siciliano G, Migliore L (2011) Folate, homocysteine, vitamin B12, and polymorphisms of genes participating in one-carbon metabolism in late-onset Alzheimer's disease patients and healthy controls. antioxid redox signal. Dec 15 [Epub ahead of print]
19. Cronin S, Furie KL, Kelly PJ (2005) Dose-related association of MTHFR 677T allele with risk of ischemic stroke: Evidence from a cumulative meta-analysis. Stroke 36:1581-1587
20. Genin E, Hannequin D, Wallon D, Sleegers K, Hiltunen M, Combarros O, Bullido MJ, Engelborghs S, De Deyn P, Berr C, Pasquier F, Dubois B, Tognoni G, Fiévet N, Brouwers N, Bettens K, Arosio B, Coto E, Del Zompo M, Mateo I, Epelbaum J, Frank-Garcia A, Helisalmi S, Porcellini E, Pilotto A, Forti P, Ferri R, Scarpini E, Siciliano G, Solfrizzi V, Sorbi S, Spalletta G, Valdivieso F, Vepsäläinen S, Alvarez V, Bosco P, Mancuso M, Panza F, Nacmias B, Bossů P, Hanon O, Piccardi P, Annoni G, Seripa D, Galimberti D, Licastro F, Soininen H, Dartigues JF, Kamboh MI, Van Broeckhoven C, Lambert JC, Amouyel P, Campion D (2011) APOE and Alzheimer disease: a major gene with semi-dominant inheritance. Mol Psychiatry May 10 [Epub ahead of print]
21. Gerdes LU, Gerdes C, Kervinen K, Savolainen M, Klausen IC, Hansen PS, Kesäniemi YA, Faergeman O (2000) The apolipoprotein E4 allele determines prognosis and the effect on prognosis of simvastatin in survivors of myocardial infarction. Circulation 101:1366-1371
22. Ghareeb DA, Hafez HS, Hussien HM, Kabapy NF (2011) Nonalcoholic fatty liver induces insulin resistance and metabolic disorders with development of brain damage and dysfunction. Metab Brain Dis 26:253-267
23. Giambattistelli F, Bucossi S, Salustri C, Panetta V, Mariani S, Siotto M, Ventriglia M, Vernieri F, Dell'acqua ML, Cassetta E, Rossini PM, Squitti R (2011) Effects of hemochromatosis and transferrin gene mutations on iron dyshomeostasis, liver dysfunction and on the risk of Alzheimer's disease. Neurobiol Aging Apr 20 [Epub ahead of print]
24. Gorgone G, Ursini F, Altamura C, Bressi F, Tombini M, Curcio G, Chiovenda P, Squitti R, Silvestrini M, Ientile R, Pisani F, Rossini PM, Vernieri F (2009) Hyperhomocysteinemia, intima-media thickness and C677T MTHFR gene polymorphism: a correlation study in patients with cognitive impairment. Atherosclerosis 206:309-313
25. Gu Y, Nieves JW, Stern Y, Luchsinger JA, Scarmeas N (2010) Food combination and Alzheimer disease risk: a protective diet. Arch Neurol 67:699-706
26. Halsted CH, Villanueva JA, Devlin AM et al (2002) Metabolic interactions of alcohol and folate. J Nutr 132:2367S-2372S
27. Harwood DG, Kalechstein A, Barker WW, Strauman S, St George-Hyslop P, Iglesias C, Loewenstein D, Duara R (2010) The effect of alcohol and tobacco consumption, and apolipoprotein E genotype, on the age of onset in Alzheimer's disease. Int J Geriatr Psychiatry 25:511-518
28. Herrmann W, Obeid R, Schorr H, Zarzour W, Geisel J (2003) Homocysteine, methylenetetrahydrofolate reductase C677T polymorphism and the B-vitamins: a facet of nature-nurture interplay. Clin Chem Lab Med 41:547-553
29. Ho AJ, Stein JL, Hua X, Lee S, Hibar DP, Leow AD, Dinov ID, Toga AW, Saykin AJ, Shen L, Foroud T, Pankratz N, Huentelman MJ, Craig DW, Gerber JD, Allen AN, Corneveaux JJ, Stephan DA, DeCarli CS, DeChairo BM, Potkin SG, Jack CR Jr, Weiner MW, Raji CA, Lopez OL, Becker JT, Carmichael OT, Thompson PM, Initiative Alzheimer's Disease Neuroimaging (2010) A commonly carried allele of the obesity-related FTO gene is associated with reduced brain volume in the healthy elderly. Proc Natl Acad Sci U S A A107:8404-8409
30. Holmes MV, Newcombe P, Hubacek JA, Sofat R, Ricketts SL, Cooper J, Breteler MM, Bautista LE, Sharma P, Whittaker JC, Smeeth L, Fowkes FG, Algra A, Shmeleva V, Szolnoki Z, Roest M, Linnebank M, Zacho J, Nalls MA, Singleton AB, Ferrucci L, Hardy J, Worrall BB, Rich SS, Matarin M, Norman PE, Flicker L, Almeida OP, van Bockxmeer FM, Shimokata H, Khaw KT, Wareham NJ, Bobak M, Sterne JA, Smith GD, Talmud PJ, van Duijn C, Humphries SE, Price JF, Ebrahim S, Lawlor DA, Hankey GJ, Meschia JF, Sandhu MS, Hingorani AD, Casas JP (2011) Effect modification by population dietary folate on the association between MTHFR genotype, homocysteine, and stroke risk: a meta-analysis of genetic studies and randomised trials. Lancet 378:584-594
31. Hua Y, Zhao H, Kong Y, Ye M (2011) Association between the MTHFR gene and Alzheimer's disease: a meta-analysis. Int J Neurosci 121:462-471
32. Hudson JM, Pollux PM, Mistry B, Hobson S (2012) Beliefs about Alzheimer's disease in Britain. Aging Ment Health. doi:10.1080/13607863.2012.660620
33. Humphries SE, Talmud PJ, Hawe E, Bolla M, Day IN, Miller GJ (2001) Apolipoprotein E4 and CHD in middle-aged men who smoke: a prospective study. Lancet 358:115-119
34. Karuppagounder SS, Xu H, Shi Q, Chen LH, Pedrini S, Pechman D, Baker H, Beal MF, Gandy SE, Gibson GE (2009) Thiamine deficiency induces oxidative stress and exacerbates the plaque pathology in Alzheimer's mouse model. Neurobiol Aging 30:1587-1600
35. Keijzer M, den Heijer BM, Blom HJ, Bos GM, Willems HP, Gerrits WB, Rosendaal FR (2002) Interaction between hyperhomocystei-nemia, mutated methylenetetrahydrofolatereductase (MTHFR) and inherited thrombophilic factors in recurrent venous thrombosis. Thromb Haemost 88:723-728
36. Keller L, Xu W, Wang HX, Winblad B, Fratiglioni L, Graff C (2011) The obesity related gene, FTO, interacts with APOE, and is associated with Alzheimer's disease risk: a prospective cohort study. J Alzheimers Dis 23:461-469
37. Klerk M, Verhoef P, Clarke R, Blom HJ, Kok FJ, Schouten EG, MTHFR Studies Collaboration Group (2002) MTHFR 677C→T polymorphism and risk of coronary heart disease: a meta-analysis. J Am Med Assoc 288:2023-2031
38. Kotze MJ, Thiart R (2003) Genetics of dyslipidaemia. CME J 21:399-402
39. Kotze MJ, Davis HJ, Bissbort S, Langenhoven E, Brusnicky J, Oos-thuizen CJ (1993a) Intrafamilial variability in the clinical expression of familial hypercholesterolemia: importance of risk factor determination for genetic counselling. Clin Genet 43:295-299
40. Kotze MJ, de Villiers WJS, Steyn K, Kriek JA, Marais AD, Langenhoven E, Herbert JS, Graadt van Roggen JF, van der Westhuyzen DR, Coetzee GA (1993b) Phenotypic variation among familial hypercho-lesterolemics heterozygous for either one of two Afrikaner founder LDL receptor mutations. Arterioscler Thromb 13:1460-1468
41. Kotze MJ, Kriegshäuser G, Thiart R, de Villiers JNP, Scholtz CL, Kury F, Moritz A, Oberkanins C (2003) Simultaneous detection of multiple familial hypercholesterolaemia mutations facilitates an improved diagnostic service in South African patients at high risk of cardiovascular disease. Mol Diagn 7:169-174
42. Kotze MJ, Thiart R, Hugo FJ, Potocnik FCW (2006) Cardiovascular genetic assessment and treatment in middle age to reduce the risk of heart disease and dementia in old age. SA Fam Pract 48:53-54
43. Kotze MJ, Van Velden D, Van Rensburg SJ, Erasmus R (2009) Pathogenic mechanisms underlying iron deficiency and iron overload: New insights for clinical application. J Int Fed Clin Chem Lab Med 02-01:1-15
44. Lehmann DJ, Schuur M, Warden DR, Hammond N, Belbin O, Kölsch H, Lehmann MG, Wilcock GK, Brown K, Kehoe PG, Morris CM, Barker R, Coto E, Alvarez V, Deloukas P, Mateo I, Gwilliam R, Combarros O, Arias-Vásquez A, Aulchenko YS, Ikram MA, Breteler MM, van Duijn CM, Oulhaj A, Heun R, Cortina-Boija M, Morgan K, Robson K, Smith AD (2012) Transferrin and HFE genes interact in Alzheimer's disease risk: the Epistasis Project. Neurobiol Aging 33(202): e1-e13
45. Lin M, Zhao L, Fan J, Lian XG, Ye JX, Wu L, Lin H (2011) Association between HFE polymorphisms and susceptibility to Alzheimer's disease: a meta-analysis of 22 studies including 4,365 cases and 8,652 controls. Mol Biol Rep Jun 24. [Epub ahead of print]
46. Liu H, Yang M, Li GM, Qiu Y, Zheng J, Du X, Wang JL, Liu RW (2010a) The MTHFR C677T polymorphism contributes to an increased risk for vascular dementia: a meta-analysis. J Neurol Sci 294:74-80
47. Liu G, Zhu H, Lagou V, Gutin B, Stallmann-Jorgensen IS, Treiber FA, Dong Y, Snieder H (2010b) FTO variant rs9939609 is associated with body mass index and waist circumference, but not with energy intake or physical activity in European- and African-American youth. BMC Med Genet 11:57
48. Liu Y, Lee SY, Neely E, Nandar W, Moyo M, Simmons Z, Connor JR (2011) Mutant HFE H63D protein is associated with prolonged endoplasmic reticulum stress and increased neuronal vulnerability. J Biol Chem 286:13161-13170
49. Lopez-Garcia E, Schulze MB, Meigs JB, Manson JE, Rifai N, Stampfer MJ, Willett WC, Hu FB (2005) Consumption of trans fatty acids is related to plasma biomarkers of inflammation and endothelial dysfunction. J Nutr 135:562-566
50. Marais AD, Firth JC, Blom DJ (2004) Familial hypercholesterolemia in South Africa. Sem Vasc Med 4:93-95
51. Matsuzaki T, Sasaki K, Hata J, Hirakawa Y, Fujimi K, Ninomiya T, Suzuki SO, Kanba S, Kiyohara Y, Iwaki T (2011) Association of Alzheimer disease pathology with abnormal lipid metabolism: the Hisayama Study. Neurology 77:1068-1075
52. Moleres A, Ochoa MC, Rendo-Urteaga T, Martínez-González MA, Azcona San Julián MC, Alfredo Martinez J, Marti A (2011) Dietary fatty acid distribution modifies obesity risk linked to the rs9939609 polymorphism of the fat mass and obesity-associated gene in a Spanish case-control study of children. Br J Nutr 29:1-6
53. Moriyama Y, Okamura T, Kajinami K, Iso H, Inazu A, Kawashiri M, Mizuno M, Takeda Y, Sakamoto Y, Kimura H, Suzuki H, Mabuchi H (2002) Effects of serum B vitamins on elevated plasma homocysteine levels associated with the mutation of methylenete-trahydrofolate reductase gene in Japanese. Atherosclerosis 164:321-328
54. Morris MC, Evans DA, Bienias JL, Tangney CC, Wilson RS (2004) Dietary fat intake and 6-year cognitive change in an older biracial community population. Neurology 62:1573-1579
55. Mozaffarian D, Katan MB, Ascherio A, Stampfer MJ, Willett WC (2006) Trans fatty acids and cardiovascular disease. N Engl J Med 354:1601-1613
56. Nandar W, Connor JR (2011) HFE gene variants affect iron in the brain. J Nutr 141:729S-739S
57. Petot GJ, Traore F, Debanne SM, Lerner AJ, Smyth KA, Friedland RP (2003) Interactions of apolipoprotein E genotype and dietary fat intake of healthy older persons during mid-adult life. Metabolism 52:279-281
58. Poon IO (2008) Effects of antihypertensive drug treatment on the risk of dementia and cognitive impairment. Pharmacotherapy 28:366-375
59. Potocnik FCV, Bouwens C, van Rensburg SJ (2005) Neurological ageing factors: neurobiology of ageing and prevention of dementia. CME 23:307-309
60. Pratico D, Tangirala RK, Rader DJ, Rokach J, FitzGerald GA (1998) Vitamin E suppresses isoprostano generation in vivo and reduces atherosclerosis in Apo E-deficient mice. Nat Med 4:1189-1192
61. Ravaglia G, Forti P, Maioli F, Martelli M, Servadei L, Brunetti N, Porcellini E, Licastro F (2005) Homocysteine and folate as risk factors for dementia and Alzheimer disease. Am J Clin Nutr 82:636-643
62. Rocchi A, Orsucci D, Tognoni G, Ceravolo R, Siciliano G (2009) The role of vascular factors in late-onset sporadic Alzheimer's disease. Genetic and molecular aspects. Curr Alzheimer Res 6:224-237
63. Roest M, van der Schouw YT, de Valk B, Marx JJ, Tempelman MJ, de Groot PG, Sixma JJ, Banga JD (1999) Heterozygosity for a hereditary hemochromatosis gene is associated with cardiovascular death in women. Circulation 100:1268-1273
64. Romero LJ, Garry PJ, Schuyler M, Bennahum DA, Qualls C, Ballinger L, Kelly V, Schmitt C, Skipper B, Ortiz IE, Rhyne RL (2005) Emotional responses to APO E genotype disclosure for Alzheimer disease. J Genet Couns 14:141-150
65. Rondeau V, Iron A, Letenneur L, Commenges D, Duchêne F, Arveiler B, Dartigues JF (2006) Analysis of the effect of aluminum in drinking water and transferrin C2 allele on Alzheimer's disease. Eur J Neurol 13:1022-1025
66. Sampietro M, Caputo L, Casatta A, Meregalli M, Pellagatti A, Tagliabue J, Annoni G, Vergani C (2001) The hemochromatosis gene affects the age of onset of sporadic Alzheimer's disease. Neurobiol Aging 22:563-568
67. Scarmeas N, Stern Y, Tang MX, Mayeux R, Luchsinger JA (2006) Mediterranean diet and risk for Alzheimer's disease. Ann Neurol 59:912-921
68. Schaefer EJ, Bongard V, Beiser AS, Lamon-Fava S, Robins SJ, Au R, Tucker KL, Kyle DJ, Wilson PW, Wolf PA (2006) Plasma phosphatidylcholine, docosahexaenoic acid content and risk of dementia and Alzheimer disease: the Framingham Heart Study. Arch Neurol 63:1545-1550
69. Seneff S, Wainwright G, Mascilelli L (2011) Nutrition and Alzheimer's disease: the detrimental role of a high carbohydrate diet. Eur J Intern Med 22:134-140
70. Seshadri S, Drachman DA, Lippa CF (1995) Apolipoprotein E E4 allele and the lifetime risk of Alzheimer's disease. What physicians know, and what they should know. Arch Neurol 52:1074-1079
71. Seshadri S, Beiser A, Selhub J, Jacques PF, Rosenberg IH, D'Agostino RB, Wilson PW, Wolf PA (2002) Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. N Engl J Med 346:476-483
72. Shmeleva V, Kapustin MSI, Papayan LP, Sobczyńska-Malefora A, Harrington DJ, Savidge GF (2003) Prevalence of hyperhomocystei-nemia and the MTHFR C677T polymorphism in patients with arterial and venous thrombosis from North Western Russia. Thromb Res 111:351-356
73. Siuda J, Gorzkowska A, Patalong-Ogiewa M, Krzystanek E, Czech E, Wiechula B, Garczorz W, Danch A, Jasinska-Myga B, Opala G (2009) From mild cognitive impairment to Alzheimer's disease-influence of homocysteine, vitamin B12 and folate on cognition over time: results from one-year follow-up. Neurol Neurochir Pol 43:321-329
74. Solomon A, Kivipelto M, Wolozin B, Zhou J, Whitmer RA (2009) Midlife serum cholesterol and increased risk of Alzheimer's and vascular dementia three decades later. Dement Geriatr Cogn Disord 28:75-80
75. Styczyńska M, Strosznajder JB, Religa D, Chodakowska-Zebrowska M, Pfeffer A, Gabryelewicz T, Czapski GA, Kobrys M, Karciauskas G, Barcikowska M (2008) Association between genetic and environmental factors and the risk of Alzheimer's disease. Folia Neuro-pathol 46:249-254
76. Szolnoki Z, Somogyvari F, Kondacs A, Szobo M, Fodor L, Bene J, Melegh B (2003) Evaluation of the modifying effects of unfavourable genetypes on classical clinical risk factors for ischaemic stroke. J Neurol Neurosurg Psychiatry 74:1615-1620
77. Troen AM, Shea-Budgell M, Shukitt-Hale B, Smith DE, Selhub J, Rosenberg IH (2008) B-vitamin deficiency causes hyperhomo-cysteinemia and vascular cognitive impairment in mice. Proc Natl Acad Sci USA 105:12474-12479
78. Van Rensburg SJ, Carstens ME, Potocnik FC, Aucamp AK, Taljaard JJ (1993) Increased frequency of the transferrin C2 subtype in Alzheimer's disease. Neuroreport 4:1269-1271
79. Van Rensburg SJ, Potocnik FCV, de Villiers JNP, Kotze MJ, Taljaard JJF (2000) Earlier age of onset in Alzheimer's disease patients with both the transferrin C2 and apolipoprotein E4 alleles. Ann N Y Acad Sci 903:200-203
80. Van Rensburg SJ, Potocnik FCV, Kotze MJ, Stein DJ (2010) Antemor-tem Markers. In: Abou-Saleh MT, Katona CLE, Kumar A (eds) Principles and practice of geriatric psychiatry, 3rd edn. Wiley, Sussex, pp 299-303
81. Van Velden DP, van der Merwe S, Fourie E, Blackhurst DM, Kidd M, Kotze MJ, Mansvelt EPG (2007) The influence of a Mediterranean-like diet with and without red wine on patients with the metabolic syndrome. S Afr J Enol Vitic 28:44-49
82. Vergotine J, Thiart R, Scholtz CL, Kotze MJ (2001) Clinical versus molecular diagnosis of heterozygous familial hyper-cholesterolaemia in the South African population. S Afr Med J 91:1053-1059
83. Volzke H, Wolff B, Grimm R, Robinson DM, Sxhuster G, Herrmann FH, Motz W, Rettig R (2005) Interaction between factor V Leiden and serum LDL cholesterol increases the risk of atherosclerosis. Atherosclerosis 180:341-347
84. Wald DS, Law M, Morris JK (2002) Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. Br Med J 325:1202
85. Whitmer RA, Gunderson EP, Barrett-Connor E, Quesenberry CP Jr, Yaffe K (2005a) Obesity in middle age and future risk of dementia: a 27 year longitudinal population based study. Br Med J 330:1360
86. Whitmer RA, Sidney S, Selby J, Johnston SC, Yaffe K (2005b) Midlife cardiovascular risk factors and risk of dementia in late life. Neurology 64:277-281
87. World Health Organisation: Joint effects of risk factors. http://www.who.int/healthinfo/global-burden-disease/global-health-risks/en/ index.html. Accessed 14 March 2012
88. Zambenedetti P, De Bellis G, Biunno I, Musicco M, Zatta P (2003) Transferrin C2 variant does confer a risk for Alzheimer's disease in caucasians. J Alzheimers Dis 5:423-427
89. Zhang MY, Miao L, Li YS, Hu GY (2010) Meta-analysis of the methylenetetrahydrofolate reductase C677T polymorphism and susceptibility to Alzheimer's disease. Neurosci Res 68:142-150