Pathophysiologic relationship between Alzheimer's disease, cerebrovascular disease, and cardiovascular risk: A review and synthesis

Alzheimer's and Dementia: Diagnosis, Assessment and Disease Monitoring

Volumn 7, Issue , 2017, Pages 69-87

  Santos, Cláudia Y ^a,b   Snyder, Peter J ^a,b,c   Wu, Wen Chih ^c   Zhang, Mia ^d   Echeverria, Ana ^e   Alber, Jessica ^a,c  

^a RHODE ISLAND HOSPITAL   (United States)

^b UNIVERSITY OF RHODE ISLAND   (United States)

^c BROWN UNIVERSITY   (United States)

^d GRIFFITH UNIVERSITY   (Australia)

^e UNIVERSITY OF PUERTO RICO SCHOOL OF MEDICINE   (Puerto Rico)

Author keywords

Alzheimer's disease; Cardiovascular disease; Cerebrovascular disease; Dementia; Risk factors; Vascular contributions to cognitive impairment and dementia; VCID

Indexed keywords

5,10 METHYLENETETRAHYDROFOLATE REDUCTASE (FADH2); AMYLOID BETA PROTEIN; ANGIOTENSIN RECEPTOR ANTAGONIST; APOLIPOPROTEIN E; BETA ADRENERGIC RECEPTOR BLOCKING AGENT; DIPEPTIDYL CARBOXYPEPTIDASE INHIBITOR; DIURETIC AGENT; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; INSULIN; METFORMIN;

AEROBIC EXERCISE; AIR POLLUTION; ALZHEIMER DISEASE; ARTERIAL STIFFNESS; ATHEROSCLEROSIS; BLOOD BRAIN BARRIER; BRAIN BLOOD FLOW; CARDIOVASCULAR DISEASE; CEREBROVASCULAR DISEASE; CHOLESTEROL BLOOD LEVEL; CHOLINERGIC TRANSMISSION; COMORBIDITY; DIABETES MELLITUS; FITNESS; GENE MUTATION; GENETIC ASSOCIATION; GENETIC POLYMORPHISM; GENETIC RISK; HUMAN; HYPERTENSION; HYPOTENSION; LOCUS CERULEUS; MAJOR DEPRESSION; MILD COGNITIVE IMPAIRMENT; MYCOSIS; NERVE DEGENERATION; NONHUMAN; OBESITY; REVIEW; SMOKING;

EID: 85013643545     PISSN: None     EISSN: 23528729     Source Type: Journal    
DOI: 10.1016/j.dadm.2017.01.005     Document Type: Review

References (293)

1. [1] Oeppen, J., Vaupel, J.W., Broken limits to life expectancy. Science 296 (2002), 1029–1031.
2. [2] Christensen, K., Doblhammer, G., Rau, R., Vaupel, J.W., Ageing populations: the challenges ahead. Lancet 374 (2009), 11196–11208.
3. [3] Hebert, L.E., Weuve, J., Scherr, P.A., Evans, D.A., Alzheimer disease in the United States (2010-2050) estimated using the 2010 census. Neurology 80 (2013), 1778–1783.
4. [4] Alzheimer's Association. 2015 Alzheimer's disease facts and figures. Alzheimer's Demen, 11, 2015, 332.
5. [5] van Norden, A.G.W., van Dijk, E.J., de Laat, K.F., Scheltens, P., OldeRikkert, M.G.M., de Leeuw, F.E., Dementia: Alzheimer pathology and vascular factors: From mutually exclusive to interaction. Biochim Biophys Acta 1822 (2012), 340–349.
6. [6] Au, R., Piers, R.J., Lancashire, L., Back to the future: Alzheimer's disease heterogeneity revisited. Alzheimer's Dement 1 (2015), 368–370.
7. [7] Nygaard, H.B., Current and emerging therapies for Alzheimer's Disease. Clin Ther 35 (2013), 1480–1489.
8. [8] Latta, C.H., Brothers, H.M., Wilcock, D.M., Neuroinflammation in Alzheimer's disease: a source of heterogeneity and Target for personalized therapy. Neurosci 302 (2015), 103–111.
9. [9] Barage, S.H., Sonawane KD Amyloid cascade hypothesis: Pathogenesis and therapeutic strategies in Alzheimer's disease. Neuropeptides 52 (2015), 1–18.
10. [10] Arvanitakis, Z., Grodstein, F., Bienias, J.L., Schneider, J.A., Wilson, R.S., Kelly, J.F., et al. Relation of NSAIDs to incident AD, change in cognitive function, and AD pathology. Neurol 70 (2008), 2219–2225.
11. [11] Leoutsakos, J.M.S., Muthen, B.O., Breitner, J.C.S., Lyketsos, C.G., Effects of non-steroidal anti-inflammatory drug treatments on cognitive decline vary by phase of pre-clinical Alzheimer disease: findings from the randomized controlled Alzheimer's Disease Anti-inflammatory Prevention Trial. Geriatr Psychiatry 27 (2012), 364–374.
12. [12] Cummings, J.L., Vinters, H.V., Cole, G.M., Khachaturian, Z.S., Etiologies, pathophysiology, cognitive reserve, and treatment opportunities. Neurol 51 (1998), 2–17.
13. [13] Henley, D.B., Sundell, K.L., Sethuraman, G., Siemers, E.R., Safety profile of Alzheimer's disease populations in Alzheimer's Disease Neuroimaging Initiative and other 18-month studies. Alzheimers Dement 8 (2012), 407–416.
14. [14] Khachaturian, Z., Lombardo, J., Khachaturian, A., New methods for the analysis of complex diseases. Alzheimers Dement 6 (2011), 475–481.
15. [15] Van Broeckhoven, C., Molecular genetics of Alzheimer disease: identification of genes and gene mutations. Eur Neurol 35 (1995), 8–19.
16. [16] Goate, A., ChartierHarlin, M., Mullan, M., Brown, J., Crawford, F., Fidani, L., et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature 349 (1991), 704–706.
17. [17] Sherrington, R., Rogaev, E.I., Liang, Y., Rogaeva, E.A., Levasque, G., Ikeda, M., et al. Cloning of a gene bearing mis-sense mutations in early-onset familial Alzheimer's disease. Nature 375 (1995), 754–760.
18. [18] Levy-Lahad, E., Wasco, W., Poorkaj, P., Romano, D.M., Oshima, J., Pettingell, W.H., et al. Candidate gene for the chromosome 1 familial Alzheimer's disease locus. Science 269 (1995), 973–977.
19. [19] Rogaev, E.I., Sherrington, R., Rogeava, E.A., Levesque, G., Ikeda, M., Liang, Y., 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 376 (1995), 775–778.
20. [20] Hardy, J., Amyloid, the presenilins and Alzheimer disease. Trends Neurosci 20 (1997), 154–159.
21. [21] Cruchaga, C., Haller, G., Chakraverty, S., Mayo, K., Vallania, F.L., Mitra, R.D., et al. Rare variants in APP, PSEN1 and PSEN2 increase risk for AD in late-onset Alzheimer's disease families. PLoS One, 7, 2012, 5.
22. [22] Lord, J., Lu, A.J., Cruchaga, C., Identification of rare variants in Alzheimer's disease. Front Genet, 5, 2014, 369.
23. [23] Bales, K.R., VErina, T., Dodel, R.C., Du, Y., Altstiel, L., Bender, M., et al. Lack of apolipoprotein E dramatically reduces amyloid beta peptide deposition. Nat Genet 17 (1997), 263–264.
24. [24] Corder, E.H., Saunders, A.M., Strittmatter, W.J., Schmechel, D.E., Gaskell, P.C., Small, G.W., et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 261 (1993), 921–923.
25. [25] Corder, E.H., Saunders, A.M., Risch, N.J., Strittmatter, W.J., Schmechel, D.E., Gaskell, P.C. Jr., et al. Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease. Nat Genet 7 (1994), 180–184.
26. [26] Adluru, N., Destiche, D.J., Lu, S.Y., Doran, S.T., Birdsill, A.C., Melah, K.E., et al. White matter microstructure in late middle-age: Effects of apolipoprotein E4 and parental family history of Alzheimer's disease. Neuroimage Clin 4 (2014), 730–742.
27. [27] Wang, C., Yu, J.T., Wang, H.F., Jiang, T., Tan, C.C., Meng, X.F., et al. Meta-analysis of peripheral blood apolipoprotein E levels in Alzheimer's disease. PLoS One, 9, 2014, e89041.
28. [28] Rasmussen, K.L., Tybjaerg-Hansen, A., Nordestgaard, B.G., Frikke-Schmidt, R., Plasma levels of apolipoprotein E and risk of dementia in the general population. Ann Neurol 77 (2015), 301–311.
29. [29] Mcllroy, S.P., Dynan, K.B., Lawson, J.T., Patterson, C.C., Passmore, A.P., Moderate elevated plasma homocysteine, Methylenetrtrahydrofolate Reductase Genotype, and Risk for Stroke, Vascular Dementia, and Alzheimer Disease in Northern Ireland. Stroke 33 (2002), 2351–2356.
30. [30] Mansoori, N., Tripathi, M., Luthra, K., Alam, R., Lakshmy, R., Sharma, S., et al. MTHFR (677 and 1298) and IL-6-174 G/C genes in pathogenesis of Alzheimer's and vascular dementia and their epistatic interaction. Neurobiol Aging 33 (2012), 1003.e1–1003.e8.
31. [31] Andreassen, O.A., Djurovic, S., Thompson, W.K., Schork, A.J., Kendler, K.S., O'Donovan, M.C., et al. Improved detection of common variants associated with schizophrenia by leveraging pleiotropy with cardiovascular-disease risk factors. Am J Hum Genet 92 (2013), 197–209.
32. [32] Yokoyama, J.S., Wang, Y., Schork, A.J., Thompson, W.K., Karch, C.M., Cruchaga, C., et al., Alzheimer's Disease Neuroimaging I. Association between genetic traits for immune-mediated diseases and Alzheimer disease. JAMA Neurol 73 (2016), 691–697.
33. [33] Desikan, R.S., Schork, A.J., Wang, Y., Thompson, W.K., Dehghan, A., Ridker, P.M., et al., Inflammation Working G, International Genomics of Alzheimer's Disease P, DemGene I. Polygenic overlap between C-reactive Protein, Plasma Lipids, and Alzheimer disease. Circulation 131 (2015), 2061–2069.
34. [34] Dawber, T.R., Meadors, G.F., Moore, F.E. Jr., Epidemiological approaches to heart disease: the framingham study. Am J Public Health Nations Health 41 (1951), 279–281.
35. [35] Harrison, S.L., Ding, J., Tang, E.Y., Siervo, M., Robinson, L., Jagger, C., et al. Cardiovascular disease risk models and longitudinal changes in cognition: a systematic review. PLoS One, 9, 2014, e114431.
36. [36] Kanne, W.B., McGee, D., Gordon, T., A general cardiovascular risk profile: The Framingham study. Am J Cardiol 38 (1976), 46–51.
37. [37] Glodzik, L., Rusinek, H., Brys, M., Tsui, W.H., Switalski, R., Mosconi, L., et al. Framingham cardiovascular risk profile correlates with impaired hippocampal and cortical vasoreactivity to hypercapnia. J Cereb Blood Flow Metab 31 (2011), 671–679.
38. [38] Jefferson, A.L., Hohman, T.J., Liu, D., Haj-Hassan, S., Gifford, K.A., Benson, E.M., et al. Adverse vascular risk is related to cognitive decline in older adults. J Alzheimers Dis 44 (2015), 1361–1373.
39. [39] Viticchi, G., Falsetti, L., Buratti, L., Boria, C., Luzzi, S., Bartolini, M., et al. Framingham risk score can predict cognitive decline progression in Alzheimer's disease. Neurobiol Aging 36 (2015), 2940–2945.
40. [40] Laughlin, G.A., McEvoy, L.K., von Mühlen, D., Daniels, L.B., Kritz-Silverstein, D., Bergstrom, J., et al. Sex differences in the association of Framingham Cardiac Risk Score with cognitive decline in community-dwelling elders without clinical heart disease. Psychosom Med 73 (2011), 683–689.
41. [41] Dregan, A., Stewart, R., Gulliford, M.C., Cardiovascular risk factors and cognitive decline in adults aged 50 and over: a population-based cohort study. Age Ageing 42 (2013), 338–345.
42. [42] Kaffashian, S., Dugravot, A., Elbaz, A., Shipley, M.J., Sabia, S., Kivimäki, M., et al. Predicting cognitive decline: a dementia risk score vs. the Framingham vascular risk scores. Neurology 80 (2013), 1300–1306.
43. [43] Unverzagt, F.W., McClure, L.A., Wadley, V.G., Jenny, N.S., Go, R.C., Cushman, M., et al. Vascular risk factors and cognitive impairment in a stroke-free cohort. Neurology 77 (2011), 1729–1736.
44. [44] Kivipelto, M., Ngandy, T., Laatikainen, T., Winblad, B., Soininen, H., Tuomilehto, J., Risk Score for prediction of dementia risk in 20 years among middle aged people: a longitudinal, population-based study. Neurology 5 (2006), 735–741.
45. [45] Virta, J.J., Heikkilä, K., Perola, M., Koskenvuo, M., Räihä, I., Rinne, J.O., et al. Midlife cardiovascular risk factors and late cognitive impairment. Eur J Epidemiol 28 (2013), 405–410.
46. [46] Exalto, L.G., Quesenberry, C.P., Barnes, D., Kivipelto, M., Biessels, G.J., Whitmer, R.A., Midlife risk score for the prediction of dementia four decades later. Alzheimers Dement 10 (2014), 562–570.
47. [47] De Jong, G.I., De Vos, R.A., Steur, E.N., Luiten, P.G., Cerebrovascular hypoperfusion: a risk factor for Alzheimer's disease? Animal model and postmortem human studies. Ann Ny Acad Sci 826 (1997), 56–74.
48. [48] Feke, G.T., Hyman, B.T., Stern, R.A., Pasquale, L.R., Retinal blood flow in mild cognitive impairment and Alzheimer's disease. Alzheimer's Demen 1 (2015), 144–151.
49. [49] Skoog, I., Vascular aspects in Alzheimer's disease. J Neural Transm 59 (2000), 37–43.
50. [50] Power, M.C., Schneider, A.L., Wruck, L., Griswold, M., Coker, L.H., Alonso, A., et al. Life-course blood pressure in relation to brain volumes. Alzheimers Dement 16 (2016), 890–899.
51. [51] Santos, C.Y., Lim, Y.Y., Wu, W.C., Polynice, S., Schindler, R., Maruff, P., et al. Resting-State Cardiac Workload is related to both increased neocortical aggregation of β-Amyloid and relative impairment in spatial working memory in Pre-clinical Alzheimer's disease. J Alzheimers Dis 50 (2016), 127–131.
52. [52] Skoog, I., Lernfelt, B., Landahl, S., Palmertz, B., Andreasson, L.A., Nilsson, L., et al. 15-year longitudinal study of blood pressure and dementia. Lancet 347 (1996), 1141–1145.
53. [53] Skoog, I., Gustafson, D., Update on hypertension and Alzheimer's disease. Neurol Res 28 (2006), 605–611.
54. [54] Launer, L.J., Ross, G.W., Petrovitch, H., Masaki, K., Foley, D., White, L.R., et al. Midlife blood pressure and dementia: the Honolulu Asia Aging Study. Neurobiol Aging 21 (2000), 49–55.
55. [55] Kivipelto, M., Helkala, E.L., Laakso, M.P., Hanninen, T., Hallikainen, M., Alhainen, K., et al. Midlife vascular risk factors and Alzheimer's disease in later life: longitudinal, population based study. BMJ 322 (2001), 1447–1451.
56. [56] Ruitenberg, A., Skoog, I., Ott, A., Aevarsson, O., Witteman, J.C., Lernfelt, B., et al. Blood pressure and risk of dementia: results from the rotterdam study and the Gothenburg H-70 Study. Dement Geriatr Cogn Disord 12 (2001), 33–39.
57. [57] Power, M.C., Weuve, J., Gagne, J.J., McQueen, M.B., Viswanathan, A., Blacker, D., The association between blood pressure and incident Alzheimer disease: a systematic review and meta-analysis. Epidemiology 22 (2011), 646–659.
58. [58] Whitmer, R.A., Gustafson, D.R., Barrett-Connor, E., Haan, M.N., Gunderson, E.P., Yaffe, K., Central obesity and increased risk of dementia more than three decades later. Neurology 71 (2008), 1057–1064.
59. [59] Corrada, M., Hayden, K.M., Bullain, S.S., Paganini-Hill, A., DeMoss, J., Aguirre, C., et al. Age of onset of hypertension and risk of dementia in the oldest-old: the 90+ study. Alzheimer Dement, 10, 2014, 501.
60. [60] Khachaturian, A.S., Zandi, P.P., Lyketsos, C.G., Hayden, K.M., Skoog, I., Norton, M.C., et al. Antihypertensive medication use and incident Alzheimer disease: the cache County Study. Arch Neurol 63 (2006), 686–692.
61. [61] Yasar, S., Xia, J., Yao, W., Furberg, C.D., Xue, Q.L., Mercado, C.I., et al. Antihypertensive drugs decrease risk of Alzheimer disease: ginkgo evaluation of memory study. Neurology 81 (2013), 896–903.
62. [62] Gelber, R.P., Ross, G.W., Petrovitch, H., Masaki, K.H., Launer, L.J., White, L.R., Antihypertensive medication use and risk of cognitive impairment: the Honolulu-Asia Aging Study. Neurology 81 (2013), 888–895.
63. 63 Soto, M.E., Abellan van Kan, G., Nourhashemi, F., Gillette-Guyonnet, S., Cesari, M., Cantet, C., et al. Angiotestin converting enzyme inhibitors and Alzheimer's disease progression in older adults: results from the Reseau sur la Maladie d'Alzheimer Francais Cohort. J Am Ger Soc 61 (2013), 1482–1484.
64. [64] Rosenberg, P.B., Mielke, M.M., Tschanz, J., Cook, L., Corcoran, C., Hayden, K.M., et al. Effects of Cardiovascular Medications on Rate of Functional Decline in Alzheimer Disease. Am J Geriatr Psychiatry 16 (2008), 883–892.
65. [65] Verghese, J., Lipton, R.B., Katz, M.J., Hall, C.B., Derby, C.A., Kuslansky, G., et al. Leisure Activities and the Risk of Dementia in the Elderly. N Engl J Med 348 (2003), 2508–2516.
66. [66] Nilsson, S.E., Read, S., Berg, S., Johansson, B., Melander, A., Lindblad, U., Low systolic blood pressure is associated with impaired cognitive function in the oldest old: longitudinal observations in a population-based sample 80 years and older. Aging Clin Exp Res 19 (2007), 41–47.
67. [67] Qiu, C., Von Strauss, E., Fastbom, J., Winblad, B., Fratiglioni, L., Low blood pressure and risk of dementia in the Kungsholmen project: a 6-year follow-up study. Arch Neurol 60 (2003), 223–228.
68. [68] Kennelly, S.P., Lawlor, B.A., Kenny, R.A., Blood pressure and dementia – a comprehensive review. Ther Adv Neurol Disord 2 (2009), 241–260.
69. [69] Björkhem, I., Meaney, S., Brain cholesterol: long secret life behind a barrier. Arterioscler Thromb Vasc Biol 24 (2004), 806–815.
70. [70] Baum, L., Wiebusch, H., Pang, C.P., Roles for lipoprotein lipase in Alzheimer's disease: an association study. Microsc Res Tech 50 (2000), 291–296.
71. [71] Blain, J.F., Aumont, N., Théroux, L., Dea, D., Poirier, J., A polymorphism in lipoprotein lipase affects the severity of Alzheimer's diseasepathophysiology. Eur J Neurosci 24 (2006), 1245–1251.
72. [72] Xie, C., Wang, Z.C., Liu, X.F., Yang, M.S., The common biological basis for common complex diseases: evidence from lipoprotein lipase gene. Eur J Hum Genet 18 (2010), 3–7.
73. [73] Blain, J.F., Poirier, J., Cholesterol homeostasis and the pathophysiology of Alzheimer's disease. Expert Rev Neurother 4 (2004), 823–829.
74. [74] Kalaria, R.N., Akinyemi, R., Ihara, M., Does vascular pathology contribute to Alzheimer changes?. J Neurol Sci 322 (2012), 141–147.
75. [75] Koudinov, A.R., Koudinova, N.V., Essential role for cholesterol in synaptic plasticity and neuronal degeneration. FASEB J 15 (2001), 1858–1860.
76. [76] Mauch, D.H., Nagler, K., Schumacher, S., Goritz, C., Muller, E.C., Otto, A., et al. CNS synaptogenesis promoted by glia-derived cholesterol. Science 294 (2001), 1354–1357.
77. [77] Snowdon, D.A., Greiner, L.H., Mortimer, J.A., Riley, K.P., Greiner, P.A., Markesberry, W.R., Brain infarction and clinical expression of Alzheimer's disease. The Nun Study. JAMA 277 (1997), 813–817.
78. [78] Hofman, A., Ott, A., Breteler, M.M.B., Bots, M.L., Slooter, A.J., van Harskamp, F., et al. Atheriosclerosis, apolipoprotein E, and prevalence of dementia and Alzheimer's disease in the Rotterdam study. Lancet 349 (1997), 151–154.
79. [79] Eichner, J.E., Dunn, S.T., Perveen, G., Thompson, D.M., Stewart, K.E., Stroehla, B.C., Apolipoprotein E polymorphism and cardiovascular disease: a HuGE review. Am J Epidemiol 155 (2002), 487–495.
80. [80] Notkola, I.L., Sulkava, R., Pekkanen, J., Erkinjuntti, T., Ehnholm, C., Kivinen, P., et al. Serum total cholesterol, apolipoprotein E epsilon 4 allele, and Alzheimer's disease. Neuroepidemiology 17 (1998), 14–20.
81. [81] Mielke, M.M., Zandi, P.P., Shao, H., Waern, M., Ostling, S., Guo, X., et al. The 32-year relationship between cholesterol and dementia from midlife to late life. Neurology 75 (2010), 1888–1895.
82. [82] Mielke, M.M., Zandi, P.P., Sjogren, M., Gustafson, D., Ostling, S., Steen, B., et al. High total cholesterol levels in late life associated with a reduced risk of dementia. Neurology 64 (2005), 1689–1695.
83. [83] Wolozin, B., Kellman, W., Ruosseau, P., Celesia, G.G., Siegel, G., Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-metyglutaryl coenzyme A reductase inhibitors. Arch Neurol 57 (2000), 1439–1443.
84. [84] Li, G., Larson, E.B., SOnnen, J.A., Shofer, J.B., Petrie, E.C., Schantz, A., et al. Statin therapy is associated with reduced neuropathologic changes in Azlheimer's disease. Neurology 69 (2007), 878–885.
85. [85] Jick, H., Zornberg, G.L., Jick, S.S., Seshadri, S., Drachman, D.A., Statins and the risk of dementia. Lancet 11 (2000), 1627–1631.
86. [86] Feldman, H.H., Doody, R.S., Kivipelto, M., Sparks, D.L., Waters, D.D., Jones, R.W., et al. Randomized controlled trial of atorvastatin in mild to moderate Alzheimer disease: LEADe. Neurology 74 (2010), 956–964.
87. [87] McGuinness, B., Craig, D., Bullock, R., Passmore, P., Statins for the prevention of dementia. Cochrane Database Syst Rev, 2, 2009, CD003160.
88. [88] Biessels, G.J., Staekenborg, S., Brunner, E., Brayne, C., Scheltens, P., Risk of dementia in diabetes mellitus: a systematic review. Lancet Neurol 5 (2006), 64–74.
89. [89] Schilling, M.A., Unraveling Alzheimer's: Making Sense of the Relationship between Diabetes and Alzheimer's Disease. J Alzheimer's Dis 51 (2016), 961–977.
90. [90] Carantoni, M., Zuliani, G., Munari, M.R., D'Elia, K., Palmieri, E., Fellin, R., Alzheimer disease and vascular dementia: Relationships with fasting glucose and insulin levels. Dement Geriatr Cogn Disord 11 (2000), 176–178.
91. [91] Razay, G., Wilcock, G.K., Hyperinsulinemia andAlzheimer's disease. Age Ageing 23 (1994), 396–399.
92. [92] Fujisawa, Y., Sasaki, K., Akiyama, K., Increased insulin levels after OGTT load in peripheral blood and cerebrospinal fluid of patients with dementia of Alzheimer type. Biol Psychiatry 30 (1991), 1219–1228.
93. [93] Craft, S., Baker, L.D., Montine, T.J., Minoshima, S., Watson, G.S., Claxton, A., et al. Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment a pilot clinical trial. Arch Neurol 69 (2012), 29–38.
94. [94] Reger, M.A., Watson, G.S., Green, P.S., Wilkinson, C.W., Baker, L.D., Cholerton, B., et al. Intranasal insulin improves cognition and modulates beta-amyloid in early AD. Neurology 70 (2008), 440–448.
95. [95] Freiherr, J., Hallschmid, M., Frey, W.H. II, Bruenner, Y.F., Chapman, C.D., Hoelscher, C., et al. Intranasal Insulin as a treatment for Alzheimer's disease: A review of basic research and clinical evidence. CNS Drugs 27 (2013), 505–514.
96. [96] Talbot, K., Wang, H.-Y., Kazi, H., Han, L.-Y., Bakshi, K.P., Stucky, A., et al. Demonstrated brain insulin resistance in Alzheimer's disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. J Clin Invest 122 (2012), 1316–1338.
97. [97] de la Monte, S.M., Type 3 diabetes is sporadic Alzheimer's disease: mini-review. Eur Neuropsychopharmacol 24 (2014), 1954–1960.
98. [98] Ahmed, S., Mahmood, Z., Zahid, S., Linking insulin with Alzheimer's disease: emergence as type III diabetes. Neurolog Sci 36 (2015), 1763–1769.
99. [99] Chatterjee, S., Peters, S.A., Woodward, M., Mejia Arango, S., Batty, G.D., Beckett, N., et al. Type 2 Diabetes as a Risk Factor for Dementia in Women Compared With Men: A Pooled Analysis of 2.3 Million People Comprising More Than 100,000 Cases of Dementia. Diabetes Care 39 (2016), 300–307.
100. [100] Ott, A., Stolk, R.P., van Harskamp, F., Pols, H.A., Hofman, A., Breteler, M.M., Diabetes mellitus and the risk of dementia: The Rotterdam Study. Neurology 53 (1999), 1937–1942.
101. [101] Xu, W.L., von Strauss, E., Qiu, C.X., Winblad, B., Fratiglioni, L., Uncontrolled diabetes increases the risk of Alzheimer's disease. Diabetologia, 52, 2009, 1031.
102. [102] Ahtiluoto, S., Diabetes, Alzheimer disease, and vascular dementia: a population-based neuropathologic study. Neurology, 75, 2010, 13.
103. [103] Huang, C.C., Chung, C.M., Leu, H.B., Lin, L.Y., Chiu, C.C., Hsu, C.Y., et al. Diabetes mellitus and the risk of Alzheimer's disease: a nationwide population-based study. PLoS ONE, 9, 2014, e87095.
104. [104] Luchsinger, J.A., Tang, M.X., Shea, S., Mayeux, R., Hyperinsulinemia and risk of Alzheimer disease. Neurology 63 (2004), 1187–1192.
105. [105] Luchsinger, J.A., Perez, T., Chang, H., Mehta, P., Steffener, J., Pradabhan, G., et al. Metformin in Amnestic Mild Cognitive Impairment: Results of a Pilot Randomized Placebo Controlled Clinical Trial. J Alzheimers Dis 51 (2016), 501–514.
106. [106] Roses, A.D., Saunders, A.M., Lutz, M.W., Zhang, N., Hariri, A.R., Asin, K.E., et al. New applications of disease genetics and pharmacogenetics to drug development. Curr Opin Pharmacol 14 (2014), 81–89.
107. [107] Claxton, A., Baker, L.D., Hanson, A., Trittschuh, E.H., Cholerton, B., Morgan, A., et al. Long-acting intranasal insulin detemir improves cognition for adults with mild cognitive impairment or early-stage Alzheimer's disease dementia. J Alzheimers Dis 44 (2015), 897–906.
108. [108] Novak, V., Milberg, W., Hao, Y., Munshi, M., Novak, P., Galica, A., et al. Enhancement of vasoreactivity and cognition by intranasal insulin in type 2 diabetes. Diabetes Care 37 (2014), 751–759.
109. [109] Hughes, T.M., Craft, S., The role of insulin in the vascular contributions to age-related dementia. Biochim Biophys Acta 1862 (2016), 983–991.
110. [110] Scarmeas, N., Luchsinger, J.A., Schupf, N., Brickman, A.M., Cosentino, S., Tang, M.X., et al. Physical Activity, Diet, and Risk of Alzheimer Disease. JAMA 302 (2009), 627–637.
111. [111] Morris, M.C., Tangney, C.C., Wang, Y., Sacks, F.M., Bennett, D.A., Aggarwal, N.T., MIND diet associated with reduced incidence of Alzheimer's disease. Alzheimer Dement 11 (2015), 1007–1014.
112. [112] Morris, M.C., Tangney, C.C., Wang, Y., Sacks, F.M., Barnes, L.L., Bennett, D.A., et al. MIND diet slows cognitive decline with aging. Alzheimer Dement 11 (2015), 1015–1022.
113. [113] Martins, I.J., Hone, E., Foster, J.K., Sünram-Lea, S.I., Gnjec, A., Fuller, S.J., et al. Apolipoprotein E, cholesterol metabolism, diabetes, and the convergence of risk factors for Alzheimer's disease and cardiovascular disease. Mol Psychiatry 11 (2006), 721–736.
114. [114] Gustafson, D.R., Adiposity and cognitive decline: underlying mechanisms. J Alzheimers Dis 30:Suppl 2 (2012), S97–S112.
115. [115] Elias, M.F., Elias, P.K., Sullivan, L.M., Wolf, P.A., D'Agostino, R.B., Lower cognitive function in the presence of obesity and hypertension: the Framingham heart study. Int J Obes Relat Metab Disord 27 (2003), 260–268.
116. [116] Hayden, K.M., Zandi, P.P., Lyketsos, C.G., Khachaturian, A.S., Bastian, L.A., Charoonruk, G., et al. Vascular risk factors for incident Alzheimer disease and vascular dementia: the Cache County study. Alzheimer Dis Assoc Disord 20 (2006), 93–100.
117. [117] 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 163 (2003), 1524–1528.
118. [118] Anstey, K.J., Cherbuin, N., Budge, M., Young, J., Body mass index in midlife and late-life as a risk factor for dementia: a meta-analysis of prospective studies. Obes Rev 12 (2011), e426–e437.
119. [119] Whitmer, R.A., Gunderson, E.P., Quesenberry, C.P. Jr., Zhou, J., Yaffe, K., Body mass index in midlife and risk of Alzheimer disease and vascular dementia. Curr Alzheimer Res 4 (2007), 103–109.
120. [120] Luchsinger, J.A., Patel, B., Tang, M.X., Schupf, N., Mayeux, R., Measures of adiposity and dementia risk in elderly persons. Arch Neurol 64 (2007), 392–398.
121. [121] Profenno, L.A., Porteinsoon, A.P., Faraone, S.V., Meta-analysis of Alzheimer's disease risk with obesity, diabetes, and related disorders. Inflamm Alzheimer Dis 67 (2009), 505–512.
122. [122] Luepker, R.V., Lakshminarayan, K., Cardiovascular and cerebrovascular diseases. Oxford textbook Public Health Pract Public Health 3 (2009), 971–996.
123. [123] Baker, L.D., Frank, L.L., Foster-Schubert, K., Green, P.S., Wilkinson, C.W., McTiernan, A., et al. Aerobic exercise improves cognition for older adults with glucose intolerance, a risk factor for Alzheimer's disease. J Alzheimers Dis 22 (2010), 569–579.
124. [124] Cotman, C.W., Berchtold, N.C., Exercise: a behavioral intervention to enhance brain health and plasticity. Trends Neurosci 25 (2002), 295–301.
125. [125] Scarmeas, N., Luchsinger, J.A., Schupf, N., Brickman, A.M., Cosentino, S., Tang, M.X., et al. Exercise plays a preventive role against Alzheimer's disease. J Alzheimers Dis 20 (2010), 777–783.
126. [126] Erickson, K.I., Voss, M.W., Prakash, R.S., Basak, C., Szabo, A., Chaddock, L., et al. Exercise training increases size of hippocampus and improves memory. Proc Natl Acad Sci U.S.A 198 (2011), 3017–3022.
127. [127] Baker, L.D., Frank, L.L., Foster-Schubert, K., Green, P.S., Wilkinson, C.W., McTiernan, A., et al. Effects of aerobic exercise on mild cognitive impairment: a controlled trial. Arch Neurol 67 (2010), 71–79.
128. [128] Colcombe, S.J., Erickson, K.I., Raz, N., Webb, A.G., Cohen, N.J., McAuley, E., et al. Aerobic fitness reduces brain tissue loss in aging humans. J Gerontol A Biol Sci Med Sci 58 (2003), 176–180.
129. [129] Whiteman, A., Young, D.E., He, X., Chen, T.C., Wagenaar, R.C., Stern, C., et al. Interaction between serum BDNF and aerobic fitness predicts recognition memory in healthy young adults. Behav Brain Res 259 (2014), 302–312.
130. [130] Yaffe, K., Barnes, D., Nevitt, M., Lui, L.Y., Covinsky, K., A prospective study of physical activity and cognitive decline in elderly women: women who walk. Arch Intern Med 161 (2001), 1703–1708.
131. [131] Podewils, L.J., Guallar, E., Kuller, L.H., Fried, L.P., Lopez, O.L., Carlson, M., et al. Physical activity, APOE genotype, and dementia risk: findings from the Cardiovascular Health Cognition Study. Am J Epidemiol 161 (2005), 639–651.
132. [132] Larson, E.B., Wang, L., Bowen, J.D., McCormick, W.C., Teri, L., Crane, P., et al. Exercise is associated with reduced risk for incident dementia among persons 65 years of age and older. Ann Intern Med 144 (2006), 73–81.
133. [133] Colcombe, S.J., Erickson, K.I., Scalf, P.E., Kim, J.S., Prakash, R., McAuley, E., et al. Aerobic exercise training increases brain volume in aging humans. J Gerontol A Biol Sci Med Sci 61 (2006), 1166–1170.
134. [134] Papenberg, G., Ferencz, B., Mangialasche, F., Mecocci, P., Cecchetti, R., Kalpouzos, G., et al. Physical activity and inflammation: effects on gray-matter volume and cognitive decline in aging. Hum Brain Mapp 37 (2016), 3462–3473.
135. [135] Groot, C., Hooghiemstra, A.M., Raijmakers, P.G., van Berckel, B.N., Scheltens, P., Scherder, E.J., et al. The effect of physical activity on cognitive function in patients with dementia: A meta-analysis of randomized control trials. Ageing Res Rev 25 (2016), 13–23.
136. [136] Sink, K.M., Espeland, M.A., Castro, C.M., Church, T., Cohen, R., Dodson, J.A., et al. Effect of a 24-month physical activity intervention vs health education on cognitive outcomes in sedentary older adults: the LIFE randomized trial. JAMA 314 (2015), 781–790.
137. [137] Espeland, M.A., Lipska, K., Miller, M.E., Rushing, J., Cohen, R.A., Verghese, J., et al., Investigators ftLS. Effects of Physical Activity Intervention on Physical and Cognitive Function in Sedentary Adults With and Without Diabetes. J Gerontol A Biol Sci Med Sci, 2016 glw179.
138. [138] Demeersman, R.E., Heart-rate-variability and aerobic fitness. Am Heart J 125 (1993), 726–731.
139. [139] Tulppo, M.P., Mäkikallio, T.H., Seppänen, T., Laukkanen, R.T., Huikuri, H.V., Vagal modulation of heart rate during exercise: effects of age and physical fitness. Am J Physiol Heart Circ Physiol 274 (1998), 424–429.
140. [140] Kemp, A.H., Quintana, D.S., The relationship between mental and physical health: insights from the study of heart rate variability. Int J Psychophysiol 89 (2013), 288–296.
141. [141] Thayer, J.F., Yamamoto, S.S., Brosschot, J.F., The relationship of autonomic imbalance, heart rate variability and cardiovascular disease risk factors. Int J Cardiol 141 (2010), 122–131.
142. [142] Dywan, J., Mathewson, K.J., Choma, B.L., Rosenfeld, B., Segalowitz, S.J., Autonomic and electrophysiological correlates of emotional intensity in older and younger adults. Psychophysiology 45 (2008), 389–397.
143. [143] Basile, J.N., Bloch, M.J., Determining the relative antihypertensive potency and relative cardiovascular risk reduction associated with different thiazide and thiazide-type diuretics. JCH 15 (2013), 359–361.
144. [144] Malacco, E., Mancia, G., Rappelli, A., Menotti, A., Zuccaro, M.S., Coppini, A., Shell Investigators. Treatment of isolated systolic hypertension: the SHELL study results. Blood Press 12 (2013), 160–167.
145. [145] Jamerson, K., Weber, M.A., Bakris, G.L., Dahlöf, B., Pitt, B., Shi, V., et al. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med 359 (2008), 2417–2428.
146. [146] Yusuf, S., Teo, K., Anderson, C., Pogue, J., Dyal, L., Copland, I., et al. Effects of the angiotensin–receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: a randomised controlled trial. Lancet 372 (2008), 1174–1183.
147. [147] Tofler, G.H., Spinaze, M., Shaw, E., Buckley, T., Therapy for triggered acute risk prevention in subjects at increased cardiovascular risk. Am J Cardiol 111 (2013), 1755–1758.
148. [148] Shaw, E., Tofler, G.H., Buckley, T., Bajorek, B., Ward, M., Therapy for triggered acute risk prevention: a study of feasibility. Heart Lung Circ 18 (2009), 347–352.
149. [149] Kendrick, J., Shlipak, M.G., Targher, G., Cook, T., Lindenfeld, J., Chonchol, M., Effect of Lovastatin on primary prevention of cardiovascular events in mild CKD and kidney function loss: a post hoc analysis of the Air Force/Texas Coronary Atherosclerosis Prevention Study. Am J Kid Dis 55 (2010), 42–49.
150. [150] Tikkanen, M.J., Fayyad, R., Faergeman, O., Olsson, A.G., Wun, C.C., Laskey, R., et al., IDEAL Investigators. Effect of intensive lipid lowering with atorvastatin on cardiovascular outcomes in coronary heart disease patients with mild-to-moderate baseline elevations in alanine aminotransferase levels. Int J Cardiol 168 (2013), 3846–3852.
151. [151] Velentgas, P., West, W., Cannuscio, C.C., Watson, D.J., Walker, A.M., Cardiovascular risk of selective cyclooxygenase-2 inhibitors and other non-aspirin non-steroidal anti-inflammatory medications. Pharmacoepidemiol Drug Safe 15 (2006), 641–652.
152. [152] Roumie, C.L., Choma, N.N., Kaltenbach, L., Mitchel, E.F., Arbogast, P.G., Griffin, M.R., Non-aspirin NSAIDs, cyclooxygenase-2 inhibitors and risk for cardiovascular events–stroke, acute myocardial infarction, and death from coronary heart disease. Pharmacoepidemiol Drug Safe 18 (2009), 1053–1063.
153. [153] Cederholm, J., Zethelius, B., Nilsson, P.M., Eeg-Olofsson, K., Eliasson, B., Gudbjornsdottir, S., Effect of tight control of HbA1c and blood pressure on cardiovascular diseases in type 2 diabetes: an observational study from the Swedish National Diabetes Register (NDR). Diabetes Res Clin Pract 86 (2009), 74–81.
154. [154] Varma, S., Piatt, G.A., The effect of controlling the ABC's of diabetes on cardiovascular disease in a community-based endocrinology practice. JDM, 3, 2013, 4.
155. [155] Speretta, G.F., Silva, A.A., Vendramini, R.C., Zanesco, A., Delbin, M.A., Menani, J.V., et al. Resistance training prevents the cardiovascular changes caused by high-fat diet. Life Sci 146 (2016), 154–162.
156. [156] Mora, S., Cook, N., Buring, J.E., Ridker, P.M., Lee, I.M., Physical activity and reduced risk of cardiovascular events. potential mediating mechanisms. Circulation, 116, 2007, 19.
157. [157] Dehghan, M., Mente, A., Teo, K.K., Gao, P., Sleight, P., Dagenais, G., et al. Relationship between healthy diet and risk of cardiovascular disease among patients on drug therapies for secondary prevention. Circulation 126 (2012), 2705–2712.
158. [158] Rumawas, M.E., Meigs, J.B., Dwyer, J.T., McKeown, N.M., Jacques, P.F., Mediterranean-style dietary pattern, reduced risk of metabolic syndrome traits, and incidence in the Framingham Offspring Cohort. Am J Clin Nutr 90 (2009), 1608–1614.
159. [159] Luchsinger, J.A., Reitz, C., Honig, L.S., Tang, M.X., Shea, S., Mayeux, R., Aggregation of vascular risk factors and risk of incident Alzheimer disease. Neurology 65 (2005), 545–551.
160. [160] Peters, R., Poulter, R., Warner, J., Beckett, N., Burch, L., Bulpitt, C., Smoking, dementia and cognitive decline in the elderly, a systematic review. BMC Geriatr, 8, 2008, 36.
161. [161] Cataldo, J.K., Prochaska, J.J., Glantz, S.A., Cigarette smoking is a risk factor for Alzheimer's Disease: an analysis controlling for tobacco industry affiliation. J Alzheimers Dis 19 (2010), 465–480.
162. [162] Bazzano, L.A., He, J., Muntner, P., Vupputuri, S., Whelton, P.K., Relationship between cigarette smoking and novel risk factors for cardiovascular disease in the United States. Ann Intern Med 138 (2003), 891–897.
163. [163] Hankey, G.J., Eikelboom, J.W., Homocysteine and vascular disease. Lancet 354 (1999), 407–413.
164. [164] Sachdev, P.S., Parslow, R.A., Lux, O., Salonikas, C., Wen, W., Naidoo, D., et al. Relationship of homocysteine, folic acid and vitamin B12 with depression in a middle-aged community sample. Psychol Med 35 (2005), 529–538.
165. [165] Seshadri, S., Wolf, P.A., Beiser, A.S., Selhub, J., Au, R., Jacques, P.F., et al. Association of plasma total homocysteine levels with subclinical brain injury: cerebral volumes, white matter hyperintensity, and silent brain infarcts at volumetric magnetic resonance imaging in theFramingham Offspring Study. Arch Neurol 65 (2008), 642–649.
166. [166] Ambrose, J.A., Barua, R.S., The pathophysiology of cigarette smoking and cardiovascular disease: an update. J Am Coll Cardiol 43 (2004), 1731–1737.
167. [167] Giunta, B., Deng, J., Jin, J., Sadic, E., Rum, S., Zhou, H., et al. Evaluation of how cigarette smoke is a direct risk factor for Alzheimer's disease. Technol Innov 14 (2012), 39–48.
168. [168] Merchant, C., Tang, M.X., Albert, S., Manly, J., Stern, Y., Mayeux, R., The influence of smoking on the risk of Alzheimer's disease. Neurology 52 (1999), 1408–1412.
169. [169] Anstey, K.J., von Sanden, C., Salim, A., O'Kearney, R., Smoking as a risk factor for dementia and cognitive decline: a meta-analysis of prospective studies. Am J Epidemiol 166 (2007), 367–378.
170. [170] Barnes, D.E., The projected impact of risk factor reduction on Alzheimer's disease prevalence. Lancet Neurol 10 (2011), 819–828.
171. [171] Rapp, M.A., Schnaider-Beeri, M., Grossman, H.T., Sano, M., Perl, D.P., Purohit, D.P., et al. Increased hippocampal plaques and tangles in patients with Alzheimer disease with a lifetime history of major depression. Arch Gen Psychiatry 63 (2006), 161–167.
172. [172] Meeks, T.W., Ropacki, S.A., Jest, D.V., The neurobiology of neuropsychiatric syndromes in dementia. Curr Opin Psychiatry 19 (2006), 581–586.
173. [173] Snyder, P.J., Pearn, A.M., Historical note on Darwin's consideration of early-onset dementia in older persons, thirty-six years before Alzheimer's initial case report. Alzheimer Dement 3 (2007), 137–142.
174. [174] Zweig, Rm, Ross, C.A., Hedreen, J.C., The neuropathology of aminergic nuclei in Alzheimer's disease. Ann Neurol 24 (1988), 233–242.
175. [175] Zubenko, G.S., Moosy, J., Kopp, U., Neurochemical correlates of major depression in primary dementia. Arch Neurol 47 (1990), 209–214.
176. [176] Forstl, H., Burns, A., Luthert, P., Clinical and neuropathological correlates of depression in Alzheimer's disease. Psychol Med 22 (1992), 877–884.
177. [177] Charlson, F.J., Stapelberg, N.J., Baxter, A.J., Whiteford, H.A., Should global burden of disease estimates include depression as a risk factor for coronary heart disease?. BMC Med, 9, 2011, 47.
178. [178] Elderon, L., Whooley, M.A., Depression and cardiovascular disease. Prog Cardiovasc Dis 55 (2013), 511–523.
179. [179] Panagiotakos, D.B., Pitsavos, C., Chrysohoou, C., Kavouras, S., Stefanadis, C., The associations between leisure-time physical activity and inflammatory and coagulation markers related to cardiovascular disease: The attica study. Prev Med 40 (2005), 432–437.
180. [180] Eastwood, M.R., Rifat, S.L., Nobbs, H., Ruderman, J., Mood disorder following cerebrovascular accident. Br J Psych 154 (1989), 195–200.
181. [181] Tiemeier, H., van Tuijl, H.R., Hofman, A., Meijer, J., Kiliaan, A.J., Breteler, M.M.B., Vitamin B12, folate, and homocysteine in depression: the Rotterdam Study. Am J Psychiatr 159 (2002), 2099–2101.
182. [182] Flicker, L., Martins, R.N., Thomas, J., Acres, J., Taddei, K., Norman, P., et al. Homocysteine, Alzheimer genes and proteins and measures of cognition and depression in older men. J Alzheimers Dis 6 (2004), 329–336.
183. [183] Alonso, R., Pisa, D., Rabano, A., Carrasco, L., Alzheimer's disease and disseminated mycoses. Eur J Clin Microbiol Infect Dis 33 (2014), 1125–1132.
184. [184] Pisa, D., Alonso, R., Rabano, A., Rodal, I., Carrasco, L., Different brain regions are infected with fungi in Alzheimer's disease. Sci Rep, 4, 2015, 15015.
185. [185] Soscia, S.J., Kirby, J.E., Washicosky, K.J., Tucker, S.M., Ingelsson, M., Hyman, B., et al. The Alzheimer's disease-associated Amyloid β-Protein is an Antimicrobial Peptide. PLoS One, 5, 2010, 9505.
186. [186] Ciornei, C.D., Tapper, H., Bjartell, A., Sternby, N.H., Bodelsson, M., Human antimicrobial peptide LL-37 is present in atherosclerotic plaques and induces death of vascular smooth muscle cells: a laboratory study. BMC Cardiovasc Disord, 6, 2006, 49.
187. [187] Subasinghe, S., Unabia, S., Barrow, C.J., Mok, S.S., Aguilar, M.I., Small, D.H., Cholesterol is necessary both for the toxic effect of Abeta peptides on vascular smooth muscle cells and for Abeta binding to vascular smooth muscle cell membranes. J Neurochem 84 (2003), 471–479.
188. [188] Miklossy, J., Emerging roles of pathogens in Alzheimer's disease. Expert Rev Mol Med 13 (2011), 30–34.
189. [189] Santos-Gallego, C.G., Badimon, J.J., The sum of two evils: pneumonia and myocardial infarction: is platelet activation the missing link?. J Am Coll Cardiol 64 (2014), 1926–1928.
190. [190] Wei, Y., Zhang, J.J., Li, Z., Gow, A., Chung, K.F., Hu, M., et al. Chronic exposure to air pollution particles increases the risk of obesity and metabolic syndrome: findings from a natural experiment in Beijing. FASEB J 30 (2016), 2115–2122.
191. [191] Mordukhovich, I., Coull, B., Kloog, I., Koutrakis, P., Vokonas, P., Schwartz, J., Exposure to sub-chronic and long-term particulate air pollution and heart rate variability in an elderly cohort: the Normative Aging Study. Environ Health, 6, 2015, 87.
192. [192] Brook, R.D., Cardiovascular effects of air pollution. Clin Sci 115 (2008), 175–187.
193. [193] Wu, Y.C., Lin, Y.C., Yu, H.L., Chen, J.H., Chen, T.F., Sun, Y., et al. Association between air pollutants and dementia risk in the elderly. Alzheimer Dement 1 (2015), 220–228.
194. [194] Bostrom, K., Hassler, O., A pilot microradiological investigation on the occurrence of calcifications in various arteries of the human body. J Gerontol 21 (1966), 97–102.
195. [195] Moody, D.M., Brown, W.R., Challa, V.R., Anderson, R.L., Periventricular venous collagenosis: association with leukoaraiosis. Radiology 194 (1995), 469–476.
196. [196] Farkas, E., Luiten, P.G., Cerebral microvascular pathology in aging and Alzheimer's disease. Prog Neurobiol 64 (2001), 575–611.
197. [197] Diemer, N.H., Double-tracer study of the fine regional blood-brain barrier glucose transfer in the rat by computer-assisted autoradiography. J Cereb Blood Flow Metab 5 (1985), 282–289.
198. [198] Grammas, P., Sanchez, A., Tripathy, D., Luo, E., Martinez, J., Vascular signaling abnormalities in Alzheimer disease. Cleve Clin J Med 78 (2011), 50–53.
199. [199] Marchant, N.L., Reed, B.R., Sanossian, N., Madison, C.M., Kriger, S., Dhada, R., et al. The Aging brain and cognition: contribution of vascular injury and Aβ to mild cognitive dysfunction. JAMA Neurol 70 (2013), 488–495.
200. [200] Ikram, M., Poels, M., van der Lugt, A., Hofman, A., Krestin, G., Breteler, M., et al. Cerebral microbleeds are associates with worse cognitive function: The Rotterdam Scan Study. Alzheimer Dement, 7, 2011, 296.
201. [201] Braaten, A.J., Parsons, T.D., McCue, R., Sellers, A., Burns, W.J., Neurcognitive differential diagnosis of dementing disease Alzheimer's dementia, Vascular dementia, Frontotemporal dementia and Major depressive disorder. Intern J Neurosci 116 (2006), 1271–1293.
202. [202] Karantzoulis, S., Galvin, J.E., Distinguishing Alzheimer's disease from other major forms of dementia. Expert Rev Neurother 11 (2011), 1579–1591.
203. [203] Truelsen, T., Begg, S., Mathers, C., The global burden of cerebrovascular disease. Global Burden of Disease. 2000, World Health Organization, Geneva.
204. [204] Jellinger, K.A., Alzheimer disease and cerebrovascular pathology: an update. J Neural Transm 109 (2002), 813–836.
205. [205] Chui, H.C., Zheng, L., Reed, B.R., Vinters, H.V., Vascular risk factors and Alzheimer's disease: are these risk factors for plaques and tangles or for concomitant vascular pathology that increases the likelihood of dementia? An evidence-based review. Alzheimers Res Ther, 4, 2012, 1.
206. [206] Arvanitains, Z., Capuano, A.W., Leurgans, S.E., Bennet, D.A., Schneider, J.A., Relation of cerebral vessel disease to Alzheimer's disease dementia and cognitive function in elderly people: a cross-sectional study. Lancet Neurol 15 (2016), 934–943.
207. [207] Jefferson, A.L., Beiser, A., Himali, J., Seshadri, S., O'Donnell, C.J., Manning, W., et al. Low Cardiac Index is associated with incident dementia and Alzheimer's disease: the Framingham Heart Study. Alzheimer Dement, 10, 2014, 678.
208. [208] Carmichael, O.T., Kuller, L.H., Lopez, O.L., Thompson, P.M., Dutton, R.A., Lu, A., et al. Ventricular volume and dementia progression in the Cardiovascular Health Study. Neurbiol Aging 28 (2007), 389–397.
209. [209] Guo, X., Ostling, S., Skoog, I., Risk of Dementia is increased both before and after stroke. Alzheimer Dement 10 (2014), 747–748.
210. [210] Mosley, T.H., Knopman, D.S., Catellier, D.J., Bryan, N., Hutchinson, R.G., Grothues, C.A., et al. Cerebral MRI findings and cognitive functioning: The Atherosclerosis Risk in Communities Study. Neurology 64 (2005), 2056–2062.
211. [211] Vemuri, P., Lesnick, T.G., Przybelski, S.A., Knopman, D.S., Preboske, G.M., Kantarci, K., et al. Vascular and amyloid pathologies are independent predictor of cognitive decline in normal elderly. Brain 138 (2015), 761–771.
212. [212] Ye, B.S., Seo, S.W., Kim, G.H., Noh, Y., Cho, H., Yoon, C.W., et al. Amyloid burden, cerebrovascular disease, brain atrophy, and cognition in cognitively impaired patients. Alzheimer Dement 11 (2015), 494–503.
213. [213] Willis, T., Instructions and prescripts for curing the apoplexy. Pordage, S., (eds.) The London Practice of Physic or the Whole Practical Part of Physic, 1679 Dring T, Harper C, Leigh J, Martyn S.
214. [214] Lobstein, J., Traite d'anatomie pathologique. Levrault Paris, 2, 1833.
215. [215] Alzheimer, A., Uber einen eigenartigc Erkrankung der Hirnrinde. Allg Z Psychiatrie Psych Gericht Med 64 (1907), 146–148.
216. [216] Alzheimer A. Uber eigenartige Krankheitsfalle des spateren Alters. Zeitschrift fur die gesamte Neurologie und Psychiatrie 1911;11:356-85.
217. [217] Grook, T., Bartus, R., Ferris, S.H., Whitehouse, P., Cohen, G.D., Gershon, S., Age associated memory impairment: proposed diagnostic criteria and measures of clinical change-report of a National Institute of Mental Health Work Group. Dev Neuropsychol 2 (1986), 261–276.
218. [218] Sperling, R.A., Aisen, P.S., Beckett, L.A., Bennett, D.A., Craft, S., Fagan, A.M., 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. Alzheimer Dement 7 (2011), 280–292.
219. [219] Albert, M.S., DeKosky, S.T., Dickson, D., Dubois, B., Feldman, H.H., Fox, N.C., et al. The diagnosis of mild cognitive impairment due to Alzheimer's disease: Recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimer Dement 7 (2011), 270–279.
220. [220] McKhann, G.M., Knopman, D.S., Chertkow, H., Hyman, B.T., Jack, C.R., Kawas, C.H., et al. The diagnosis of dementia due to Alzheimer's disease: Recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimer Dement 7 (2011), 263–269.
221. [221] Jack, C.R. Jr., Albert, M.S., Knopman, D.S., McKhann, G.M., Sperling, R.A., Carrillo, M.C., et al. Introduction to the recommendations from the National Institute on Aging- Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimer Dement 7 (2011), 257–262.
222. [222] Hyman, B.T., Phelps, C.H., Beach, T.G., Bigio, E.H., Cairns, N.J., Carrillo, M.C., et al. National Institute on Aging- Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease. Alzheimer Dement 8 (2012), 1–13.
223. [223] Hanlon, C.S., Rubinsztein, D.C., Arginine residues at codons 112 and 158 in the apolipoprotein E gene correspond to the ancestral state in humans. Atherosclerosis 112 (1995), 85–90.
224. [224] Corbo, R.M., Scacchi, R., Apolipoprotein E (APOE) allele distribution in the world. Is APOE*4 a ‘thrifty’ allele?. Ann Hum Genet 63 (1999), 301–310.
225. [225] Toledo, J.B., Arnold, S.E., Raible, K., Brettschneider, J., Xie, S.X., Grossman, M., et al. Contribution of cerebrovascular disease in autopsy confirmed neurodegenerative cases in the National Azlheimer's Coordinating Centre. Brain 136 (2013), 2697–2706.
226. [226] Kaffashian, S., Dugravot, A., Nabi, H., Batty, G.D., Brunner, E., Kivimäki, M., et al. Predictive utility of the Framingham general cardiovascular disease risk profile for cognitive function: evidence from the Whitehall II study. Eur Heart J 32 (2011), 2326–2332.
227. [227] Stukas, S., Robert, J., Wellington, C.L., High-density lipoproteins and cerebrovascular integrity in Alzheimer's disease. Cell Metab 19 (2014), 574–591.
228. [228] Berman, S.E., Rivera-Rivera, L.A., Clark, L.R., Racine, A.N., Keevil, J.G., Bratzke, L.C., et al. Intracranial arterial 4D-flow is associated with metrics of brain health and Alzheimer's disease. Alzheimer Dement 1 (2015), 420–428.
229. [229] Suri, S., Mackay, C.E., Kelly, M.E., Germuska, M., Tunbridge, E.M., Frisoni, G.B., et al. Reduced cerebrovascular reactivity in young adults carrying the APOE Ɛ4 allele. Alzheimer Dement 11 (2015), 648–657.
230. [230] Sabayan, B., Jansen, S., Oleksik, A.M., van Osch, M.J.P., van Buchem, M.A., van Vliet, P., et al. Cerebrovascular hemodynamics in Alzheimer's disease and vascular dementia: A meta-analysis of transcranial Doppler studies. Ageing Res Rev 11 (2012), 271–277.
231. [231] Austin, S.A., Santhanam, A.V., Hinton, D.J., Choi, D.S., Katusic, Z.S., Endothelial nitric oxide deficiency promotes Alzheimer's disease pathology. J Neurochem 127 (2013), 691–700.
232. [232] Katusic, Z.S., Austin, S.A., Endothelial nitric oxide: protector of a healthy mind. Eur Heart J 35 (2014), 888–894.
233. [233] Atochin, D.N., Huang, P.L., Endothelial nitric oxide synthase transgenic models of endothelial dysfunction. Pflugers Arch 460 (2010), 965–974.
234. [234] Iadecola, C., Neurovascular regulation in the normal brain and in Alzheimer's disease. Nat Rev Neurosci 5 (2004), 347–360.
235. [235] Gorelick, P.B., Scuteri, A., Black, S.E., DeCarli, C., Greenberg, S.M., Iadecola, C., et al. Vascular contributions to cognitive impairment and dementia: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 42 (2011), 2672–2713.
236. [236] Hardy, J.A., Higgins, G.A., Alzheimer's disease: the amyloid cascade hypothesis. Science 256 (1992), 184–185.
237. [237] Patterson, B.W., Elbert, D.L., Mawuenyega, K.G., Kasten, T., Ovod, V., Ma, S., et al. Age and amyloid effects on human central nervous system amyloid-beta kinetics. Ann Neurol 78 (2015), 439–453.
238. [238] Yau, W.Y.W., Tudorascu, D.L., McDade, E.M., Ikonomovic, S., James, J.A., Minhas, D., et al. Longitudinal assessment of neuroimaging and clinical markers in autosomal dominant Alzheimer's disease: a prospective cohort study. Lancet Neurol 14 (2015), 804–813.
239. [239] Blennow, K., Wallin, A., Fredman, P.K., Gottfries, C.G., Svennerholm, L., Blood-brain barrier disturbance in patients with Alzheimer's disease is related to vascular factors. Acta Neurol Scand 81 (1990), 323–326.
240. [240] Keable, A., Fenna, K., Yuen, H.M., Johnston, D.A., Smyth, N.R., Smith, C., et al. Deposition of amyloid β in the walls of human leptomeningeal arteries in relation to perivascular drainage pathways in cerebral amyloid angiopathy. Biochim Biophys Acta 1862 (2016), 1037–1046.
241. [241] Sudduth, T.L., Weekman, E.M., Brothers, H.M., Braun, K., Wilcock, D.M., β-amyloid deposition is shifted to the vasculature and memory impairment is exacerbated when hyperhomocysteinemia is induced in APP/PS1 transgenic mice. Alzheimers Res Ther, 6, 2014, 32.
242. [242] Suo, Z., Humphrey, J., Kundtz, A., Sethi, F., Placzek, A., Crawford, F., et al. Soluble Alzheimers β-amyloid constricts the cerebral vasculature in vivo. Neurosci Lett 257 (1998), 77–80.
243. [243] Miao, J., Xu, F., Davis, J., Holler, I.O., Verbeek, M.M., Nostrand, W.E.V., Cerebral microvascular amyloidβ protein deposition induces vascular degeneration and neuroinflammation in transgenic mice expressing human vasculotropic mutant amyloidβ precursor protein. Am J Pathol 167 (2005), 505–515.
244. [244] Hughes, T., Kuller, L., Barinas-Mitchell, E., McDade, E., Mackey, R., Mathis, C., et al. Arterial Stiffness is associated with amyloid deposition in the brain independent of blood pressure. Alzheimer Dement 9 (2013), 19–20.
245. [245] O'Rourke, M.F., Safar, M.E., Dzau, V., The cardiovascular continuum extended aging effects on the aorta and microvasculature. Vas Med 15 (2010), 461–468.
246. [246] Hughes, T.M., Craft, S., Lopez, O.L., Review of the potential role of arterial stiffness in the pathogenesis of Alzheimer's disease. Neurodegener Dis Manag 5 (2015), 121–135.
247. [247] Henry-Feugeas, M.C., Roy, C., Shouman-Claeys, W., Leukoaraiosis and pulse-wave encephalopathy: obstervations wit phase-contrast MRI in mild cognitive impairment. J Neuroradiol 36 (2009), 212–218.
248. th ed., 2011, Arnold, London.
249. [249] Singer, J., Trollor, J.N., Baune, B.T., Sachdev, P.S., Smith, E., Arterial stiffness, the brain and cognition: A systematic review. Ageing Res Rev 15 (2014), 16–27.
250. [250] Meyer, E.P., Ulmann-Schuler, A., Staufenbiel, M., Krucker, T., Altered morphology and 3D architecture of brain vasculature in a mouse model for Alzheimer's disease. Proc Natl Acad Sci U S A 105 (2008), 3587–3592.
251. [251] Williams, M.A., McGowan, A.J., Cardwell, C.R., Cheung, C.Y., Craig, D., Passmore, P., et al. Retinal microvascular network attenuation in Alzheimer's disease. Alzheimer Dement 1 (2015), 229–235.
252. [252] Cheung, C.Y., Ong, Y.T., Ikram, M.K., Ong, S.Y., Li, X., Hilal, S., et al. Microvascular network alterations in the retina of patients with Alzheimer's disease. Alzheimer Dement 10 (2013), 135–142.
253. [253] Drake, C.T., Iadecola, C., The role of neuronal signaling in controlling cerebral blood flow. Brain Lang 102 (2007), 141–152.
254. [254] Zipser, B.D., Johanson, C.E., Gonzalez, L., Berzin, T.M., Tavares, R., Hulette, C.M., et al. Microvascular injury and blood-brain barrier leakage in Alzheimer's disease. Neurobiol Aging 28 (2007), 977–986.
255. [255] Kalaria, R.N., Cerebral vessels in ageing and Alzheimer's disease. Pharmacol Ther 72 (1996), 193–214.
256. [256] Zlokovic, B.V., Neurovascular mechanisms of Alzheimer's neurodegeneration. Trends Neurosci, 28, 2005, 4.
257. [257] Heiss, W.D., Kessler, J., Szelies, B., Grond, M., Fink, G., Herholz, K., Positron emission tomography in the differential diagnosis of organic dementias. J Neural Trans Suppl 33 (1991), 13–19.
258. [258] Cataldi, M., The changing landscape of voltage-gated calcium channels in neurovascular disorders and in neurodegenerative diseases. Curr Neuropharmacol 11 (2013), 276–297.
259. [259] Hartz, A.M., Bauer, B., Soldner, E.L., Wolf, A., Boy, S., Backhaus, R., et al. Amyloid-beta contribuites to blood-brain barrier leakage in transgenic human amyloid precursor protein mice and in humans with cerebral amyloid angiopathy. Stroke 43 (2012), 514–523.
260. [260] McGeer, P.L., McGeer, E.G., The inflammatory response system of brain: implications for therapy of Alzheimer and other neurodegenerative diseases. Brain Res Brain Res Rev 21 (1995), 195–218.
261. [261] Hafezi-Moghadam, A., Thomas, K.L., Wagner, D.D., ApoE deficiency leads to a progressive age-dependent blood-brain barrier leakage. Am J Physiol 292 (2007), 1256–1262.
262. [262] Methia, N., Andre, P., Hafezi-Moghadam, A., Economopoulos, M., Thomas, K.L., Wagner, D.D., ApoE deficiency compromises the blood brain barrier especially after injury. Mol Med 7 (2001), 810–815.
263. [263] Girouard, H., Iadecola, C., Neurovascular coupling in the normal brain and in hypertension, stroke, and Alzheimer's disease. J Appl Physiol 100 (2006), 328–335.
264. [264] Chaitanya, G.V., Cromer, W., Wells, S., Jennings, M., Mathis, M., Minagar, J.M., et al. Metabolic modulation of cytokine-induced brain endothelial adhesion molecule expression. Microcirculation 19 (2012), 155–165.
265. [265] Snyder, P.J., Johnson, L.N., Lim, Y.Y., Santos, C.Y., Alber, J., Maruff, P., Fernández, B., Nonvascular retinal imaging markers of preclinical Alzheimer's disease. Alzheimer Dement 4 (2016), 169–178.
266. [266] Davies, P., Maloney, A.J.F., Selective loss of central cholinergic neurons in Alzheimer's disease. Lancet, 2, 1976, 1403.
267. [267] Whitehouse, P.J., Price, D.L., Struble, R.G., Clark, A.W., Coyle, J.T., Delon, M.R., Alzheimer's disease and senile dementia: loss of neurons in the basal forebrain. Science 215 (1982), 1237–1239.
268. [268] Strong, R., Huang, J.S., Huang, S.S., Chung, H.D., Hale, C., Burke, W.J., Degeneration of the cholinergic innervation of the locus coerelus in Alzheimer's disease. Brain Res, 542, 1991, 28.
269. [269] Jodo, E., Aston-Jones, G., Activiation of locus coeruleus by prefrontal cortex is mediated by excitatory amino acid inputs. Brain Res 768 (1997), 327–332.
270. [270] Espana, R.A., Berridge, C.W., Organisation of noradrenergic efferents to arousal-related basal forebrain structures. J Comp Neurol 496 (2006), 668–683.
271. [271] Grudzien, A., Shaws, P., Weintraub, S., Bigio, E., Mash, D.C., Mesulam, M.M., Locus coerelus neurofibrillary degeneration in aging, mild cognitive impairment and early Alzheimer's disease. Neurobiol Aging 28 (2007), 327–335.
272. [272] Collier, T.J., Greene, J.G., Felten, D.L., Stevens, S.Y., Steece Colier, K., Reduced cortical noradrenergic neurotransmission is associated with increased neophobia and impaired spatial memory in aged rats. Neurobiol Aging 25 (2004), 209–221.
273. rd Edition, 1992, Oxford Universuty Press, Oxford, 36–53.
274. [274] Herring, N., Danson, E.J.F., Paterson, D.J., Cholinergic control of the heart rate by nitric oxide in site specific. News Physiol Sci 12 (2002), 202–206.
275. [275] Beach, T.G., Honer, W.G., Hughes, L.H., Cholinergic fibre loss associated with diffuse plaques in the non-demented elderly: the preclinical stage of Alzheimer's disease?. Acta Neuropathol 93 (1997), 146–153.
276. [276] Schliebs, R., Arendt, T., The cholinergic system in aging and neuronal degeneration. Beh Brain Res 221 (2011), 555–563.
277. [277] Lim, Y.Y., Maruff, P., Schindler, R., Ott, B.R., Salloway, S., Yoo, D.C., et al. Disruption of cholinergic neurotransmission exarcerbates Aβ-related cognitive impairment in preclinical Alzheimer's disease. Neurobiol Aging 36 (2015), 2709–2715.
278. [278] Kouznetsova, E., Schliebs, R., Role of cholinergic system in B-amyloid related changes in perivascular innervation of cerebral microvessels in transgenic Tg2576 Alzheimer-like mice. J Neurochem, 101, 2007, 63.
279. [279] Bürger, S., Noack, M., Kirazov, L.P., Kirazov, E.P., Naydenov, C.L., Kouznetsova, E., et al. Vascular endothelial growth factor (VEGF) affects processing of the amyloid precursor protein and B-amyloidogenesis in brain slice cultures derived from transgenic Tg2576 mouse brain. Int J Dev Neurosci 27 (2009), 517–523.
280. [280] De la Torre, J.C., Alzheimer disease as a vascular disorder: nosological evidence. Stroke 33 (2002), 1152–1162.
281. [281] Kalaria, R.N., The role of cerebral ischemia in Alzheimer's disease. Neurobiolo Aging 21 (2000), 321–330.
282. [282] Jendroska, K., Poewe, W., Daniel, S.E., Pluess, J., Iwerssen-Schmidt, H., Paulsen, J., et al. Ischemic stress induces deposition of amyloid beta immunoreactivity in human brain. Acta Neuropathol 90 (1995), 461–466.
283. [283] Iadecola, C., The overlap between neurodegenerative and vascular factors in the pathogenesis of dementia. Acta Neuropathol 120 (2010), 287–296.
284. [284] Esiri, M.M., Nagy, Z., Smith, M.Z., Barnetson, L., Smith, A.D., Cerebrovascular disease and threshold for dementia in the early stages of Alzheimer's disease. Lancet 354 (1999), 919–920.
285. [285] Schneider, J.A., Wilson, R.S., Bienias, J.L., Evans, D.A., Bennett, D.A., Cerebral infarctions and the likelihood of dementia from Alzheimer disease pathology. Neurology 62 (2004), 1148–1155.
286. [286] Helzner, E.P., Luchsinger, J.A., Scarmeas, N., Cosentino, S., Brickman, A.M., Glymour, M.M., et al. Contribution of vascular risk factors to the progression in Alzheimer disease. Arch Neurol 66 (2009), 343–348.
287. [287] Silvestrini, M., Pasqualetti, P., Baruffaldi, R., Bartolini, M., Handouk, Y., Matteis, M., et al. Cerebrovascular reactivity and cognitive decline in patients with Alzheimer disease. Stroke 37 (2006), 1010–1015.
288. [288] Steven, C., World Dementia Council issues risk reduction statement. Global action against dementia. Alzheimer's Association Statement. 2015.
289. [289] Baumgart, M., Snyder, H.M., Carrillo, M.C., Fazio, S., Kim, H., Johns, H., Summary of the evidence on modifiable risk factors for cognitive decline and dementia: a population-based perspective. Alhzeimer Dement 11 (2015), 718–726.
290. [290] Glodzik, L., Rusinek, H., Kamer, A., Pirraglia, E., Tsui, W., Mosconi, L., et al. Effects of vascular risk factors, statins and antihypertensive drugs on PiB deposition in cognitively normal subjects. Alzheimer Dement 2 (2016), 95–104.
291. [291] Deckers, K., van Boxtel, M.P.J., Schiepers, O.J.G., de Vugt, M., Muñoz Sánchez, J.L., Anstey, K.J., et al. Target risk factors for dementia prevention: a systematic review and Delphi consensus study on the evidence for observational studies. Int Journ Geri Psychiatr 30 (2015), 234–246.
292. [292] Sindi, S., Mangialasche, F., Kivipelto, M., Advances in the prevention of Alzheimer's disease. J Intern Med 275 (2014), 229–250.
293. [293] Kivipelto, M., Soloman, A., Ahtiluoto, S., The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER): study design and progress. Alzheimer Dement 9 (2013), 657–665.