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Defining the Relationship Between Hypertension, Cognitive Decline, and Dementia: a Review

  • Keenan A. Walker
  • Melinda C. Power
  • Rebecca F. GottesmanEmail author
Secondary Hypertension: Nervous System Mechanisms (M Wyss, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Secondary Hypertension: Nervous System Mechanisms

Abstract

Hypertension is a highly prevalent condition which has been established as a risk factor for cardiovascular and cerebrovascular disease. Although the understanding of the relationship between cardiocirculatory dysfunction and brain health has improved significantly over the last several decades, it is still unclear whether hypertension constitutes a potentially treatable risk factor for cognitive decline and dementia. While it is clear that hypertension can affect brain structure and function, recent findings suggest that the associations between blood pressure and brain health are complex and, in many cases, dependent on factors such as age, hypertension chronicity, and antihypertensive medication use. Whereas large epidemiological studies have demonstrated a consistent association between high midlife BP and late-life cognitive decline and incident dementia, associations between late-life blood pressure and cognition have been less consistent. Recent evidence suggests that hypertension may promote alterations in brain structure and function through a process of cerebral vessel remodeling, which can lead to disruptions in cerebral autoregulation, reductions in cerebral perfusion, and limit the brain’s ability to clear potentially harmful proteins such as β-amyloid. The purpose of the current review is to synthesize recent findings from epidemiological, neuroimaging, physiological, genetic, and translational research to provide an overview of what is currently known about the association between blood pressure and cognitive function across the lifespan. In doing so, the current review also discusses the results of recent randomized controlled trials of antihypertensive therapy to reduce cognitive decline, highlights several methodological limitations, and provides recommendations for future clinical trial design.

Keywords

Hypertension Hypotension Blood pressure Cognition Cognitive impairment Dementia 

Notes

Acknowledgements

Keenan A. Walker was supported by the NIA (T32 AG027668).

Compliance with Ethical Standards

Conflict of Interest

Drs. Walker and Power declare no conflicts of interest relevant to this manuscript. Dr. Gottesman reports personal fees from American Academy of Neurology, outside the submitted work, as an Associate Editor for the journal Neurology.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Mills KT, Bundy JD, Kelly TN, Reed JE, Kearney PM, Reynolds K, et al. Global disparities of hypertension prevalence and control. Circulation. 2016;134:441–50.PubMedCrossRefGoogle Scholar
  2. 2.
    Kearney PM, Whelton M, Reynolds K, Muntner P, Whelton PK, He J. Global burden of hypertension: analysis of worldwide data. Lancet. 2005;365:217–23.PubMedCrossRefGoogle Scholar
  3. 3.
    Fanning JP, Wong AA, Fraser JF. The epidemiology of silent brain infarction: a systematic review of population-based cohorts. BMC Med. 2014;12:119.PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Knopman DS, Penman AD, Catellier DJ, Coker LH, Shibata DK, Sharrett AR, et al. Vascular risk factors and longitudinal changes on brain MRI: the ARIC study. Neurology American Academy of Neurology. 2011;76:1879–85.Google Scholar
  5. 5.
    Bezerra DC, Sharrett AR, Matsushita K, Gottesman RF, Shibata D, Mosley TH, et al. Risk factors for lacune subtypes in the Atherosclerosis Risk In Communities (ARIC) study. Neurology. 2012;78:102–8.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    MacMahon S, Peto R, Collins R, Godwin J, MacMahon S, Cutler J, et al. Blood pressure, stroke, and coronary heart disease. Part 1, prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias. Lancet. 1990;335:765–74.PubMedCrossRefGoogle Scholar
  7. 7.
    Shah NS, Vidal JS, Masaki K, Petrovitch H, Ross GW, Tilley C, et al. Midlife blood pressure, plasma beta-amyloid, and the risk for Alzheimer disease: the Honolulu Asia Aging Study. Hypertension. 2012;59:780–6.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Rönnemaa E, Zethelius B, Lannfelt L, Kilander L. Vascular risk factors and dementia: 40-year follow-up of a population-based cohort. Dement Geriatr Cogn Disord. 2011;31:460–6.PubMedCrossRefGoogle Scholar
  9. 9.
    Kennelly SP, Lawlor BA, Kenny RA. Blood pressure and dementia—a comprehensive review. Ther Adv Neurol Disord. 2009;2:241–60.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Lande MB, Kaczorowski JM, Auinger P, Schwartz GJ, Weitzman M. Elevated blood pressure and decreased cognitive function among school-age children and adolescents in the United States. J. Pediatr. 2003. p. 720–4.Google Scholar
  11. 11.
    •• Power MC, Tchetgen EJT, Sparrow D, Schwartz J, Weisskopf MG. Blood pressure and cognition: factors that may account for their inconsistent association. Epidemiology. 2013;24:886–93. This longitudinal study demonstrated the importance of examining hypertension duration; a greater duration of time since the onset of hypertension was associated with lower cognitive function later in life. Google Scholar
  12. 12.
    Swan GE, DeCarli C, Miller BL, Reed T, Wolf PA, Jack LM, et al. Association of midlife blood pressure to late-life cognitive decline and brain morphology. Neurology. 1998;51:986–93.PubMedCrossRefGoogle Scholar
  13. 13.
    •• Launer LJ, Masaki K, Petrovitch H, Foley D, Havlik RJ. The association between midlife blood pressure levels and late-life cognitive function. The Honolulu-Asia Aging Study. JAMA. 1995;274:1846–51. One of the earliest prospective observational studies to demonstrate a link between midlife systolic blood pressure and reduced cognitive function later in life. PubMedCrossRefGoogle Scholar
  14. 14.
    Shang S, Li P, Deng M, Jiang Y, Chen C, Qu Q. The age-dependent relationship between blood pressure and cognitive impairment: a cross-sectional study in a rural area of Xi’an. China PLoS One. 2016;11:e0159485.PubMedCrossRefGoogle Scholar
  15. 15.
    Singh-Manoux A, Marmot M. High blood pressure was associated with cognitive function in middle-age in the Whitehall II study. J Clin Epidemiol. 2005;58:1308–15.PubMedCrossRefGoogle Scholar
  16. 16.
    Gillett SR, Thacker EL, Letter AJ, McClure LA, Wadley VG, Unverzagt FW, et al. Correlates of incident cognitive impairment in the REasons for Geographic And Racial Differences in Stroke (REGARDS) Study. Clin Neuropsychol. 2015;29:466–86.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Wolf PA, Beiser A, Elias MF, Au R, Vasan RS, Seshadri S. Relation of obesity to cognitive function: importance of central obesity and synergistic influence of concomitant hypertension. The Framingham Heart Study. Curr Alzheimer Res. 2007;4:111–6.PubMedCrossRefGoogle Scholar
  18. 18.
    Pavlik VN, Hyman DJ, Doody R. Cardiovascular risk factors and cognitive function in adults 30–59 years of age (NHANES III). Neuroepidemiology. 2005;24:42–50.PubMedCrossRefGoogle Scholar
  19. 19.
    Tzourio C, Dufouil C, Ducimetiere P, Alperovitch A. Cognitive decline in individuals with high blood pressure: a longitudinal study in the elderly. Neurology. 1999;53:1948–52.PubMedCrossRefGoogle Scholar
  20. 20.
    Knopman D, Boland L, Mosley T, Howard G, Liao D, Szklo M, et al. Cardiovascular risk factors and cognitive decline in middle-aged adults. Neurology. 2001;56:42–8.PubMedCrossRefGoogle Scholar
  21. 21.
    Knopman DS, Mosley TH, Catellier DJ, Coker LH. Atherosclerosis Risk In Communities Study brain MRI study. Fourteen-year longitudinal study of vascular risk factors, APOE genotype, and cognition: the ARIC MRI Study. Alzheimers. Dement. 2009;5:207–14.CrossRefGoogle Scholar
  22. 22.
    • Gottesman RF, Schneider ALC, Albert M, Alonso A, Bandeen-Roche K, Coker L, et al. Midlife hypertention and 20-year cognitive change. JAMA Neurol. 2014;21287:1–10. This large longitudinal study found that hypertension and high blood pressure during midlife were associated with greater cognitive decline over a 20-year follow-up period. Google Scholar
  23. 23.
    • Swan GE, Carmelli D, Larue A. Systolic blood pressure tracking over 25 to 30 years and cognitive performance in older adults. Stroke. 1998;29:2334–40. This is one of the few longitudinal studies that has examined how the trajectory of blood pressure over multiple decades relates to cognition later in life. PubMedCrossRefGoogle Scholar
  24. 24.
    Kilander L, Nyman H, Boberg M, Hansson L, Lithell H. Hypertension is related to cognitive impairment: a 20-year follow-up of 999 men. Hypertension. 1998;31:780–6.PubMedCrossRefGoogle Scholar
  25. 25.
    Kilander L, Nyman H, Boberg M, Lithell H. The association between low diastolic blood pressure in middle age and cognitive function in old age. A population-based study. Age Ageing. 2000;29:243–8.PubMedCrossRefGoogle Scholar
  26. 26.
    Farmer ME, Kittner SJ, Abbott RD, Wolz MM, Wolf PA, White LR. Longitudinally measured blood pressure, antihypertensive medication use, and cognitive performance: the Framingham Study. J Clin Epidemiol. 1990;43:475–80.PubMedCrossRefGoogle Scholar
  27. 27.
    Cerhan JR, Folsom AR, Mortimer JA, Shahar E, Knopman DS, McGovern PG, et al. Correlates of cognitive function in middle-aged adults. Atherosclerosis risk in communities (ARIC) study investigators. Gerontology. 1998;44:95–105.PubMedCrossRefGoogle Scholar
  28. 28.
    Schneider ALC, Sharrett AR, Patel MD, Alonso A, Coresh J, Mosley T, et al. Education and cognitive change over 15 years: the atherosclerosis risk in communities study. J Am Geriatr Soc. 2012;60:1847–53.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Vinyoles E, De la Figuera M, Gonzalez-Segura D. Cognitive function and blood pressure control in hypertensive patients over 60 years of age: COGNIPRES study. Curr Med Res Opin. 2008;24:3331–9.PubMedCrossRefGoogle Scholar
  30. 30.
    Guo Z, Fratiglioni L, Winblad B, Viitanen M. Blood pressure and performance on the Mini-Mental State Examination in the very old. Cross-sectional and longitudinal data from the Kungsholmen Project. Am J Epidemiol. 1997;145:1106–13.PubMedCrossRefGoogle Scholar
  31. 31.
    Wadley VG, McClure LA, Howard VJ, Unverzagt FW, Go RC, Moy CS, et al. Cognitive status, stroke symptom reports, and modifiable risk factors among individuals with no diagnosis of stroke or transient ischemic attack in the REasons for Geographic and Racial Differences in Stroke (REGARDS) study. Stroke. 2007;38:1143–7.PubMedCrossRefGoogle Scholar
  32. 32.
    Elias MF, Wolf PA, D’Agostino RB, Cobb J, White LR. Untreated blood pressure level is inversely related to cognitive functioning: the Framingham Study. Am J Epidemiol. 1993;138:353–64.PubMedCrossRefGoogle Scholar
  33. 33.
    Elias MF, Elias PK, Sullivan LM, Wolf PA, D’Agostino RB. Lower cognitive function in the presence of obesity and hypertension: the Framingham heart study. Int J Obes Relat Metab Disord. 2003;27:260–8.PubMedCrossRefGoogle Scholar
  34. 34.
    Reitz C, Tang M-X, Manly J, Mayeux R, Luchsinger JA. Hypertension and the risk of mild cognitive impairment. Arch Neurol. 2007;64:1734–40.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Tsivgoulis G, Alexandrov AV, Wadley VG, Unverzagt FW, Go RCP, Moy CS, et al. Association of higher diastolic blood pressure levels with cognitive impairment. Neurology. 2009;73:589–95.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Pandav R, Dodge HH, DeKosky ST, Ganguli M. Blood pressure and cognitive impairment in India and the United States: a cross-national epidemiological study. Arch Neurol. 2003;60:1123–8.PubMedCrossRefGoogle Scholar
  37. 37.
    Cacciatore F, Abete P, Ferrara N, Paolisso G, Amato L, Canonico S, et al. The role of blood pressure in cognitive impairment in an elderly population. Osservatorio Geriatrico Campano Group J Hypertens. 1997;15:135–42.PubMedGoogle Scholar
  38. 38.
    Waldstein SR, Giggey PP, Thayer JF, Zonderman AB. Nonlinear relations of blood pressure to cognitive function: the Baltimore longitudinal study of aging. Hypertension. 2005;45:374–9.PubMedCrossRefGoogle Scholar
  39. 39.
    Morris MC, Scherr PA, Hebert LE, Bennett DA, Wilson RS, Glynn RJ, et al. Association between blood pressure and cognitive function in a biracial community population of older persons. Neuroepidemiology. 2002;21:123–30.PubMedCrossRefGoogle Scholar
  40. 40.
    Hebert LE, Scherr PA, Bennett DA, Bienias JL, Wilson RS, Morris MC, et al. Blood pressure and late-life cognitive function change: a biracial longitudinal population study. Neurology. 2004;62:2021–4.PubMedCrossRefGoogle Scholar
  41. 41.
    Di Carlo A, Baldereschi M, Amaducci L, Maggi S, Grigoletto F, Scarlato G, et al. Cognitive impairment without dementia in older people: prevalence, vascular risk factors, impact on disability. The Italian Longitudinal Study On Aging. J Am Geriatr Soc. 2000;48:775–82.PubMedCrossRefGoogle Scholar
  42. 42.
    André-Petersson L, Hagberg B, Janzon L, Steen G. A comparison of cognitive ability in normotensive and hypertensive 68-year-old men: results from population study “Men Born in 1914,” in Malmӧ. Sweden Exp Aging Res. 2001;27:319–40.PubMedCrossRefGoogle Scholar
  43. 43.
    Haan MN, Shemanski L, Jagust WJ, Manolio TA, Kuller L. The role of APOE epsilon4 in modulating effects of other risk factors for cognitive decline in elderly persons. JAMA. 1999;282:40–6.PubMedCrossRefGoogle Scholar
  44. 44.
    Glynn RJ, Beckett LA, Hebert LE, Morris MC, Scherr PA, Evans DA. Current and remote blood pressure and cognitive decline. JAMA. 1999;281:438–45.PubMedCrossRefGoogle Scholar
  45. 45.
    Bohannon AD, Fillenbaum GG, Pieper CF, Hanlon JT, Blazer DG. Relationship of race/ethnicity and blood pressure to change in cognitive function. J Am Geriatr Soc. 2002;50:424–9.PubMedCrossRefGoogle Scholar
  46. 46.
    Scherr PA, Hebert LE, Smith LA, Evans DA. Relation of blood pressure to cognitive function in the elderly. Am J Epidemiol. 1991;134:1303–15.PubMedCrossRefGoogle Scholar
  47. 47.
    Kuo H-K, Sorond F, Iloputaife I, Gagnon M, Milberg W, Lipsitz LA. Effect of blood pressure on cognitive functions in elderly persons. J Gerontol A Biol Sci Med Sci. 2004;59:1191–4.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Budge MM, De Jager C, Hogervorst E, Smith AD. Total plasma homocysteine, age, systolic blood pressure, and cognitive performance in older people. J Am Geriatr Soc. 2002;50:2014–8.PubMedCrossRefGoogle Scholar
  49. 49.
    Cherbuin N, Reglade-Meslin C, Kumar R, Jacomb P, Easteal S, Christensen H, et al. Risk factors of transition from normal cognition to mild cognitive disorder: the PATH through life study. Dement Geriatr Cogn Disord. 2009;28:47–55.PubMedCrossRefGoogle Scholar
  50. 50.
    Gorelick PB, Nyenhuis D. Blood pressure and treatment of persons with hypertension as it relates to cognitive outcomes including executive function. J Am Soc Hypertens. 2012;6:309–15.PubMedCrossRefGoogle Scholar
  51. 51.
    •• Muller M, Sigurdsson S, Kjartansson O, Aspelund T, Lopez OL, Jonnson PV, et al. Joint effect of mid- and late-life blood pressure on the brain: the AGES-Reykjavik Study. Neurology. 2014;82:2187–95. This large longitudinal study demonstrated that the association between late-life blood pressure, cognition, and brain volume was dependent on midlife blood pressure; a combination of midlife hypertension and low late-life diastolic blood pressure was associated with worse outcomes. PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Suhr JA, Stewart JC, France CR. The relationship between blood pressure and cognitive performance in the Third National Health and Nutrition Examination Survey (NHANES III). Psychosom Med. 2004;66:291–7.PubMedGoogle Scholar
  53. 53.
    Adams HR, Szilagyi PG, Gebhardt L, Lande MB. Learning and attention problems among children with pediatric primary hypertension. Pediatrics. 2010;126:e1425–9.PubMedCrossRefGoogle Scholar
  54. 54.
    Lande MB, Batisky DL, Kupferman JC, Samuels J, Hooper SR, Falkner B, et al. Neurocognitive function in children with primary hypertension. J. Pediatr. 2016.Google Scholar
  55. 55.
    Hill CM, Hogan AM, Onugha N, Harrison D, Cooper S, McGrigor VJ, et al. Increased cerebral blood flow velocity in children with mild sleep-disordered breathing: a possible association with abnormal neuropsychological function. Pediatrics. 2006;118:e1100–8.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Ditto B, Séguin JR, Tremblay RE. Neuropsychological characteristics of adolescent boys differing in risk for high blood pressure. Ann Behav Med. 2006;31:231–7.PubMedCrossRefGoogle Scholar
  57. 57.
    O’Callaghan S, Kenny RA. Neurocardiovascular instability and cognition. Yale J Biol Med. 2016;89:59–71.PubMedPubMedCentralGoogle Scholar
  58. 58.
    O’Brien E, Coats A, Owens P, Petrie J, Padfield PL, Littler WA, et al. Use and interpretation of ambulatory blood pressure monitoring: recommendations of the British Hypertension Society. BMJ. 2000;320:1128–34.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Rose KM, Tyroler HA, Nardo CJ, Arnett DK, Light KC, Rosamond W, et al. Orthostatic hypotension and the incidence of coronary heart disease: the Atherosclerosis Risk in Communities study. Am J Hypertens. 2000;13:571–8.PubMedCrossRefGoogle Scholar
  60. 60.
    Rose KM, Holme I, Light KC, Sharrett AR, Tyroler HA, Heiss G. Association between the blood pressure response to a change in posture and the 6-year incidence of hypertension: prospective findings from the ARIC study. J Hum Hypertens. 2002;16:771–7.PubMedCrossRefGoogle Scholar
  61. 61.
    Czajkowska J, Ozhog S, Smith E, Perlmuter LC. Cognition and hopelessness in association with subsyndromal orthostatic hypotension. J Gerontol A Biol Sci Med Sci. 2010;65:873–9.PubMedCrossRefGoogle Scholar
  62. 62.
    Elmståhl S, Widerström E. Orthostatic intolerance predicts mild cognitive impairment: incidence of mild cognitive impairment and dementia from the Swedish general population cohort good aging in Skåne. Clin Interv Aging Dove Press. 2014;9:1993–2002.CrossRefGoogle Scholar
  63. 63.
    Frewen J, Savva GM, Boyle G, Finucane C, Kenny RA. Cognitive performance in orthostatic hypotension: findings from a nationally representative sample. J Am Geriatr Soc. 2014;62:117–22.PubMedCrossRefGoogle Scholar
  64. 64.
    Frewen J, Finucane C, Savva GM, Boyle G, Kenny RA. Orthostatic hypotension is associated with lower cognitive performance in adults aged 50 plus with supine hypertension. J Gerontol A Biol Sci Med Sci. 2014;69:878–85.PubMedCrossRefGoogle Scholar
  65. 65.
    Schoon Y, Lagro J, Verhoeven Y, Rikkert MO, Claassen J. Hypotensive syndromes are not associated with cognitive impairment in geriatric patients. Am J Alzheimers Dis Other Demen. 2013;28:47–53.PubMedCrossRefGoogle Scholar
  66. 66.
    Rose KM, Couper D, Eigenbrodt ML, Mosley TH, Sharrett AR, Gottesman RF. Orthostatic hypotension and cognitive function: the Atherosclerosis Risk in Communities Study. Neuroepidemiology. 2010;34:1–7.PubMedCrossRefGoogle Scholar
  67. 67.
    Viramo P, Luukinen H, Koski K, Laippala P, Sulkava R, Kivelä SL. Orthostatic hypotension and cognitive decline in older people. J Am Geriatr Soc. 1999;47:600–4.PubMedCrossRefGoogle Scholar
  68. 68.
    Kanemaru A, Kanemaru K, Kuwajima I. The effects of short-term blood pressure variability and nighttime blood pressure levels on cognitive function. Hypertens Res. 2001;24:19–24.PubMedCrossRefGoogle Scholar
  69. 69.
    Bellelli G, Frisoni GB, Lucchi E, Guerini F, Geroldi C, Magnifico F, et al. Blunder reduction in night-time blood pressure is associated with cognitive deterioration in subjects with long-standing hypertension. Blood Press Monit. 2004;9:71–6. 6pPubMedCrossRefGoogle Scholar
  70. 70.
    Sakakura K, Ishikawa J, Okuno M, Shimada K, Kario K. Exaggerated ambulatory blood pressure variability is associated with cognitive dysfunction in the very elderly and quality of life in the younger elderly. Am J Hypertens. 2007;20:720–7.PubMedCrossRefGoogle Scholar
  71. 71.
    Allan LM, Ballard CG, Allen J, Murray A, Davidson AW, McKeith IG, et al. Autonomic dysfunction in dementia. J Neurol Neurosurg Psychiatry BMJ Group. 2007;78:671–7.CrossRefGoogle Scholar
  72. 72.
    Rigat B, Hubert C, Alhenc-Gelas F, Cambien F, Corvol P, Soubrier F. An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest. 1990;86:1343–6.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Schuch JB, Constantin PC, da Silva VK, Korb C, Bamberg DP, da Rocha TJ, et al. ACE polymorphism and use of ACE inhibitors: effects on memory performance. Age (Dordr). 2014;36:9646.Google Scholar
  74. 74.
    Saidi S, Zammiti W, Slamia LB, Ammou SB, Almawi WY, Mahjoub T. Interaction of angiotensin-converting enzyme and apolipoprotein E gene polymorphisms in ischemic stroke involving large-vessel disease. J Thromb Thrombolysis. 2009;27:68–74.PubMedCrossRefGoogle Scholar
  75. 75.
    Hassan A, Lansbury A, Catto AJ, Guthrie A, Spencer J, Craven C, et al. Angiotensin converting enzyme insertion/deletion genotype is associated with leukoaraiosis in lacunar syndromes. J Neurol Neurosurg Psychiatry. 2002;72:343–6.PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Bartrés-Faz D, Junqué C, Clemente IC, López-Alomar A, Valveny N, López-Guillén A, et al. Angiotensin I converting enzyme polymorphism in humans with age-associated memory impairment: relationship with cognitive performance. Neurosci Lett. 2000;290:177–80.PubMedCrossRefGoogle Scholar
  77. 77.
    • Richard F, Berr C, Amant C, Helbecque N, Amouyel P, Alperovitch A. Effect of the angiotensin I-converting enzyme I/D polymorphism on cognitive decline. The EVA Study Group. Neurobiol Aging. 2000;21:75–80. One of the first large prospective studies to demonstrate a relationship between the angiotensin I-converting enzyme I/D polymorphism and cognitive decline in the elderly. PubMedCrossRefGoogle Scholar
  78. 78.
    Raz N, Dahle CL, Rodrigue KM, Kennedy KM, Land S. Effects of age, genes, and pulse pressure on executive functions in healthy adults. Neurobiol Aging. 2011;32:1124–37.PubMedCrossRefGoogle Scholar
  79. 79.
    Wang B, Jin F, Yang Z, Lu Z, Kan R, Li S, et al. The insertion polymorphism in angiotensin-converting enzyme gene associated with the APOE epsilon 4 allele increases the risk of late-onset Alzheimer disease. J Mol Neurosci. 2006;30:267–71.PubMedCrossRefGoogle Scholar
  80. 80.
    Lehmann DJ, Cortina-Borja M, Warden DR, Smith AD, Sleegers K, Prince JA, et al. Large meta-analysis establishes the ACE insertion-deletion polymorphism as a marker of Alzheimer’s disease. Am J Epidemiol. 2005;162:305–17.PubMedCrossRefGoogle Scholar
  81. 81.
    Taylor WD, Benjamin S, McQuoid DR, Payne ME, Krishnan RR, MacFall JR, et al. AGTR1 gene variation: association with depression and frontotemporal morphology. Psychiatry Res - Neuroimaging. 2012;202:104–9.PubMedCrossRefGoogle Scholar
  82. 82.
    Zannas AS, McQuoid DR, Payne ME, Macfall JR, Ashley-Koch A, Steffens DC, et al. Association of gene variants of the renin-angiotensin system with accelerated hippocampal volume loss and cognitive decline in old age. Am J Psychiatry. 2014;171:1214–21.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    McFall GP, Sapkota S, McDermott KL, Dixon RA. Risk-reducing Apolipoprotein E and Clusterin genotypes protect against the consequences of poor vascular health on executive function performance and change in nondemented older adults. Neurobiol Aging. 2016;42:91–100.PubMedCrossRefGoogle Scholar
  84. 84.
    Andrews S, Das D, Anstey KJ, Easteal S. Interactive effect of APOE genotype and blood pressure on cognitive decline: the PATH through life study. J Alzheimers Dis. 2015;44:1087–98.PubMedGoogle Scholar
  85. 85.
    de Frias CM, Warner SK, Willis SL. Hypertension moderates the effect of APOE on 21-year cognitive trajectories. Psychol Aging. 2014;29:431–9.PubMedCrossRefGoogle Scholar
  86. 86.
    Li W, Wang T, Xiao S. Type 2 diabetes mellitus might be a risk factor for mild cognitive impairment progressing to Alzheimer’s disease. Neuropsychiatr Dis Treat. 2016;12:2489–95.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Xu W, Qiu C, Gatz M, Pedersen NL, Johansson B, Fratiglioni L. Mid- and late-life diabetes in relation to the risk of dementia: a population-based twin study. Diabetes. 2009;58:71–7.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Raffaitin C, Gin H, Empana J-P, Helmer C, Berr C, Tzourio C, et al. Metabolic syndrome and risk for incident Alzheimer’s disease or vascular dementia: the Three-City Study. Diabetes Care. 2009;32:169–74.PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Rosendorff C, Beeri MS, Silverman JM. Cardiovascular risk factors for Alzheimer’s disease. Am. J. Geriatr. Cardiol. 2007. p. 143–9.Google Scholar
  90. 90.
    Prince M, Bryce R, Albanese E, Wimo A, Ribeiro W, Ferri CP. The global prevalence of dementia: a systematic review and metaanalysis. Alzheimers Dement. 2013;9:63–75.PubMedCrossRefGoogle Scholar
  91. 91.
    Gorelick PB, Scuteri A, Black SE, Decarli C, Greenberg SM, 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. 2011. p. 2672–713.Google Scholar
  92. 92.
    Lopez MF, Krastins B, Ning M. The role of apolipoprotein E in neurodegeneration and cardiovascular disease. Expert Rev Proteomics. 2014;11:371–81.PubMedCrossRefGoogle Scholar
  93. 93.
    Traylor M, Adib-Samii P, Harold D, Alzheimer’s Disease Neuroimaging Initiative, International Stroke Genetics Consortium (ISGC), UK Young Lacunar Stroke DNA resource, Dichgans M, et al. Shared genetic contribution to Ischaemic Stroke and Alzheimer’s Disease. Ann. Neurol. 2016;Google Scholar
  94. 94.
    Schneider JA, Arvanitakis Z, Bang W, Bennett DA. Mixed brain pathologies account for most dementia cases in community-dwelling older persons. Neurology. 2007;69:2197–204.PubMedCrossRefGoogle Scholar
  95. 95.
    Sonnen JA, Larson EB, Crane PK, Haneuse S, Li G, Schellenberg GD, et al. Pathological correlates of dementia in a longitudinal, population-based sample of aging. Ann Neurol. 2007;62:406–13.PubMedCrossRefGoogle Scholar
  96. 96.
    Iadecola C. Vascular and metabolic factors in Alzheimer;s disease and related dementias: introduction. Cell Mol Neurobiol. 2016 Mar;36:151–4.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Rodrigue KM, Rieck JR, Kennedy KM, Devous MD, Diaz-Arrastia R, Park DC. Risk factors for β-amyloid deposition in healthy aging: vascular and genetic effects. JAMA Neurol. 2013;70:600–6.PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Zlokovic BV. Neurovascular pathways to neurodegeneration in Alzheimer’s disease and other disorders. Nat. Rev Neurosci. 2011;12:723–38.PubMedPubMedCentralGoogle Scholar
  99. 99.
    • Launer LJ, Ross GW, Petrovitch H, Masaki K, Foley D, White LR, et al. Midlife blood pressure and dementia: the Honolulu-Asia aging study. Neurobiol Aging. 2000;21:49–55. This prospective observational study provided early evidence that treatment of blood pressure reduced the risk for dementia associated with midlife hypertension. PubMedCrossRefGoogle Scholar
  100. 100.
    Kivipelto M, Helkala EL, Laakso MP, Hänninen T, Hallikainen M, Alhainen K, et al. Apolipoprotein e4 allele, elevated midlife total cholesterol level, and high midlife systolic blood pressure are independent risk factors for late-life Alzheimer disease. Ann Intern Med. 2002;137:149–55.PubMedCrossRefGoogle Scholar
  101. 101.
    Yamada M, Kasagi F, Sasaki H, Masunari N, Mimori Y, Suzuki G. Association between dementia and midlife risk factors: the Radiation Effects Research Foundation Adult Health Study. J Am Geriatr Soc. 2003;51:410–4.PubMedCrossRefGoogle Scholar
  102. 102.
    Petrovitch H, White LR, Izmirilian G, Ross GW, Havlik RJ, Markesbery W, et al. Midlife blood pressure and neuritic plaques, neurofibrillary tangles, and brain weight at death: the HAAS. Neurobiol Aging. 2000;21:57–62.PubMedGoogle Scholar
  103. 103.
    Morris MC, Scherr PA, Hebert LE, Glynn RJ, Bennett DA, Evans DA. Association of incident Alzheimer disease and blood pressure measured from 13 years before to 2 years after diagnosis in a large community study. Arch Neurol. 2001;58:1640–6.PubMedCrossRefGoogle Scholar
  104. 104.
    Power MC, Weuve J, Gagne JJ, McQueen MB, Viswanathan A, Blacker D. The association between blood pressure and incident Alzheimer disease: a systematic review and meta-analysis. Epidemiology. 2011;22:646–59.PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Forti P, Pisacane N, Rietti E, Lucicesare A, Olivelli V, Mariani E, et al. Metabolic syndrome and risk of dementia in older adults. J Am Geriatr Soc. 2010;58:487–92.PubMedCrossRefGoogle Scholar
  106. 106.
    • Li G, Rhew IC, Shofer JB, Kukull WA, Breitner JCS, Peskind E, et al. Age-varying association between blood pressure and risk of dementia in those aged 65 and older: a community-based prospective cohort study. J Am Geriatr Soc. 2007;55:1161–7. This prospective study found strong evidence for an age-dependent association between systolic blood pressure and dementia risk: the association between high systolic blood pressure and dementia risk decreased with increasing age. PubMedCrossRefGoogle Scholar
  107. 107.
    Verghese J, Lipton RB, Hall CB, Kuslansky G, Katz MJ. Low blood pressure and the risk of dementia in very old individuals. Neurology. 2003;61:1667–72.PubMedCrossRefGoogle Scholar
  108. 108.
    Shah RC, Wilson RS, Bienias JL, Arvanitakis Z, Evans DA, Bennett DA. Relation of blood pressure to risk of incident Alzheimer’s disease and change in global cognitive function in older persons. Neuroepidemiology. 2005;26:30–6.PubMedCrossRefGoogle Scholar
  109. 109.
    Muller M, Tang M-X, Schupf N, Manly JJ, Mayeux R, Luchsinger JA. Metabolic syndrome and dementia risk in a multiethnic elderly cohort. Dement Geriatr Cogn Disord. 2007;24:185–92.PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Qiu C, Winblad B, Fastbom J, Fratiglioni L. Combined effects of APOE genotype, blood pressure, and antihypertensive drug use on incident AD. Neurology. 2003;61:655–60.PubMedCrossRefGoogle Scholar
  111. 111.
    Petitti DB, Crooks VC, Buckwalter JG, Chiu V. Blood pressure levels before dementia. Arch Neurol. 2005;62:112–6.PubMedCrossRefGoogle Scholar
  112. 112.
    Ruitenberg A, Skoog I, Ott A, Aevarsson O, Witteman JCM, 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. 2001;12:33–9.PubMedCrossRefGoogle Scholar
  113. 113.
    Qiu C, Winblad B, Marengoni A, Klarin I, Fastbom J, Fratiglioni L. Heart failure and risk of dementia and Alzheimer disease: a population-based cohort study. Arch Intern Med. 2006;166:1003–8.PubMedCrossRefGoogle Scholar
  114. 114.
    Nilsson SE, 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. 2007;19:41–7.PubMedCrossRefGoogle Scholar
  115. 115.
    Qiu C, Von Strauss E, Winblad B, Fratiglioni L. Decline in blood pressure over time and risk of dementia: a longitudinal study from the Kungsholmen project. Stroke. 2004;35:1810–5.PubMedCrossRefGoogle Scholar
  116. 116.
    Skoog I, Lernfelt B, Landahl S, Palmertz B, Andreasson LA, Nilsson L, et al. 15-year longitudinal study of blood pressure and dementia. Lancet (London, England). 1996;347:1141–5.CrossRefGoogle Scholar
  117. 117.
    Glodzik L, Rusinek H, Pirraglia E, McHugh P, Tsui W, Williams S, et al. Blood pressure decrease correlates with tau pathology and memory decline in hypertensive elderly. Neurobiol Aging. 2014;35:64–71.PubMedCrossRefGoogle Scholar
  118. 118.
    Raz N, Rodrigue KM, Kennedy KM, Acker JD. Vascular health and longitudinal changes in brain and cognition in middle-aged and older adults. Neuropsychology. 2007;21:149–57.PubMedCrossRefGoogle Scholar
  119. 119.
    Ying H, Jianping C, Jianqing Y, Shanquan Z. Cognitive variations among vascular dementia subtypes caused by small-, large-, or mixed-vessel disease. Arch Med Sci. 2016;12:747–53.PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Ninomiya T, Ohara T, Hirakawa Y, Yoshida D, Doi Y, Hata J, et al. Midlife and late-life blood pressure and dementia in Japanese elderly: the Hisayama study. Hypertension. 2011;58:22–8.PubMedCrossRefGoogle Scholar
  121. 121.
    Kimm H, Lee PH, Shin YJ, Park KS, Jo J, Lee Y, et al. Mid-life and late-life vascular risk factors and dementia in Korean men and women. Arch Gerontol Geriatr. 2011;52:e117–22.PubMedCrossRefGoogle Scholar
  122. 122.
    Yamada M, Mimori Y, Kasagi F, Miyachi T, Ohshita T, Sasaki H. Incidence and risks of dementia in Japanese women: Radiation Effects Research Foundation Adult Health Study. J Neurol Sci. 2009;283:57–61.PubMedCrossRefGoogle Scholar
  123. 123.
    Posner HB, Tang M-X, Luchsinger J, Lantigua R, Stern Y, Mayeux R. The relationship of hypertension in the elderly to AD, vascular dementia, and cognitive function. Neurology. 2002;58:1175–81.PubMedCrossRefGoogle Scholar
  124. 124.
    Leritz EC, Salat DH, Williams VJ, Schnyer DM, Rudolph JL, Lipsitz L, et al. Thickness of the human cerebral cortex is associated with metrics of cerebrovascular health in a normative sample of community dwelling older adults. NeuroImage. 2011;54:2659–71.PubMedCrossRefGoogle Scholar
  125. 125.
    Nagai M, Hoshide S, Ishikawa J, Shimada K, Kario K. Ambulatory blood pressure as an independent determinant of brain atrophy and cognitive function in elderly hypertension. J Hypertens. 2008;26:1636–41.PubMedCrossRefGoogle Scholar
  126. 126.
    Glodzik L, Mosconi L, Tsui W, de Santi S, Zinkowski R, Pirraglia E, et al. Alzheimer’s disease markers, hypertension, and gray matter damage in normal elderly. Neurobiol Aging. 2012;33:1215–27.PubMedCrossRefGoogle Scholar
  127. 127.
    Gianaros PJ, Greer PJ, Ryan CM, Jennings JR. Higher blood pressure predicts lower regional grey matter volume: consequences on short-term information processing. NeuroImage. 2006;31:754–65.PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Firbank MJ, Wiseman RM, Burton EJ, Saxby BK, O’Brien JT, Ford GA. Brain atrophy and white matter hyperintensity change in older adults and relationship to blood pressure. Brain atrophy, WMH change and blood pressure. J. Neurol. 2007;254:713–21.CrossRefGoogle Scholar
  129. 129.
    Jennings JR, Mendelson DN, Muldoon MF, Ryan CM, Gianaros PJ, Raz N, et al. Regional grey matter shrinks in hypertensive individuals despite successful lowering of blood pressure. J Hum Hypertens. 2012;26:295–305.PubMedCrossRefGoogle Scholar
  130. 130.
    Harris P, Alcantara DA, Amenta N, Lopez OL, Eiríksdóttir G, Sigurdsson S, et al. Localized measures of callosal atrophy are associated with late-life hypertension: AGES-Reykjavik Study. NeuroImage. 2008;43:489–96.PubMedPubMedCentralCrossRefGoogle Scholar
  131. 131.
    Muller M, van der Graaf Y, Visseren FL, Vlek ALM, Mali WPTM, Geerlings MI, et al. Blood pressure, cerebral blood flow, and brain volumes. The SMART-MR study. J Hypertens. 2010;28:1498–505.PubMedCrossRefGoogle Scholar
  132. 132.
    Foster-Dingley JC, Van Der Grond J, Moonen JEF, Van Den Berg-Huijsmans AA, De Ruijter W, Van Buchem MA, et al. Lower blood pressure is associated with smaller subcortical brain volumes in older persons. Am J Hypertens. 2015;28:1127–33.PubMedCrossRefGoogle Scholar
  133. 133.
    van Velsen EFS, Vernooij MW, Vrooman HA, van der Lugt A, Breteler MMB, Hofman A, et al. Brain cortical thickness in the general elderly population: the Rotterdam Scan Study. Neurosci Lett. 2013;550:189–94.PubMedCrossRefGoogle Scholar
  134. 134.
    DeCarli C, Miller BL, Swan GE, Reed T, Wolf PA, Garner J, et al. Predictors of brain morphology for the men of the NHLBI twin study. Stroke. 1999;30:529–36.PubMedCrossRefGoogle Scholar
  135. 135.
    Korf ESC, White LR, Scheltens P, Launer LJ. Midlife blood pressure and the risk of hippocampal atrophy: the Honolulu Asia Aging Study. Hypertens (Dallas, Tex 1979). 2004;44:29–34.CrossRefGoogle Scholar
  136. 136.
    • Power MC, Schneider ALC, Wruck L, Griswold M, Coker LH, Alonso A, et al. Life-course blood pressure in relation to brain volumes. Alzheimer’s Dement. 2016 Aug;890–9. This large longitudinal study found that increasing systolic blood pressure and sustained hypertension over a 10-year period during midlife, but not late-life blood pressure, was associated with smaller late-life regional brain volumes. Google Scholar
  137. 137.
    Ashby EL, Miners JS, Kehoe PG, Love S. Effects of hypertension and anti-hypertensive treatment on amyloid-ß plaque load and Aß-synthesizing and Aß-degrading enzymes in frontal cortex. J Alzheimers Dis. 2016;50:1191–203.PubMedCrossRefGoogle Scholar
  138. 138.
    Langbaum JBS, Chen K, Launer LJ, Fleisher AS, Lee W, Liu X, et al. Blood pressure is associated with higher brain amyloid burden and lower glucose metabolism in healthy late middle-age persons. Neurobiol Aging. 2012;33:827.e11–9.CrossRefGoogle Scholar
  139. 139.
    Toledo JB, Toledo E, Weiner MW, Jack CR, Jagust W, Lee VMY, et al. Cardiovascular risk factors, cortisol, and amyloid-β deposition in Alzheimer’s Disease Neuroimaging Initiative. Alzheimers Dement. 2012;8:483–9.PubMedPubMedCentralCrossRefGoogle Scholar
  140. 140.
    Beason-Held LL, Moghekar A, Zonderman AB, Kraut MA, Resnick SM. Longitudinal changes in cerebral blood flow in the older hypertensive brain. Stroke. 2007;38:1766–73.PubMedCrossRefGoogle Scholar
  141. 141.
    • Gottesman RF, Coresh J, Catellier DJ, Sharrett AR, Rose KM, Coker LH, et al. Blood pressure and white-matter disease progression in a biethnic cohort: Atherosclerosis Risk in Communities (ARIC) study. Stroke. 2010;41:3–8. This large community-based study found that cumulative systolic blood pressure measured over a period of 5 visits was a strong predictor of white matter hyperintensity progression over a 10-year period. PubMedCrossRefGoogle Scholar
  142. 142.
    Verhaaren BFJ, Vernooij MW, De Boer R, Hofman A, Niessen WJ, Van Der Lugt A, et al. High blood pressure and cerebral white matter lesion progression in the general population. Hypertension. 2013;61:1354–9.PubMedCrossRefGoogle Scholar
  143. 143.
    Shams S, Martola J, Granberg T, Li X, Shams M, Fereshtehnejad SM, et al. Cerebral microbleeds: different prevalence, topography, and risk factors depending on dementia diagnosis—the Karolinska Imaging Dementia Study. Am J Neuroradiol. 2015;36:661–6.PubMedCrossRefGoogle Scholar
  144. 144.
    Poels MMF, Zaccai K, Verwoert GC, Vernooij MW, Hofman A, Van Der Lugt A, et al. Arterial stiffness and cerebral small vessel disease: the Rotterdam Scan Study. Stroke. 2012;43:2637–42.PubMedCrossRefGoogle Scholar
  145. 145.
    van Sloten TT, Protogerou AD, Henry RMA, Schram MT, Launer LJ, Stehouwer CDA. Association between arterial stiffness, cerebral small vessel disease and cognitive impairment: a systematic review and meta-analysis. Neurosci. Biobehav. Rev. 2015. p. 121–30.Google Scholar
  146. 146.
    Dufouil C, Chalmers J, Coskun O, Besançon V, Bousser MG, Guillon P, et al. Effects of blood pressure lowering on cerebral white matter hyperintensities in patients with stroke: the progress (Perindopril Protection Against Recurrent Stroke Study) magnetic resonance imaging substudy. Circulation. 2005;112:1644–50.PubMedCrossRefGoogle Scholar
  147. 147.
    Launer LJ, Lewis CE, Schreiner PJ, Sidney S, Battapady H, Jacobs DR, et al. Vascular factors and multiple measures of early brain health: CARDIA brain MRI study. PLoS One. 2015;10:e0122138.PubMedPubMedCentralCrossRefGoogle Scholar
  148. 148.
    Burgmans S, van Boxtel MPJ, Gronenschild EHBM, Vuurman EFPM, Hofman P, Uylings HBM, et al. Multiple indicators of age-related differences in cerebral white matter and the modifying effects of hypertension. NeuroImage. 2010;49:2083–93.PubMedCrossRefGoogle Scholar
  149. 149.
    Maillard P, Seshadri S, Beiser A, Himali JJ, Au R, Fletcher E, et al. Effects of systolic blood pressure on white-matter integrity in young adults in the Framingham Heart Study: a cross-sectional study. Lancet Neurol. 2012;11:1039–47.PubMedPubMedCentralCrossRefGoogle Scholar
  150. 150.
    Gons RAR, De Laat KF, Van Norden AGW, Van Oudheusden LJB, Van Uden IWM, Norris DG, et al. Hypertension and cerebral diffusion tensor imaging in small vessel disease. Stroke. 2010;41:2801–6.PubMedCrossRefGoogle Scholar
  151. 151.
    Martinez-Lemus LA, Hill MA, Meininger GA. The plastic nature of the vascular wall: a continuum of remodeling events contributing to control of arteriolar diameter and structure. Physiology. 2009;24:45–57.PubMedCrossRefGoogle Scholar
  152. 152.
    Heagerty AM, Aalkjaer C, Bund SJ, Korsgaard N, Mulvany MJ. Small artery structure in hypertension. Dual processes of remodeling and growth. Hypertension. 1993;21:391–7.PubMedCrossRefGoogle Scholar
  153. 153.
    Rizzoni D, Porteri E, Castellano M, Bettoni G, Muiesan ML, Muiesan P, et al. Vascular hypertrophy and remodeling in secondary hypertension. Hypertension. 1996;28:785–90.PubMedCrossRefGoogle Scholar
  154. 154.
    Faraco G, Iadecola C. Hypertension: A harbinger of stroke and dementia. Hypertension. 2013. p. 810–7.Google Scholar
  155. 155.
    Castorena-Gonzalez JA, Staiculescu MC, Foote C, Martinez-Lemus LA. Mechanisms of the inward remodeling process in resistance vessels: is the actin cytoskeleton involved? Microcirculation. 2014;21:219–29.PubMedPubMedCentralCrossRefGoogle Scholar
  156. 156.
    Scuteri A, Nilsson PM, Tzourio C, Redon J, Laurent S. Microvascular brain damage with aging and hypertension: pathophysiological consideration and clinical implications. J Hypertens. 2011;29:1469–77.PubMedCrossRefGoogle Scholar
  157. 157.
    Pedrinelli R, Penno G, Omo GD, Bandinelli S, Giorgi D, Di BV, et al. Microalbuminuria and transcapillary albumin leakage in essential hypertension. Hypertension. 1999;34:491–6.PubMedCrossRefGoogle Scholar
  158. 158.
    Holmstedt CA, Turan TN, Chimowitz MI. Atherosclerotic intracranial arterial stenosis: risk factors, diagnosis, and treatment. Lancet Neurol. 2013;12:1106–14.PubMedPubMedCentralCrossRefGoogle Scholar
  159. 159.
    Pantoni L. Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges. Lancet Neurol. 2010;9:689–701.PubMedCrossRefGoogle Scholar
  160. 160.
    Scuteri A, Morrell CH, Orrù M, Strait JB, Tarasov KV, Ferreli LAP, et al. Longitudinal perspective on the conundrum of central arterial stiffness, blood pressure, and aging. Hypertens. (Dallas, Tex. 1979). 2014;64:1219–27.CrossRefGoogle Scholar
  161. 161.
    Duschek S, Schandry R. Reduced brain perfusion and cognitive performance due to constitutional hypotension. Clin Auton Res. 2007;17:69–76.PubMedCrossRefGoogle Scholar
  162. 162.
    Lenzi GL, Frackowiak RS, Jones T. Cerebral oxygen metabolism and blood flow in human cerebral ischemic infarction. J Cereb Blood Flow Metab. 1982;2:321–35.PubMedCrossRefGoogle Scholar
  163. 163.
    • Muller M, Van Der Graaf Y, Visseren FL, Mali WPTM, Geerlings MI. Hypertension and longitudinal changes in cerebral blood flow: the SMART-MR study. Ann Neurol. 2012;71:825–33. The first longitudinal study to demonstrate a relationship between hypertension, high blood pressure, and declines in cerebral blood flow using magnetic resonance angiography. PubMedCrossRefGoogle Scholar
  164. 164.
    Wong LJ, Kupferman JC, Prohovnik I, Kirkham FJ, Goodman S, Paterno K, et al. Hypertension impairs vascular reactivity in the pediatric brain. Stroke. 2011;42:1834–8.PubMedCrossRefGoogle Scholar
  165. 165.
    Capone C, Faraco G, Peterson JR, Coleman C, Anrather J, Milner TA, et al. Central cardiovascular circuits contribute to the neurovascular dysfunction in angiotensin II hypertension. J Neurosci. 2012;32:4878–86.PubMedPubMedCentralCrossRefGoogle Scholar
  166. 166.
    Pires PW, Jackson WF, Dorrance AM. Regulation of myogenic tone and structure of parenchymal arterioles by hypertension and the mineralocorticoid receptor. Am. J. Physiol. Hear. Circ. 2015;309:H127–36.CrossRefGoogle Scholar
  167. 167.
    Matsushita K, Kuriyama Y, Nagatsuka K, Nakamura M, Sawada T, Omae T. Periventricular white matter lucency and cerebral blood flow autoregulation in hypertensive patients. Hypertension. 1994;23:565–8.PubMedCrossRefGoogle Scholar
  168. 168.
    Wang T, Li Y, Guo X, Huang D, Ma L, Wang DJJ, et al. Reduced perfusion in normal-appearing white matter in mild to moderate hypertension as revealed by 3D pseudocontinuous arterial spin labeling. J Magn Reson Imaging. 2016;43:635–43.PubMedCrossRefGoogle Scholar
  169. 169.
    Heiss W-D. The ischemic penumbra: correlates in imaging and implications for treatment of ischemic stroke. Cerebrovasc Dis. 2011;32:307–20.PubMedCrossRefGoogle Scholar
  170. 170.
    Iadecola C. Neurovascular regulation in the normal brain and in Alzheimer’s disease. Nat Rev Neurosci. 2004;5:347–60.PubMedCrossRefGoogle Scholar
  171. 171.
    Koike MA, Green KN, Blurton-Jones M, Laferla FM. Oligemic hypoperfusion differentially affects tau and amyloid-β. Am J Pathol. 2010;177:300–10.PubMedPubMedCentralCrossRefGoogle Scholar
  172. 172.
    Gentile MT, Poulet R, Di Pardo A, Cifelli G, Maffei A, Vecchione C, et al. Beta-amyloid deposition in brain is enhanced in mouse models of arterial hypertension. Neurobiol Aging. 2009;30:222–8.PubMedCrossRefGoogle Scholar
  173. 173.
    Wang X, Xing A, Xu C, Cai Q, Liu H, Li L. Cerebrovascular hypoperfusion induces spatial memory impairment, synaptic changes, and amyloid-β oligomerization in rats. J Alzheimers Dis. 2010;21:813–22.PubMedGoogle Scholar
  174. 174.
    Walsh DM, Klyubin I, Fadeeva JV, Cullen WK, Anwyl R, Wolfe MS, et al. Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature. 2002;416:535–9.PubMedCrossRefGoogle Scholar
  175. 175.
    Li L, Zhang X, Yang D, Luo G, Chen S, Le W. Hypoxia increases Abeta generation by altering beta- and gamma-cleavage of APP. Neurobiol Aging. 2009;30:1091–8.PubMedCrossRefGoogle Scholar
  176. 176.
    • Carnevale D, Mascio G, D’Andrea I, Fardella V, Bell RD, Branchi I, et al. Hypertension induces brain β-amyloid accumulation, cognitive impairment, and memory deterioration through activation of receptor for advanced glycation end products in brain vasculature. Hypertension. 2012;60:188–97. This study provides convincing evidence for a link between hypertension and increased Alzheimer’s disease pathology that occurs as a result of an upregulation of receptor for advanced glycation end products (RAGE) in cerebral vessels. PubMedPubMedCentralCrossRefGoogle Scholar
  177. 177.
    Girouard H, Iadecola C. Neurovascular coupling in the normal brain and in hypertension, stroke, and Alzheimer disease. J Appl Physiol. 2006;100:328–35.PubMedCrossRefGoogle Scholar
  178. 178.
    Kazama K, Wang G, Frys K, Anrather J, Iadecola C. Angiotensin II attenuates functional hyperemia in the mouse somatosensory cortex. Am J Physiol Heart Circ Physiol. 2003;285:H1890–9.PubMedCrossRefGoogle Scholar
  179. 179.
    Xia W, Rao H, Spaeth AM, Huang R, Tian S, Cai R, et al. Blood pressure is associated with cerebral blood flow alterations in patients with T2DM as revealed by perfusion functional MRI. Medicine (Baltimore). 2015;94:e2231.CrossRefGoogle Scholar
  180. 180.
    Jennings JR, Muldoon MF, Ryan C, Price JC, Greer P, Sutton-Tyrrell K, et al. Reduced cerebral blood flow response and compensation among patients with untreated hypertension. Neurology. 2005;64:1358–65.PubMedCrossRefGoogle Scholar
  181. 181.
    Capone C, Faraco G, Park L, Cao X, Davisson RL, Iadecola C. The cerebrovascular dysfunction induced by slow pressor doses of angiotensin II precedes the development of hypertension. Am J Physiol Heart Circ Physiol. 2011;300:H397–407.PubMedCrossRefGoogle Scholar
  182. 182.
    Laplante MA, Wu R, Moreau P, De Champlain J. Endothelin mediates superoxide production in angiotensin II-induced hypertension in rats. Free Radic Biol Med. 2005;38:589–96.PubMedCrossRefGoogle Scholar
  183. 183.
    Duron E, Hanon O. Antihypertensive treatments, cognitive decline, and dementia. J. Alzheimer’s Dis. 2010. p. 903–14.Google Scholar
  184. 184.
    •• McGuinness B, Todd S, Passmore P, Bullock R. Blood pressure lowering in patients without prior cerebrovascular disease for prevention of cognitive impairment and dementia. Cochrane Database Syst. Rev. 2009. p. CD004034. This is a 2009 Cochrane review of the effectiveness of blood pressure lowering for prevention of cognitive impairment and dementia. Google Scholar
  185. 185.
    Tzourio C, Anderson C, Chapman N, Woodward M, Neal B, MacMahon S, 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;163:1069–75.PubMedCrossRefGoogle Scholar
  186. 186.
    Forette F, Seux ML, Staessen JA, Thijs L, Birkenhäger WH, Babarskiene MR, et al. Prevention of dementia in randomised double-blind placebo-controlled systolic hypertension in Europe (Syst-Eur) trial. Lancet. 1998;352:1347–51.PubMedCrossRefGoogle Scholar
  187. 187.
    Bosch J, Yusuf S, Pogue J, Sleight P, Lonn E, Rangoonwala B, et al. Use of ramipril in preventing stroke: double blind randomised trial. BMJ. 2002;324:699.PubMedPubMedCentralCrossRefGoogle Scholar
  188. 188.
    Anderson C, Teo K, Gao P, Arima H, Dans A, Unger T, et al. Renin-angiotensin system blockade and cognitive function in patients at high risk of cardiovascular disease: analysis of data from the ONTARGET and TRANSCEND studies. Lancet Neurol. 2011;10:43–53.PubMedCrossRefGoogle Scholar
  189. 189.
    SHEP. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP). SHEP Cooperative Research Group. JAMA. 1991;265:3255–64.CrossRefGoogle Scholar
  190. 190.
    Lithell H, Hansson L, Skoog I, Elmfeldt D, Hofman A, Olofsson B, et al. The study on cognition and prognosis in the elderly (SCOPE): principal results of a randomized double-blind intervention trial. J Hypertens. 2003;21:875–86.PubMedCrossRefGoogle Scholar
  191. 191.
    Peters R, Beckett N, Forette F, Tuomilehto J, Clarke R, Ritchie C, et al. Incident dementia and blood pressure lowering in the Hypertension in the Very Elderly Trial cognitive function assessment (HYVET-COG): a double-blind, placebo controlled trial. Lancet Neurol. 2008;7:683–9.PubMedCrossRefGoogle Scholar
  192. 192.
    Prince MJ, Bird AS, Blizard RA, Mann AH. Is the cognitive function of older patients affected by antihypertensive treatment? Results from 54 months of the Medical Research Council’s trial of hypertension in older adults. BMJ. 1996;312:801–5.PubMedPubMedCentralCrossRefGoogle Scholar
  193. 193.
    Wright JW, Stubley L, Pederson ES, Kramár EA, Hanesworth JM, Harding JW. Contributions of the brain angiotensin IV-AT4 receptor subtype system to spatial learning. J Neurosci. 1999;19:3952–61.PubMedGoogle Scholar
  194. 194.
    Takeda S, Sato N, Takeuchi D, Kurinami H, Shinohara M, Niisato K, et al. Angiotensin receptor blocker prevented beta-amyloid-induced cognitive impairment associated with recovery of neurovascular coupling. Hypertension. 2009;54:1345–52.PubMedCrossRefGoogle Scholar
  195. 195.
    Marpillat NL, Macquin-Mavier I, Tropeano A-I, Bachoud-Levi A-C, Maison P. Antihypertensive classes, cognitive decline and incidence of dementia: a network meta-analysis. J Hypertens. 2013;31:1073–82.CrossRefGoogle Scholar
  196. 196.
    Wharton W, Stein JH, Korcarz C, Sachs J, Olson SR, Zetterberg H, et al. The effects of ramipril in individuals at risk for Alzheimer’s disease: results of a pilot clinical trial. J Alzheimers Dis. 2012;32:147–56.PubMedPubMedCentralGoogle Scholar
  197. 197.
    Hughes TM, Sink KM. Hypertension and its role in cognitive function: current evidence and challenges for the future. Am J Hypertens. 2016;29:149–57.PubMedCrossRefGoogle Scholar
  198. 198.
    Bossers WJR, van der Woude LHV, Boersma F, Scherder EJA, van Heuvelen MJG. Recommended measures for the assessment of cognitive and physical performance in older patients with dementia: a systematic review. Dement Geriatr Cogn Dis Extra. 2012;2:589–609.PubMedPubMedCentralCrossRefGoogle Scholar
  199. 199.
    Dubois B, Slachevsky A, Litvan I, Pillon B. The FAB: a frontal assessment battery at bedside. Neurology. 2000;55:1621–6.PubMedCrossRefGoogle Scholar
  200. 200.
    • Ambrosius WT, Sink KM, Foy CG, Berlowitz DR, Cheung AK, Cushman WC, et al. The design and rationale of a multicenter clinical trial comparing two strategies for control of systolic blood pressure: the Systolic Blood Pressure Intervention Trial (SPRINT). Clin Trials. 2014;11:532–46. Outlines the design and rationale for the parent study of the recent Systolic Blood Pressure Intervention Trial: Memory and Cognition in Decreased Hypertension (SPRINT-MIND) trial PubMedCrossRefGoogle Scholar
  201. 201.
    SPRINT Research Group, Wright JT, Williamson JD, Whelton PK, Snyder JK, Sink KM, et al. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med. 2015;373:2103–16.CrossRefGoogle Scholar
  202. 202.
    McNiece KL, Poffenbarger TS, Turner JL, Franco KD, Sorof JM, Portman RJ. Prevalence of hypertension and pre-hypertension among adolescents. J Pediatr. 2007;150:640–644.e1.PubMedCrossRefGoogle Scholar
  203. 203.
    Lande MB, Kupferman JC. Cognitive function in hypertensive children. Curr Hypertens Rep. 2015;17:508.PubMedCrossRefGoogle Scholar
  204. 204.
    Tsao CW, Himali JJ, Beiser AS, Larson MG, DeCarli C, Vasan RS, et al. Association of arterial stiffness with progression of subclinical brain and cognitive disease. Neurology. 2016;86:619–26.PubMedPubMedCentralCrossRefGoogle Scholar
  205. 205.
    Waldstein SR, Rice SC, Thayer JF, Najjar SS, Scuteri A, Zonderman AB. Pulse pressure and pulse wave velocity are related to cognitive decline in the Baltimore Longitudinal Study of Aging. Hypertens. (Dallas, Tex. 1979). 2008;51:99–104.CrossRefGoogle Scholar
  206. 206.
    Liao D, Cooper L, Cai J, Toole J, Bryan N, Burke G, et al. The prevalence and severity of white matter lesions, their relationship with age, ethnicity, gender, and cardiovascular disease risk factors: the ARIC Study. Neuroepidemiology. 1997;16:149–62.PubMedCrossRefGoogle Scholar
  207. 207.
    Nation DA, Edmonds EC, Bangen KJ, Delano-Wood L, Scanlon BK, Han SD, et al. Pulse pressure in relation to tau-mediated neurodegeneration, cerebral amyloidosis, and progression to dementia in very old adults. JAMA Neurol. 2015;72:546.PubMedPubMedCentralCrossRefGoogle Scholar
  208. 208.
    Webb AJS, Simoni M, Mazzucco S, Kuker W, Schulz U, Rothwell PM. Increased cerebral arterial pulsatility in patients with leukoaraiosis: arterial stiffness enhances transmission of aortic pulsatility. Stroke. 2012;43:2631–6.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Keenan A. Walker
    • 1
  • Melinda C. Power
    • 2
  • Rebecca F. Gottesman
    • 1
    • 3
    Email author
  1. 1.Department of NeurologyJohns Hopkins University School of MedicineBaltimoreUSA
  2. 2.Department of Epidemiology and BiostatisticsGeorge Washington University Milken Institute School of Public HealthWashingtonUSA
  3. 3.Department of EpidemiologyJohns Hopkins University School of MedicineBaltimoreUSA

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