Heart disease is the major leading cause of death and disability in the world. Mainly affecting the elderly population, heart disease and its main outcome, cardiovascular disease, have become an important risk factor in the development of cognitive decline and Alzheimer’s disease (AD). This paper examines the evidence linking chronic brain hypoperfusion induced by a variety of cardiovascular deficits in the development of cognitive impairment preceding AD. The evidence indicates a strong association between AD and cardiovascular risk factors, including ApoE4, atrial fibrillation, thrombotic events, hypertension, hypotension, heart failure, high serum markers of inflammation, coronary artery disease, low cardiac index, and valvular pathology. In elderly people whose cerebral perfusion is already diminished by their advanced age, additional reduction of cerebral blood flow stemming from abnormalities in the heart-brain vascular loop ostensibly increases the probability of developing AD. Evidence also suggests that a neuronal energy crisis brought on by relentless brain hypoperfusion may be responsible for protein synthesis abnormalities that later result in the classic neurodegenerative lesions involving the formation of amyloid-beta plaques and neurofibrillary tangles. Insight into how cardiovascular risk factors can induce progressive cognitive impairment offers an enhanced understanding of the multifactorial pathophysiology characterizing AD and ways at preventing or managing the cardiovascular precursors of this dementia. 1. Introduction It has been known since the Ebers papyrus [1] in 1552 BC, and probably even before then, that the brain and heart are intimately connected. The ancient Greeks and Aristotle in particular believed that the function of the brain was to “cool” the blood while the heart was the source of memory. This belief was consolidated by religious and scientific dogma for centuries. It took the most significant achievements in medicine in the 16th and 17th centuries by the Belgian anatomist Andreas Vesalius and the English physician William Harvey to challenge that prevailing dogma and describe a more accurate account of the cerebral circulation as well as the heart’s continuous pumping action inside a very precise circuit. Fast-forwarding to the 20th century, several researchers in the late 1970s became aware of an intriguing link between a sick heart and the start of cognitive deterioration that often led to vascular dementia (VaD) [2]. This link came to be known as “cardiogenic dementia”, and although it remained largely ignored
References
[1]
B. Ebbell, The Papyrus Ebers. The Greatest Egyptian Medical Document, Levin & Munksgaard, Copenhagen, Denmark, 1937.
[2]
“Cardiogenic dementia,” The Lancet, vol. 1, no. 8001, pp. 27–28, 1977.
[3]
J. de la Torre, “Basics of Alzheimer's disease prevention,” Journal of Alzheimer's Disease, vol. 20, no. 3, pp. 687–688, 2010.
[4]
C. Bergmann and M. Sano, “Cardiac risk factors and potential treatments in Alzheimer's disease,” Neurological Research, vol. 28, no. 6, pp. 595–604, 2006.
[5]
A. K. David and R. B. Taylor, Taylor’s Cardiovascular Diseases: A Handbook, Springer, 2004.
[6]
R. J. M. Lane, “‘Cardiogenic dementia’ revisited,” Journal of the Royal Society of Medicine, vol. 84, no. 10, pp. 577–579, 1991.
[7]
H. Koide, S. Kobayashi, M. Kitani, T. Tsunematsu, and Y. Nakazawa, “Improvement of cerebral blood flow and cognitive function following pacemaker implantation in patients with bradycardia,” Gerontology, vol. 40, no. 5, pp. 279–285, 1994.
[8]
S. Duschek, E. Matthias, and R. Schandry, “Essential hypotension is accompanied by deficits in attention and working memory,” Behavioral Medicine, vol. 30, no. 4, pp. 149–158, 2005.
[9]
C. Qiu, E. von Strauss, J. Fastbom, B. Winblad, and L. Fratiglioni, “Low blood pressure and risk of dementia in the Kungsholmen project: a 6-year follow-up study,” Archives of Neurology, vol. 60, no. 2, pp. 223–228, 2003.
[10]
S. R. Waldstein, P. P. Giggey, J. F. Thayer, and A. B. Zonderman, “Nonlinear relations of blood pressure to cognitive function: the Baltimore longitudinal study of aging,” Hypertension, vol. 45, no. 3, pp. 374–379, 2005.
[11]
L. E. Hebert, P. A. Scherr, D. A. Bennett et al., “Blood pressure and late-life cognitive function change: a biracial longitudinal population study,” Neurology, vol. 62, no. 11, pp. 2021–2024, 2004.
[12]
S. Duschek and R. Schandry, “Reduced brain perfusion and cognitive performance due to constitutional hypotension,” Clinical Autonomic Research, vol. 17, no. 2, pp. 69–76, 2007.
[13]
S. Kennelly and O. Collins, “Walking the cognitive “minefield” between high and low blood pressure,” Journal of Alzheimer's Disease, vol. 32, no. 3, pp. 609–621, 2012.
[14]
J. Verghese, R. B. Lipton, C. B. Hall, G. Kuslansky, and M. J. Katz, “Low blood pressure and the risk of dementia in very old individuals,” Neurology, vol. 61, no. 12, pp. 1667–1672, 2003.
[15]
S. E. Nilsson, S. Read, S. Berg, B. Johansson, A. Melander, and U. Lindblad, “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, vol. 19, no. 1, pp. 41–47, 2007.
[16]
K. Ide, F. Pott, J. J. Van Lieshout, and N. H. Secher, “Middle cerebral artery blood velocity depends on cardiac output during exercise with a large muscle mass,” Acta Physiologica Scandinavica, vol. 162, no. 1, pp. 13–20, 1998.
[17]
J. C. de la Torre, “Cerebral hemodynamics and vascular risk factors: setting the stage for Alzheimer's disease,” Journal of Alzheimer's Disease, vol. 32, no. 3, pp. 553–567, 2012.
[18]
W. D. Brown and R. S. J. Frackowiak, “Cerebral blood flow and metabolism studies in multi-infarct dementia,” Alzheimer Disease and Associated Disorders, vol. 5, no. 2, pp. 131–143, 1991.
[19]
J. C. de la Torre, “Critically attained threshold of cerebral hypoperfusion: the CATCH hypothesis of Alzheimer's pathogenesis,” Neurobiology of Aging, vol. 21, no. 2, pp. 331–342, 2000.
[20]
M. J. De Leon, L. Mosconi, K. Blennow et al., “Imaging and CSF studies in the preclinical diagnosis of Alzheimer's disease,” Annals of the New York Academy of Sciences, vol. 1097, pp. 114–145, 2007.
[21]
L. Mosconi, S. De Santi, J. Li et al., “Hippocampal hypometabolism predicts cognitive decline from normal aging,” Neurobiology of Aging, vol. 29, no. 5, pp. 676–692, 2008.
[22]
K. L. Leenders, D. Perani, A. A. Lammertsma et al., “Cerebral blood flow, blood volume and oxygen utilization: normal values and effect of age,” Brain, vol. 113, no. 1, pp. 27–47, 1990.
[23]
M. Zhao, S. Amin-Hanjani, S. Ruland, A. P. Curcio, L. Ostergren, and F. T. Charbel, “Regional cerebral blood flow using quantitative MR angiography,” American Journal of Neuroradiology, vol. 28, no. 8, pp. 1470–1473, 2007.
[24]
M. Bentourkia, A. Bol, A. Ivanoiu et al., “Comparison of regional cerebral blood flow and glucose metabolism in the normal brain: effect of aging,” Journal of the Neurological Sciences, vol. 181, no. 1-2, pp. 19–28, 2000.
[25]
L. M. Parkes, W. Rashid, D. T. Chard, and P. S. Tofts, “Normal cerebral perfusion measurements using arterial spin labeling: reproducibility, stability, and age and gender effects,” Magnetic Resonance in Medicine, vol. 51, no. 4, pp. 736–743, 2004.
[26]
S. Heo, R. S. Prakash, M. W. Voss et al., “Resting hippocampal blood flow, spatial memory and aging,” Brain Research, vol. 1315, pp. 119–127, 2010.
[27]
J. C. de la Torre, “How do heart disease and stroke become risk factors for Alzheimer's disease?” Neurological Research, vol. 28, no. 6, pp. 637–644, 2006.
[28]
M. Erecińska and I. A. Silver, “ATP and brain function,” Journal of Cerebral Blood Flow and Metabolism, vol. 9, no. 1, pp. 2–19, 1989.
[29]
D. Gebremedhin, A. R. Lange, T. F. Lowry et al., “Production of 20-HETE and its role in autoregulation of cerebral blood flow,” Circulation Research, vol. 87, no. 1, pp. 60–65, 2000.
[30]
M. Silvestrini, F. Vernieri, P. Pasqualetti et al., “Impaired cerebral vasoreactivity and risk of stroke in patients with asymptomatic carotid artery stenosis,” Journal of the American Medical Association, vol. 283, no. 16, pp. 2122–2127, 2000.
[31]
H. Markus and M. Cullinane, “Severely impaired cerebrovascular reactivity predicts stroke and TIA risk in patients with carotid artery stenosis and occlusion,” Brain, vol. 124, no. 3, pp. 457–467, 2001.
[32]
R. P. White, P. Vallance, and H. S. Markus, “Effect of inhibition of nitric oxide synthase on dynamic cerebral autoregulation in humans,” Clinical Science, vol. 99, no. 6, pp. 555–560, 2000.
[33]
O. B. Paulson, S. Strandgaard, and L. Edvinsson, “Cerebral autoregulation,” Cerebrovascular and Brain Metabolism Reviews, vol. 2, no. 2, pp. 161–192, 1990.
[34]
C. Qiu, B. Winblad, and L. Fratiglioni, “The age-dependent relation of blood pressure to cognitive function and dementia,” The Lancet Neurology, vol. 4, no. 8, pp. 487–499, 2005.
[35]
C. A. Feldstein, “Association between chronic blood pressure changes and development of Alzheimer's disease,” Journal of Alzheimer's Disease, vol. 32, no. 3, pp. 753–763, 2012.
[36]
M. Reinhard, M. Roth, T. Müller et al., “Effect of carotid endarterectomy or stenting on impairment of dynamic cerebral autoregulation,” Stroke, vol. 35, no. 6, pp. 1381–1387, 2004.
[37]
R. D. Raabe, R. B. Burr, and R. Short, “One-year Cognitive Outcomes Associated with Carotid Artery Stent Placement,” Journal of Vascular and Interventional Radiology, vol. 21, no. 7, pp. 983–988, 2010.
[38]
C. Haubrich, A. Kohnke, R. R. Diehl, W. M？ller-Hartmann, and C. Kl？tzsch, “Impact of vertebral artery disease on dynamic cerebral autoregulation,” Acta Neurologica Scandinavica, vol. 112, no. 5, pp. 309–316, 2005.
[39]
A. L. Jefferson, D. F. Tate, A. Poppas et al., “Lower cardiac output is associated with greater white matter hyperintensities in older adults with cardiovascular disease,” Journal of the American Geriatrics Society, vol. 55, no. 7, pp. 1044–1048, 2007.
[40]
T. C. De Toledo Ferraz Alves and G. F. Busatto, “Regional cerebral blood flow reductions, heart failure and Alzheimer's disease,” Neurological Research, vol. 28, no. 6, pp. 579–587, 2006.
[41]
J. C. de la Torre, “Alzheimer's disease prevalence can be lowered with non-invasive testing,” Journal of Alzheimer's Disease, vol. 14, no. 3, pp. 353–359, 2008.
[42]
K. F. Hoth, A. Poppas, D. J. Moser, R. H. Paul, and R. A. Cohen, “Cardiac dysfunction and cognition in older adults with heart failure,” Cognitive and Behavioral Neurology, vol. 21, no. 2, pp. 65–72, 2008.
[43]
J. Bogousslavsky and F. Regli, “Unilateral watershed cerebral infarcts,” Neurology, vol. 36, no. 3, pp. 373–377, 1986.
[44]
C. F. Bladin and B. R. Chambers, “Clinical features, pathogenesis, and computed tomographic characteristics of internal watershed infarction,” Stroke, vol. 24, no. 12, pp. 1925–1932, 1993.
[45]
P. Pullicino, V. Mifsud, E. Wong, S. Graham, I. Ali, and D. Smajlovic, “Hypoperfusion-related cerebral ischemia and cardiac left ventricular systolic dysfunction,” Journal of Stroke and Cerebrovascular Diseases, vol. 10, no. 4, pp. 178–182, 2001.
[46]
J. C. de la Torre, “Impaired cerebromicrovascular perfusion: summary of evidence in support of its causality in Alzheimer's disease,” Annals of the New York Academy of Sciences, vol. 924, pp. 136–152, 2000.
[47]
C. Geroldi, S. Galluzzi, C. Testa, O. Zanetti, and G. B. Frisoni, “Validation study of a CT-based weighted rating scale for subcortical ischemic vascular disease in patients with mild cognitive deterioration,” European Neurology, vol. 49, no. 4, pp. 193–209, 2003.
[48]
F. Forette, M. L. Seux, J. A. Staessen et al., “The prevention of dementia with antihypertensive treatment: new evidence from the systolic hypertension in Europe (syst-eur) study,” Archives of Internal Medicine, vol. 162, no. 18, pp. 2046–2052, 2002.
[49]
C. Qiu, B. Winblad, A. Marengoni, I. Klarin, J. Fastbom, and L. Fratiglioni, “Heart failure and risk of dementia and Alzheimer disease: a population-based cohort study,” Archives of Internal Medicine, vol. 166, no. 9, pp. 1003–1008, 2006.
[50]
C. Bertoni-Freddari, P. Fattoretti, B. Giorgetti, M. Solazzi, M. Balietti, and W. Meier-Ruge, “Role of mitochondrial deterioration in physiological and pathological brain aging,” Gerontology, vol. 50, no. 3, pp. 187–192, 2004.
[51]
M. S. Beeri, R. Ravona-Springer, J. M. Silverman, and V. Haroutunian, “The effects of cardiovascular risk factors on cognitive compromise,” Dialogues in Clinical Neuroscience, vol. 11, no. 2, pp. 201–212, 2009.
[52]
S. R. Waldstein and C. R. Wendell, “Neurocognitive function and cardiovascular disease,” Journal of Alzheimer's Disease, vol. 20, no. 3, pp. 833–842, 2010.
[53]
K. Shah, S. U. Qureshi, M. Johnson, N. Parikh, P. E. Schulz, and M. E. Kunik, “Does use of antihypertensive drugs affect the incidence or progression of dementia? A systematic review,” American Journal Geriatric Pharmacotherapy, vol. 7, no. 5, pp. 250–261, 2009.
[54]
M. M. B. Breteler, “Vascular involvement in cognitive decline and dementia. Epidemiologic evidence from the Rotterdam study and the Rotterdam scan study,” Annals of the New York Academy of Sciences, vol. 903, pp. 457–465, 2000.
[55]
M. K. Aronson, W. L. Ooi, H. Morgenstern et al., “Women, myocardial infarction, and dementia in the very old,” Neurology, vol. 40, no. 7, pp. 1102–1106, 1990.
[56]
M. Dlugaj, M. Gerwig, N. Wege et al., “Elevated levels of high-sensitivity C-reactive protein are associated with mild cognitive impairment and its subtypes: results of a population-based case-control study,” Journal of Alzheimer's Disease, vol. 28, no. 3, pp. 503–514, 2012.
[57]
M. C. Polidori, M. Marvardi, A. Cherubini, U. Senin, and P. Mecocci, “Heart disease and vascular risk factors in the cognitively impaired elderly: implications for Alzheimer's dementia,” Aging, vol. 13, no. 3, pp. 231–239, 2001.
[58]
D. L. Sparks, “Coronary artery disease, hypertension, ApoE, and cholesterol: a link to Alzheimer's disease?” Annals of the New York Academy of Sciences, vol. 826, pp. 128–146, 1997.
[59]
C. Purnell, S. Gao, C. M. Callahan, and H. C. Hendrie, “Cardiovascular risk factors and incident alzheimer disease: a systematic review of the literature,” Alzheimer Disease and Associated Disorders, vol. 23, no. 1, pp. 1–10, 2009.
[60]
O. A. Selnes, M. A. Grega, M. M. Bailey et al., “Do management strategies for coronary artery disease influence 6-year cognitive outcomes?” Annals of Thoracic Surgery, vol. 88, no. 2, pp. 445–454, 2009.
[61]
Y. Huang, “Mechanisms linking apolipoprotein e isoforms with cardiovascular and neurological diseases,” Current Opinion in Lipidology, vol. 21, no. 4, pp. 337–345, 2010.
[62]
M. Belohlavek, P. Jiamsripong, A. M. Calleja et al., “Patients with Alzheimer disease have altered transmitral flow: echocardiographic analysis of the vortex formation time,” Journal of Ultrasound in Medicine, vol. 28, no. 11, pp. 1493–1500, 2009.
[63]
B. A. Jerskey, R. A. Cohen, A. L. Jefferson et al., “Sustained attention is associated with left ventricular ejection fraction in older adults with heart disease,” Journal of the International Neuropsychological Society, vol. 15, no. 1, pp. 137–141, 2009.
[64]
A. L. Jefferson, A. Poppas, R. H. Paul, and R. A. Cohen, “Systemic hypoperfusion is associated with executive dysfunction in geriatric cardiac patients,” Neurobiology of Aging, vol. 28, no. 3, pp. 477–483, 2007.
[65]
G. S. Nelson, R. D. Berger, B. J. Fetics et al., “Left ventricular or biventricular pacing improves cardiac function at diminished energy cost in patients with dilated cardiomyopathy and left bundle-branch block,” Circulation, vol. 102, no. 25, pp. 3053–3059, 2000.
[66]
K. F. Hoth, A. Poppas, K. E. Ellison et al., “Link between change in cognition and left ventricular function following cardiac resynchronization therapy,” Journal of Cardiopulmonary Rehabilitation and Prevention, vol. 30, no. 6, pp. 401–408, 2010.
[67]
N. K. Dixit, L. D. Vazquez, N. J. Cross et al., “Cardiac resynchronization therapy: a pilot study examining cognitive change in patients before and after treatment,” Clinical Cardiology, vol. 33, no. 2, pp. 84–88, 2010.
[68]
J. R. Festa, X. Jia, K. Cheung et al., “Association of low ejection fraction with impaired verbal memory in older patients with heart failure,” Archives of Neurology, vol. 68, no. 8, pp. 1021–1026, 2011.
[69]
D. M. Lloyd-Jones, T. J. Wang, E. P. Leip et al., “Lifetime risk for development of atrial fibrillation: the framingham heart study,” Circulation, vol. 110, no. 9, pp. 1042–1046, 2004.
[70]
L. Kilander, B. Andrén, H. Nyman, L. Lind, M. Boberg, and H. Lithell, “Atrial fibrillation is an independent determinant of low cognitive function: a cross-sectional study in elderly men,” Stroke, vol. 29, no. 9, pp. 1816–1820, 1998.
[71]
A. Ott, M. M. B. Breteler, M. C. De Bruyne, F. Van Harskamp, D. E. Grobbee, and A. Hofman, “Atrial fibrillation and dementia in a population-based study: the Rotterdam study,” Stroke, vol. 28, no. 2, pp. 316–321, 1997.
[72]
T. J. Bunch, J. P. Weiss, B. G. Crandall et al., “Atrial fibrillation is independently associated with senile, vascular, and Alzheimer's dementia,” Heart Rhythm, vol. 7, no. 4, pp. 433–437, 2010.
[73]
P. Forti, F. Maioli, N. Pisacane, E. Rietti, F. Montesi, and G. Ravaglia, “Atrial fibrillation and risk of dementia in non-demented elderly subjects with and without mild cognitive impairment,” Neurological Research, vol. 28, no. 6, pp. 625–629, 2006.
[74]
C. R. Gomez, J. R. McLaughlin, P. C. Njemanze, and A. Nashed, “Effect of cardiac dysfunction upon diastolic cerebral blood flow,” Angiology, vol. 43, no. 8, pp. 625–630, 1992.
[75]
E. Ettorre, M. Cicerchia, G. De Benedetto et al., “A possible role of atrial fibrillation as a risk factor for dementia,” Archives of Gerontology and Geriatrics, vol. 49, pp. 71–76, 2009.
[76]
E. H. Corder, J. F. Ervin, E. Lockhart, M. H. Szymanski, D. E. Schmechel, and C. M. Hulette, “Cardiovascular damage in Alzheimer disease: autopsy findings from the bryan ADRC,” Journal of Biomedicine and Biotechnology, vol. 2005, no. 2, pp. 189–197, 2005.
[77]
K. D. Boudoulas, E. A. Sparks, S. E. Rittgers, C. F. Wooley, and H. Boudoulas, “Factors determining left atrial kinetic energy in patients with chronic mitral valve disease,” Herz, vol. 28, no. 5, pp. 437–444, 2003.
[78]
D. L. Sparks, J. C. Hunsaker, S. W. Scheff, R. J. Kryscio, J. L. Henson, and W. R. Markesbery, “Cortical senile plaques in coronary artery disease, aging and Alzheimer's disease,” Neurobiology of Aging, vol. 11, no. 6, pp. 601–607, 1990.
[79]
I. Skoog, L. A. Andreasson, S. Landahl, and B. Lernfelt, “A population-based study on blood pressure and brain atrophy in 85- year-olds,” Hypertension, vol. 32, no. 3, pp. 404–409, 1998.
[80]
Z. Guo, M. Viitanen, L. Fratiglioni, and B. Winblad, “Low blood pressure and dementia in elderly people: the Kungsholmen project,” British Medical Journal, vol. 312, no. 7034, pp. 805–808, 1996.
[81]
M. F. Elias, P. A. Wolf, R. B. D'Agostino, J. Cobb, and L. R. White, “Untreated blood pressure level is inversely related to cognitive functioning: the Framingham Study,” American Journal of Epidemiology, vol. 138, no. 6, pp. 353–364, 1993.
[82]
U. Kumari and K. Heese, “Cardiovascular dementia—a different perspective,” Open Biochemistry Journal, vol. 4, pp. 29–52, 2010.
[83]
R. Stewart, Q. L. Xue, K. Masaki et al., “Change in blood pressure and incident dementia: a 32-year prospective study,” Hypertension, vol. 54, no. 2, pp. 233–240, 2009.
[84]
I. Skoog, B. Lernfelt, S. Landahl et al., “15-year longitudinal study of blood pressure and dementia,” The Lancet, vol. 347, no. 9009, pp. 1141–1145, 1996.
[85]
M. Kivipelto, E. L. Helkala, M. P. Laakso et al., “Midlife vascular risk factors and Alzheimer's disease in later life: longitudinal, population based study,” British Medical Journal, vol. 322, no. 7300, pp. 1447–1451, 2001.
[86]
C. Wu, D. Zhou, C. Wen, L. Zhang, P. Como, and Y. Qiao, “Relationship between blood pressure and Alzheimer's disease in Linxian County, China,” Life Sciences, vol. 72, no. 10, pp. 1125–1133, 2003.
[87]
M. F. O'Rourke and M. E. Safar, “Relationship between aortic stiffening and microvascular disease in brain and kidney: cause and logic of therapy,” Hypertension, vol. 46, no. 1, pp. 200–204, 2005.
[88]
C. Tzourio, “Hypertension, cognitive decline, and dementia: an epidemiological perspective,” Dialogues in Clinical Neuroscience, vol. 9, no. 1, pp. 61–70, 2007.
[89]
J. C. van Swieten, G. G. Geyskes, M. M. A. Derix et al., “Hypertension in the elderly is associated with white matter lesions and cognitive decline,” Annals of Neurology, vol. 30, no. 6, pp. 825–830, 1991.
[90]
N. S. Shah, J.-S. Vidal, K. Masaki et al., “Midlife blood pressure, plasma β-amyloid, and the risk for alzheimer disease: the honolulu asia aging study,” Hypertension, vol. 59, no. 4, pp. 780–786, 2012.
[91]
J. C. de la Torre, “Cerebromicrovascular pathology in Alzheimer's disease compared to normal aging,” Gerontology, vol. 43, no. 1-2, pp. 26–43, 1997.
[92]
M. F. O'Rourke and J. Hashimoto, “Mechanical factors in arterial aging,” Journal of the American College of Cardiology, vol. 50, no. 1, pp. 1–13, 2007.
[93]
S. R. Waldstein, S. C. Rice, J. F. Thayer, S. S. Najjar, A. Scuteri, and A. B. Zonderman, “Pulse pressure and pulse wave velocity are related to cognitive decline in the Baltimore longitudinal study of aging,” Hypertension, vol. 51, no. 1, pp. 99–104, 2008.
[94]
E. Duron and O. Hanon, “Antihypertensive treatments, cognitive decline, and dementia,” Journal of Alzheimer's Disease, vol. 20, no. 3, pp. 903–914, 2010.
[95]
A. S. Khachaturian, P. P. Zandi, C. G. Lyketsos et al., “Antihypertensive medication use and incident alzheimer disease: the cache county study,” Archives of Neurology, vol. 63, no. 5, pp. 686–692, 2006.
[96]
M. M. Mielke, P. P. Zandi, K. Blennow et al., “Low serum potassium in mid life associated with decreased cerebrospinal fluid Aβ42 in late life,” Alzheimer Disease and Associated Disorders, vol. 20, no. 1, pp. 30–36, 2006.
[97]
R. D. McCabe, M. A. Bakarich, K. Srivastava, and D. B. Young, “Potassium inhibits free radical formation,” Hypertension, vol. 24, no. 1, pp. 77–82, 1994.
[98]
D. B. Young and G. Ma, “Vascular protective effects of potassium,” Seminars in Nephrology, vol. 19, no. 5, pp. 477–486, 1999.
[99]
W. T. Chen, R. A. Brace, J. B. Scott, D. K. Anderson, and F. J. Haddy, “The mechanism of the vasodilator action of potassium,” Proceedings of the Society for Experimental Biology and Medicine, vol. 140, no. 3, pp. 820–824, 1972.
[100]
J. C. de la Torre and G. B. Stefano, “Evidence that Alzheimer's disease is a microvascular disorder: the role of constitutive nitric oxide,” Brain Research Reviews, vol. 34, no. 3, pp. 119–136, 2000.
[101]
R. Ramchandra, C. J. Barrett, and S. C. Malpas, “Nitric oxide and sympathetic nerve activity in the control of blood pressure,” Clinical and Experimental Pharmacology and Physiology, vol. 32, no. 5-6, pp. 440–446, 2005.
[102]
T. Pak, P. Cadet, K. J. Mantione, and G. B. Stefano, “Morphine via nitric oxide modulates β-amyloid metabolism: a novel protective mechanism for Alzheimer's disease,” Medical Science Monitor, vol. 11, no. 10, pp. BR357–BR366, 2005.
[103]
H. B. Posner, M. X. Tang, J. Luchsinger, R. Lantigua, Y. Stern, and R. Mayeux, “The relationship of hypertension in the elderly to AD, vascular dementia, and cognitive function,” Neurology, vol. 58, no. 8, pp. 1175–1181, 2002.
[104]
P. W. Franks, “White-coat hypertension and risk of stroke: do the data really tell us what we need to know?” Hypertension, vol. 45, no. 2, pp. 183–184, 2005.
[105]
S. J. Bodlin, “Heart failure in the elderly,” Expert Review of Cardiovascular Therapy, vol. 3, no. 1, pp. 99–106, 2005.
[106]
G. Zuccalà, C. Cattel, E. Manes-Gravina, M. G. Di Niro, A. Cocchi, and R. Bernabei, “Left ventricular dysfunction: a clue to cognitive impairment in older patients with heart failure,” Journal of Neurology Neurosurgery and Psychiatry, vol. 63, no. 4, pp. 509–512, 1997.
[107]
T. C. De Toledo Ferraz Alves, L. K. Ferreira, M. Wajngarten, and G. F. Busatto, “Cardiac disorders as risk factors for Alzheimer's disease,” Journal of Alzheimer's Disease, vol. 20, no. 3, pp. 749–763, 2010.
[108]
G. Zuccalà, G. Onder, E. Marzetti et al., “Use of angiotensin-converting enzyme inhibitors and variations in cognitive performance among patients with heart failure,” European Heart Journal, vol. 26, no. 3, pp. 226–233, 2005.
[109]
A. Singh-Manoux, S. Sabia, M. Kivimaki, M. J. Shipley, J. E. Ferrie, and M. G. Marmot, “Cognition and incident coronary heart disease in late midlife: the Whitehall II study,” Intelligence, vol. 37, no. 6, pp. 529–534, 2009.
[110]
A. Solomon, M. Kivipelto, B. Wolozin, J. Zhou, and R. A. Whitmer, “Midlife serum cholesterol and increased risk of Alzheimer's and vascular dementia three decades later,” Dementia and Geriatric Cognitive Disorders, vol. 28, no. 1, pp. 75–80, 2009.
[111]
B. Mcguinness and P. Passmore, “Can statins prevent or help treat Alzheimer's disease?” Journal of Alzheimer's Disease, vol. 20, no. 3, pp. 925–933, 2010.
[112]
J. C. de la Torre, “Alzheimer's disease is incurable but preventable,” Journal of Alzheimer's Disease, vol. 20, no. 3, pp. 861–870, 2010.
[113]
K. Nilsson, L. Gustafson, M. Nornholm, and B. Hultberg, “Plasma homocysteine, apolipoprotein e status and vascular disease in elderly patients with mental illness,” Clinical Chemistry and Laboratory Medicine, vol. 48, no. 1, pp. 129–135, 2010.
[114]
M. J. Kotze and S. J. V. Rensburg, “Pathology supported genetic testing and treatment of cardiovascular disease in middle age for prevention of alzheimer's disease,” Metabolic Brain Disease, vol. 27, no. 3, pp. 255–256, 2012.
[115]
M. Thambisetty, L. Beason-Held, Y. An, M. A. Kraut, and S. M. Resnick, “APOE ε4 genotype and longitudinal changes in cerebral blood flow in normal aging,” Archives of Neurology, vol. 67, no. 1, pp. 93–98, 2010.
[116]
H. Triantafyllidi, C. Arvaniti, J. Lekakis et al., “Cognitive impairment is related to increased arterial stiffness and microvascular damage in patients with never-treated essential hypertension,” American Journal of Hypertension, vol. 22, no. 5, pp. 525–530, 2009.
[117]
O. Frank, “The basic shape of the arterial pulse. First treatise: mathematical analysis,” Journal of Molecular and Cellular Cardiology, vol. 22, no. 3, pp. 255–277, 1990.
[118]
G. F. Mitchell, M. A. Van Buchem, S. Sigurdsson et al., “Arterial stiffness, pressure and flow pulsatility and brain structure and function: the Age, Gene/Environment Susceptibility-Reykjavik Study,” Brain, vol. 134, no. 11, pp. 3398–3407, 2011.
[119]
G. F. Mitchell, H. Parise, E. J. Benjamin et al., “Changes in arterial stiffness and wave reflection with advancing age in healthy men and women: the Framingham Heart Study,” Hypertension, vol. 43, no. 6, pp. 1239–1245, 2004.
[120]
O. Hanon, S. Haulon, H. Lenoir et al., “Relationship between arterial stiffness and cognitive function in elderly subjects with complaints of memory loss,” Stroke, vol. 36, no. 10, pp. 2193–2197, 2005.
[121]
J. C. de la Torre and T. Mussivand, “Can disturbed brain microcirculation cause Alzheimer's disease?” Neurological Research, vol. 15, no. 3, pp. 146–153, 1993.
[122]
R. J. Caselli, K. Chen, W. Lee, G. E. Alexander, and E. M. Reiman, “Correlating cerebral hypometabolism with future memory decline in subsequent converters to amnestic pre-mild cognitive impairment,” Archives of Neurology, vol. 65, no. 9, pp. 1231–1236, 2008.
[123]
A. E. Roher, C. Esh, T. A. Kokjohn et al., “Circle of Willis Atherosclerosis Is a Risk Factor for Sporadic Alzheimer's Disease,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 23, no. 11, pp. 2055–2062, 2003.
[124]
H. J. Milionis, M. Florentin, and S. Giannopoulos, “Metabolic syndrome and alzheimer's disease: a link to a vascular hypothesis?” CNS Spectrums, vol. 13, no. 7, pp. 606–613, 2008.
[125]
H. Agüero-Torres, M. Kivipelto, and E. von Strauss, “Rethinking the dementia diagnoses in a population-based study: what is Alzheimer's disease and what is vascular dementia? A study from the Kungsholmen project,” Dementia and Geriatric Cognitive Disorders, vol. 22, no. 3, pp. 244–249, 2006.
[126]
D. S. Dede, B. Yavuz, B. B. Yavuz et al., “Assessment of endothelial function in Alzheimer's disease: is Alzheimer's disease a vascular disease?” Journal of the American Geriatrics Society, vol. 55, no. 10, pp. 1613–1617, 2007.
[127]
A. Ruitenberg, T. den Heijer, S. L. M. Bakker et al., “Cerebral hypoperfusion and clinical onset of dementia: the Rotterdam Study,” Annals of Neurology, vol. 57, no. 6, pp. 789–794, 2005.
[128]
J. Lindsay, D. Laurin, R. Verreault et al., “Risk factors for Alzheimer's disease: a prospective analysis from the Canadian Study of Health and Aging,” American Journal of Epidemiology, vol. 156, no. 5, pp. 445–453, 2002.
[129]
J. C. de la Torre, A. ？ada, N. Nelson, G. Davis, R. J. Sutherland, and F. Gonzalez-Lima, “Reduced cytochrome oxidase and memory dysfunction after chronic brain ischemia in aged rats,” Neuroscience Letters, vol. 223, no. 3, pp. 165–168, 1997.
[130]
J. C. de la Torre, “Impaired brain microcirculation may trigger Alzheimer's disease,” Neuroscience and Biobehavioral Reviews, vol. 18, no. 3, pp. 397–401, 1994.
[131]
A. Hofman, A. Ott, M. M. B. Breteler et al., “Atherosclerosis, apolipoprotein E, and prevalence of dementia and Alzheimer's disease in the Rotterdam Study,” The Lancet, vol. 349, no. 9046, pp. 151–154, 1997.
[132]
I. Casserly and E. Topol, “Convergence of atherosclerosis and Alzheimer's disease: inflammation, cholesterol, and misfolded proteins,” The Lancet, vol. 363, no. 9415, pp. 1139–1146, 2004.
[133]
M. Van Oijen, F. J. De Jong, J. C. M. Witteman, A. Hofman, P. J. Koudstaal, and M. M. B. Breteler, “Atherosclerosis and risk for dementia,” Annals of Neurology, vol. 61, no. 5, pp. 403–410, 2007.
[134]
J. C. de la Torre, “Is Alzheimer's disease a neurodegenerative or a vascular disorder? Data, dogma, and dialectics,” The Lancet Neurology, vol. 3, no. 3, pp. 184–190, 2004.
[135]
M. C. Polidori, L. Pientka, and P. Mecocci, “A review of the major vascular risk factors related to Alzheimer's disease,” Journal of Alzheimer's Disease, vol. 32, no. 3, pp. 521–530, 2012.
[136]
L. Mosconi, R. Mistur, R. Switalski et al., “FDG-PET changes in brain glucose metabolism from normal cognition to pathologically verified Alzheimer's disease,” European Journal of Nuclear Medicine and Molecular Imaging, vol. 36, no. 5, pp. 811–822, 2009.
[137]
J. C. Morris, “Mild cognitive impairment and preclinical Alzheimer's disease,” Geriatrics, vol. 60, no. 6, supplement, pp. 9–14, 2005.
[138]
D. H. S. Silverman and M. E. Phelps, “Application of positron emission tomography for evaluation of metabolism and blood flow in human brain: normal development, aging, dementia, and stroke,” Molecular Genetics and Metabolism, vol. 74, no. 1-2, pp. 128–138, 2001.
[139]
J. C. de la Torre, “Critical threshold cerebral hypoperfusion causes Alzheimer's disease?” Acta Neuropathologica, vol. 98, no. 1, pp. 1–8, 1999.
[140]
P. T. Lansbury, “Inhibition of amyloid formation: a strategy to delay the onset of Alzheimer's disease,” Current Opinion in Chemical Biology, vol. 1, no. 2, pp. 260–267, 1997.
[141]
E. Y. Chi, S. L. Frey, A. Winans et al., “Amyloid-beta fibrillogenesis seeded by interface-induced peptide misfolding and self-assembly,” Biophysical Journal, vol. 98, no. 10, pp. 2299–2308, 2010.
[142]
C. B. Anfinsen, “Principles that govern the folding of protein chains,” Science, vol. 181, no. 4096, pp. 223–230, 1973.
[143]
K. A. Calhoun and J. R. Swartz, “Energy systems for ATP generation in cell-free energy reactions,” in Methods in Molecular Biology, In Vitro Transcription and Translation Protocols, G. Grandi, Ed., vol. 375, Humana Press, Totowa, NJ, USA, 2nd edition, 2004.
[144]
M. Pe？as, J. Sánchez-Prieto, E. Martín-González, M. Fernández, and M. J. López-Pérez, “The energy requirement for protein synthesis in rat brain mitochondria purified by phase partition,” Revista Espanola de Fisiologia, vol. 44, no. 1, pp. 51–56, 1988.
[145]
R. Fluhrer, A. Capell, G. Westmeyer et al., “A non-amyloidogenic function of BACE-2 in the secretory pathway,” Journal of Neurochemistry, vol. 81, no. 5, pp. 1011–1020, 2002.
[146]
J. C. de la Torre, “Hemodynamic consequences of deformed microvessels in the brain in Alzheimer's disease,” Annals of the New York Academy of Sciences, vol. 826, pp. 75–91, 1997.
[147]
K. A. Josephs, J. L. Whitwell, Z. Ahmed et al., “β-amyloid burden is not associated with rates of brain atrophy,” Annals of Neurology, vol. 63, no. 2, pp. 204–212, 2008.
[148]
A. Cada, J. C. de la Torre, and F. Gonzalez-Lima, “Chronic cerebrovascular ischemia in aged rats: effects on brain metabolic capacity and behavio,” Neurobiology of Aging, vol. 21, no. 2, pp. 225–233, 2000.
[149]
N. P. Abdollahian, A. Cada, F. Gonzalez-Lima, and J. C. de la Torre, “Cytochrome oxidase: a predictive marker of neurodegeneration,” in Cytochrome Oxidase in Neuronal Metabolism and Alzheimer’s Disease, pp. 233–261, Plenum Press, New York, NY, USA, 1998.
[150]
C. Huang, L. O. Wahlund, L. Svensson, B. Winblad, and P. Julin, “Cingulate cortex hypoperfusion predicts Alzheimer's disease in mild cognitive impairment,” BMC Neurology, vol. 2, no. 1, article 9, 2002.
[151]
A. Caroli, C. Testa, C. Geroldi et al., “Cerebral perfusion correlates of conversion to Alzheimer's disease in amnestic mild cognitive impairment,” Journal of Neurology, vol. 254, no. 12, pp. 1698–1707, 2007.
[152]
J. C. de la Torre, “A turning point for Alzheimer's disease?” BioFactors, vol. 38, no. 2, pp. 78–83, 2012.
[153]
J. C. de la Torre, “Impact of heart disease and stroke on Alzheimer’s disease,” Neurological Research Special Issue, vol. 28, pp. 577–684, 2006.
[154]
J. C. de la Torre, “How do heart disease and stroke become risk factors for Alzheimer's disease?” Neurological Research, vol. 28, no. 6, pp. 637–644, 2006.
[155]
M. J. Stampfer, “Cardiovascular disease and Alzheimer's disease: common links,” Journal of Internal Medicine, vol. 260, no. 3, pp. 211–223, 2006.
[156]
J. C. de la Torre, “Alzheimer disease as a vascular disorder: nosological evidence,” Stroke, vol. 33, no. 4, pp. 1152–1162, 2002.
[157]
C. Reitz, A. M. Brickman, J. A. Luchsinger et al., “Frequency of subclinical heart disease in elderly persons with dementia,” American Journal of Geriatric Cardiology, vol. 16, no. 3, pp. 183–188, 2007.
[158]
M. Naghavi, P. Libby, E. Falk et al., “From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: part II,” Circulation, vol. 108, no. 15, pp. 1772–1778, 2003.
[159]
L. H. Kuller, O. L. Lopez, A. Newman et al., “Risk factors for dementia in the Cardiovascular Health Cognition Study,” Neuroepidemiology, vol. 22, no. 1, pp. 13–22, 2003.
[160]
S. Villeneuve, S. Belleville, F. Massoud, C. Bocti, and S. Gauthier, “Impact of vascular risk factors and diseases on cognition in persons with mild cognitive impairment,” Dementia and Geriatric Cognitive Disorders, vol. 27, no. 4, pp. 375–381, 2009.
[161]
J. A. Luchsinger, C. Reitz, L. S. Honig, M. X. Tang, S. Shea, and R. Mayeux, “Aggregation of vascular risk factors and risk of incident Alzheimer disease,” Neurology, vol. 65, no. 4, pp. 545–551, 2005.
[162]
H. Feigenbaum, W. F. Armstrong, and T. Ryan, Feigenbaum's Echocardiography, Lippincott Wiliams & Wilkins, Philadelphia, Pa, USA, 6th edition, 2005.
[163]
S. N. Ahmed, F. M. Syed, and D. T. Porembka, “Echocardiographic evaluation of hemodynamic parameters,” Critical Care Medicine, vol. 35, no. 8, pp. S323–S329, 2007.
[164]
A. E. Roher, Z. Garami, A. V. Alexandrov et al., “Interaction of cardiovascular disease and neurodegeneration: transcranial Doppler ultrasonography and Alzheimer's disease,” Neurological Research, vol. 28, no. 6, supplement, pp. 672–678, 2006.
[165]
G. Zuccalà, E. Marzetti, M. Cesari et al., “Correlates of cognitive impairment among patients with heart failure: results of a multicenter survey,” American Journal of Medicine, vol. 118, no. 5, pp. 496–502, 2005.
[166]
E. M. Reiman, J. B. S. Langbaum, and P. N. Tariot, “Alzheimers Prevention Initiative: a proposal to evaluate presymptomatic treatments as quickly as possible,” Biomarkers in Medicine, vol. 4, no. 1, pp. 3–14, 2010.
[167]
K. Kitagawa, “Cerebral blood flow measurement by PET in hypertensive subjects as a marker of cognitive decline,” Journal of Alzheimer's Disease, vol. 20, no. 3, pp. 855–859, 2010.
[168]
A. Cherubini, D. T. Lowenthal, E. Paran, P. Mecocci, L. S. Williams, and U. Senin, “Hypertension and cognitive function in the elderly,” Disease-a-Month, vol. 56, no. 3, pp. 106–147, 2010.
[169]
B. Henderson and J. C. de la Torre, “Reversal of chronic ischemia in the adult rat: common carotid anastomosis and improvement in memory dysfunction,” Society for Neuroscience, vol. 25, article 55, 1999.
[170]
H. S. Goldsmith, “Role of the omentum in the treatment of Alzheimer's disease,” Neurological Research, vol. 23, no. 6, pp. 555–564, 2001.
[171]
R. S. Marshall, R. M. Lazar, J. Pile-Spellman et al., “Recovery of brain function during induced cerebral hypoperfusion,” Brain, vol. 124, no. 6, pp. 1208–1217, 2001.
[172]
S. E. Vermeer, N. D. Prins, T. Den Heijer, A. Hofman, P. J. Koudstaal, and M. M. B. Breteler, “Silent brain infarcts and the risk of dementia and cognitive decline,” The New England Journal of Medicine, vol. 348, no. 13, pp. 1215–1222, 2003.
[173]
R. Sulkava and T. Erkinjuntti, “Vascular dementia due to cardiac arrhythmias and systemic hypotension,” Acta Neurologica Scandinavica, vol. 76, no. 2, pp. 123–128, 1987.
[174]
M. K？h？nen-V？re, S. Brunni-Hakala, M. Lindroos, K. Pitkala, T. Strandberg, and R. Tilvis, “Left ventricular hypertrophy and blood pressure as predictors of cognitive decline in old age,” Aging, vol. 16, no. 2, pp. 147–152, 2004.
[175]
K. G. Mawuenyega, W. Sigurdson, V. Ovod et al., “Decreased clearance of CNS β-amyloid in Alzheimer's disease,” Science, vol. 330, no. 6012, p. 1774, 2010.
