Cerebral and Cardiac Vascular Pathology in Alzheimer’s Disease

  • Jack C. de la Torre


A large body of evidence now indicates that Alzheimer’s disease (AD) is a vascular disorder with neurodegenerative consequences and should be treated as such. Vascular risk factors in the elderly individual who already possesses a dwindling cerebrovascular reserve due to advancing age contribute to a further decline in cerebral blood flow (CBF) that results in unrelenting brain hypoperfusion. Brain hypoperfusion, in turn, gives rise to reduced ATP synthesis, thereby provoking a metabolic energy crisis involving ischemic-sensitive neurons and glial cells. Neuronal energy compromise accelerates oxidative stress, excess production of reactive oxygen species, aberrant protein synthesis, ionic pump dysfunction, signal transduction impairment, neurotransmitter failure, abnormal processing of amyloid-β protein precursor giving rise to amyloid-β deposition, and microtubule disruption from tau hyperphosphorylation. All high-energy metabolic changes leading to oxidative stress and cellular hypometabolism precede clinical expression of AD. Regional CBF measurements using neuroimaging techniques such as PET, SPECT, echocardiography, and Doppler ultrasound can help predict AD preclinically at the mild cognitive impairment stage or even before any clinical expression of the dementia is detected. Epidemiological studies together with findings from preclinical detection tools and present-day treatments for AD are proof of concept that AD is a vascular disorder that results in brain hypoperfusion. Both peripheral and cerebral vascular pathology can contribute to brain hypoperfusion. This new paradigm prompts redirection of our thinking and our efforts to decisively manage and treat 25 million people worldwide afflicted with this disorder.


Cerebral Blood Flow Mild Cognitive Impairment Vascular Risk Factor Cerebral Hypoperfusion Brain Hypoperfusion 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



This research was supported by an Investigator-Initiated Research Grant from the Alzheimer’s Association.


  1. 1.
    de la Torre JC, Mussivand T (1993) Can disturbed brain microcirculation cause Alzheimer’s disease. Neurol Res 15:146–153PubMedGoogle Scholar
  2. 2.
    de la Torre JC (2004) Alzheimer’s disease is a vasocognopathy: a new term to describe its nature. Neurol Res 26:517–524PubMedCrossRefGoogle Scholar
  3. 3.
    Breteler MM (2000) Vascular risk factors for Alzheimer’s disease: an epidemiologic perspective. Neurobiol Aging 21:153–160PubMedCrossRefGoogle Scholar
  4. 4.
    Aguero-Torres H, Kivipelto M, von Strauss E (2006) 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. Dement Geriatr Cogn Disord 22:244–249CrossRefGoogle Scholar
  5. 5.
    de la Torre JC (2000) Critically attained threshold of cerebral hypoperfusion: the CATCH hypothesis of Alzheimer’s pathogenesis. Neurobiol Aging 903:424–436Google Scholar
  6. 6.
    Leenders KL, Perani D, Lammertsma AA (1990) Cerebral blood flow, blood volume and oxygen utilization. Normal values and effect of age. Brain 113:27–47Google Scholar
  7. 7.
    Velliquette RA, O’Connor T, Vassar R (2005) Energy inhibition elevates beta-secretase levels and activity and is potentially amyloidogenic in APP transgenic mice: possible early events in Alzheimer’s disease pathogenesis. J Neurosci 25:10874–10883PubMedCrossRefGoogle Scholar
  8. 8.
    Sjogren M, Mielke M, Gustafson D (2006) Cholesterol and Alzheimer’s disease – is there a relation. Mech Ageing Dev 127:138–147PubMedCrossRefGoogle Scholar
  9. 9.
    Sparks DL, Sabbagh MN, Connor DJ (2005) Atorvastatin for the treatment of mild to moderate Alzheimer disease: preliminary results. Arch Neurol 62:753–757PubMedCrossRefGoogle Scholar
  10. 10.
    Laufs U, La Fata V, Plutzky J, Liao JK (1998) Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors. Circulation 97:1129–1135PubMedGoogle Scholar
  11. 11.
    Endres M, Laufs U, Huang Z (1998) Stroke protection by 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors mediated by endothelial nitric oxide synthase. Proc Natl Acad Sci USA 95:8880–8885PubMedCrossRefGoogle Scholar
  12. 12.
    Wolozin B, Kellman W, Ruosseau P (2000) Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors. Arch Neurol 57:1439–1443PubMedCrossRefGoogle Scholar
  13. 13.
    Grundy SM, Cleeman JI, Daniels SR, Donato KA (2005) Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation 112:2735–2752PubMedCrossRefGoogle Scholar
  14. 14.
    Vanhanen M, Koivisto K, Moilanen L (2006) Association of metabolic syndrome with Alzheimer disease: a population-based study. Neurology 67:843–847PubMedCrossRefGoogle Scholar
  15. 15.
    Martins IJ, Hone E, Foster JK (2006) Apolipoprotein E, cholesterol metabolism, diabetes, and the convergence of risk factors for Alzheimer’s disease and cardiovascular disease. Mol Psychiatry 11:721–736PubMedCrossRefGoogle Scholar
  16. 16.
    Elias MF, Wolf PA, D’Agostino RB (1993) Untreated blood pressure level is inversely related to cognitive functioning: the Framingham Study. Am J Epidemiol 138:353–364PubMedGoogle Scholar
  17. 17.
    Ivan CS, Seshadri S, Beiser A (2004) Dementia after stroke: the Framingham Study. Stroke 35:1264–1268PubMedCrossRefGoogle Scholar
  18. 18.
    Alves TC, Busatto GF (2006) Regional cerebral blood flow reductions, heart failure and Alzheimer’s disease. Neurol Res 28:579–587PubMedCrossRefGoogle Scholar
  19. 19.
    Miklossy J (2003) Cerebral hypoperfusion induces cortical watershed microinfarcts which may further aggravate cognitive decline in Alzheimer’s disease. Neurol Res 25:605–610PubMedCrossRefGoogle Scholar
  20. 20.
    de Leeuw FE, Barkhof F, Scheltens P (2004) White matter lesions and hippocampal atrophy in Alzheimer’s disease. Neurology 62:310–312PubMedGoogle Scholar
  21. 21.
    Johnson KA, Jones K, Holman BL (1998) Preclinical prediction of Alzheimer’s disease using SPECT. Neurology 50:1563–1571PubMedGoogle Scholar
  22. 22.
    Ruitenberg A, den Heiker T, Bakker SL (2005) Cerebral hypoperfusion and clinical onset of dementia: the Rotterdam study. Ann Neurol 57:789–794PubMedCrossRefGoogle Scholar
  23. 23.
    de Leon MJ, Convit A, Wolf OT (2001) Prediction of cognitive decline in normal elderly subjects with 2-[18F]fluoro-2-deoxy-d-glucose/positron-emission tomography (FDG/PET). Proc Natl Acad Sci 98:10966–10971PubMedCrossRefGoogle Scholar
  24. 24.
    Silverman DH, Phelps ME (2001) Application of positron emission tomography for evaluation of metabolism and blood flow in human brain: normal development, aging, dementia, and stroke. Mol Genet Metab 74:128–138PubMedCrossRefGoogle Scholar
  25. 25.
    Vogels RL, Scheltens P, Schroeder-Tanka JM, Weinstein HC (2007) Cognitive impairment in heart failure: a systematic review of the literature. Eur J Heart Fail 9:440–449PubMedCrossRefGoogle Scholar
  26. 26.
    de la Torre JC (2008) Alzheimer disease prevalence can be lowered with non-invasive testing. J Alzheimers Dis 14:in pressGoogle Scholar
  27. 27.
    de la Torre JC (2008) Carotid artery ultrasound and echocardiography (CAUSE): aiming to lower Alzheimer’s disease prevalence. Submitted for publicationGoogle Scholar
  28. 28.
    de la Torre JC (2002) Alzheimer’s disease as a vascular disorder: nosological evidence. Stroke 33:1152–1162CrossRefGoogle Scholar
  29. 29.
    de la Torre JC (2004) Is Alzheimer’s a neurodegenerative or a vascular disorder? Data, dogma and dialectics. Lancet Neurol 3:184–190PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.NWGig Harbor

Personalised recommendations