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Are vascular factors involved in Alzheimer’s disease? Facts and theories

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Abstract

The hypothesis that vascular factors may contribute to the development of Alzheimer’s disease (AD) is supported by epidemiologic and pathologic observations. Arterial hypertension and diabetes have been found to be associated not only with vascular dementia, but also with AD; in addition, the treatment of hypertension with calcium antagonists seems to prevent degenerative dementias. Hypertension and hyperinsulinemia favor the deposition of amyloid substance in the brain. The histopathology of AD is marked not only by neurofibrillary tangles and senile plaques, but also by macro and micro congophilic angiopathy and ischemic white matter rarefaction. The specific AD pathological lesions, if isolated, are not able to lead to an evident clinical picture of dementia, which, on the contrary, becomes evident when vascular, mainly subcortical, lesions are associated. These and other observations suggest that vascular factors may have a role in the development of AD. An aggressive approach to these factors could be of value in the prevention of AD.

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References

  1. American Psychiatric Association: Diagnostic and statistical manual of mental disorders, 4th ed. revised. Washington, DC, APA, 1996.

    Google Scholar 

  2. McKhann G., Drachman D., Folstein M.: Clinical diagnosis of Alzheimer’s disease: Report of the NINCDS-ADRDA. Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 34: 939–944, 1984.

    Article  CAS  PubMed  Google Scholar 

  3. White L.: Is silent cerebrovascular disease an important cause of late-life cognitive decline? J. Am. Geriatr. Soc. 44: 328–330, 1996.

    CAS  PubMed  Google Scholar 

  4. Elias M.F.: Effects of chronic hypertension on cognitive functioning. Geriatrics 53 (Suppl. 1): S49–S52, 1998.

    PubMed  Google Scholar 

  5. Elias M.F., Wolf P.A., D’Agostino R.B.: Untreated blood pressure level is inversely related to cognitive functioning. The Framingham Study. Am. J. Epidemiol. 138: 353–364, 1993.

    CAS  PubMed  Google Scholar 

  6. Kilander L., Nyman H., Boberg M., Hansson L., Lithell H.: Hypertension is related to cognitive impairment. A 20-years follow-up of 999 men. Hypertension 31: 780–786, 1998.

    Article  CAS  PubMed  Google Scholar 

  7. Launer L.J., Masaki K., Petrovitch H.: The association between midlife blood pressure levels and lateLife cognitive function. JAMA 274: 1846–1851, 1995.

    Article  CAS  PubMed  Google Scholar 

  8. Palombo V., Scurti R., Muscari A., Puddu G.M., Di Iorio A., Zito M., Abate G.: Blood pressure and intellectual function in elderly subjects. Age Ageing 26: 91–98, 1997.

    Article  CAS  PubMed  Google Scholar 

  9. Skoog I., Lernfelt B., Landahl S.: 15-year longitudinal study of blood pressure and dementia. Lancet 349: 151–154, 1997.

    Article  Google Scholar 

  10. Skoog I., Landahl S., Lernfelt B.: High blood pressure and dementia. Lancet 348: 65–66, 1996 (letter).

    Article  Google Scholar 

  11. Skoog I., Andreasson L., Landhal S., Lernfelt B.: A population-based study on blood pressure and brain atrophy in 85-years olds. Hypertension 32: 404–409, 1998.

    Article  CAS  PubMed  Google Scholar 

  12. Guo Z., Vitanen M., Fratiglioni L.: Low blood pressure and dementia in elderly people: the Kungsholmen project. BMJ 312: 805–808, 1996.

    Article  CAS  PubMed  Google Scholar 

  13. Leibson C.L., Rocca W.A., Hanson V.A.: Risk of dementia among persons with diabetes mellitus: a population-based cohort study. Am. J. Epidemiol. 145: 301–308, 1997.

    Article  CAS  PubMed  Google Scholar 

  14. Yoshitake T., Kiyohara Y., Kato I.: Incidence and risk factors of vascular dementia and Alzheimer’s disease in defined elderly Japanese population. The Hisayama Study. Neurology 45: 1161–1168, 1995.

    Article  CAS  PubMed  Google Scholar 

  15. Yan S.D., Chen X., Fu J.: RAGE and amyloid-β peptide neurotoxicity in Alzheimer’s disease patients. Stroke 27: 2069–2074, 1996.

    Article  Google Scholar 

  16. Mooradian A.D.: Blood-brain barrier choline transport is reduced in diabetic rats. Diabetes 36: 1094–1097, 1987.

    Article  CAS  PubMed  Google Scholar 

  17. Kuusisto J., Koivisto K., Mykkanen L., Helkala E.L., Vanhanen M., Hanninen T., Pyorala K., Rikkinen P., Laakso M.: Essential hypertension and cognitive function. The role of hyperinsulinemia. Hypertension 22: 771–779, 1993.

    Article  CAS  PubMed  Google Scholar 

  18. Kuusisto J., Koivisto K., Mykkanen L.: Association between features of the insulin resistance syndrome and Alzheimer’s disease independently of apolipoprotein E4 phenotype: Cross sectional population based study. BMJ 315: 1045–1049, 1997.

    Article  CAS  PubMed  Google Scholar 

  19. Palovcik R.A., Phillips M.I., Kappy M.S.: Insulin inhibits pyramidal neurons in hippocampal slices. Brain Res. 309: 187–191, 1984.

    Article  CAS  PubMed  Google Scholar 

  20. Brass B.J., Nonner D., Barret J.N.: Differential effects of insulin on choline acetyltransferase and glutamic acid decarboxilase activities in neuron-rich striatal cultures. J. Neurochem. 59: 415–424, 1992.

    Article  CAS  PubMed  Google Scholar 

  21. Hong M., Lee V.M.Y.: Insulin and insulin-like growth factor-1 regulate tau phoshorylation in cultured human neurons. J. Biol. Chem. 272: 1947–1953, 1997.

    Google Scholar 

  22. Unger J., McNeill T.H., Moxley R.T.: Distribution of insulin receptor-like immunoreactivity in the rat forebrain. Neuroscience 31: 143–147, 1989.

    Article  CAS  PubMed  Google Scholar 

  23. Landin K., Blennow K., Wallin A.: Low blood pressure and blood glucose levels in Alzheimer’s disease. Evidence for a hypometabolic disorder? J. Intern. Med. 233: 357–363, 1993.

    Article  CAS  PubMed  Google Scholar 

  24. Wolf-Klein G.P., Silverstone F.A., Brod M.S.: Are Alzheimer patients healthier? J. Am. Geriatr. Soc. 36: 219–224, 1988.

    CAS  PubMed  Google Scholar 

  25. Hofman A., Ott A., Breteler M.M.B.: Atherosclerosis, apolipoprotein E, and prevalence of dementia and Alzheimer’s disease in the Rotterdam Study. Lancet 349: 151–154, 1997.

    Article  CAS  PubMed  Google Scholar 

  26. Scott R.D., Krits-Silverstein D., Barrett-Connor E., Wiederholt W.C.: The association of non-insulin-dependent diabetes mellitus and cognitive function in an older cohort. J. Am. Geriatr. Soc. 46: 1217–1222, 1998.

    CAS  PubMed  Google Scholar 

  27. Graves A.B., Van Duijn C.M., Chandra V.: Alcohol and tobacco consumption as risk factors for Alzheimer’s disease: a collaborative re-analysis of case-control studies. Int. J. Epidemiol. 20 (Suppl. 2): S48–S57, 1991.

    Article  PubMed  Google Scholar 

  28. Prince M., Cullen M., Mann A.: Risk factors for Alzheimer’s disease and dementia: a case-control study based on the MRC elderly hypertension trial. Neurology 44: 97–104, 1994.

    Article  CAS  PubMed  Google Scholar 

  29. Brenner D.E., Kukull W.A., Van Belle G., Bowen J.D., Mc-Cormick W.C., Teri L., Larson E.B.: Postmenopausal estrogen replacement therapy and the risk of Alzheimer’s disease: a population-based case-control study. Am. J. Epidemiol. 140: 262–267, 1994.

    CAS  PubMed  Google Scholar 

  30. Whitehouse P.J., Kalaria R.N.: Nicotine receptors and neu-rodegenerative dementing diseases: basic research and clinical implications. Alzheimer Dis. Assoc. Disord. 9 (Suppl. 2): 3–5, 1995.

    Article  PubMed  Google Scholar 

  31. Wilson A.L., Langley L.K., Monley J., Bauer T., Rottunda S., McFalls E., Kovera C., McCarten J.R.: Nicotine patches in Alzheimer’s disease: pilot study on learning, memory and safety. Pharmacol. Biochem. Behav. 51: 509–514, 1995.

    Article  CAS  PubMed  Google Scholar 

  32. Canadian Study of Health and Aging Working Group. The Canadian Study of Health and Aging: risk factors for Alzheimer’s disease in Canada. Neurology 44: 2073–2080, 1994.

    Article  Google Scholar 

  33. Forster D.P., Newens A.J., Kay D.W., Edwardson J.A.: Risk factors in clinically diagnosed presenile dementia of the Alzheimer type: a case-control study in northern England. J. Epidemiol. Community Health 49: 253–258, 1995.

    Article  CAS  PubMed  Google Scholar 

  34. Fielding J.E.: Smoking: health effect and control. N. Engl. J. Med. 313: 555–561, 1985.

    Article  CAS  PubMed  Google Scholar 

  35. Ferrucci L., Guralnik J.M., Salive M.E.: Cognitive impairment and risk of stroke in the older population. J. Am. Geriatr. Soc. 44: 237–241, 1996.

    CAS  PubMed  Google Scholar 

  36. Moroney J.T., Desmond D.W: Cognitive impairment and risk of stroke in the older population. J. Am. Geriatr. Soc. 44: 1410–1411, 1996 (letter).

    CAS  PubMed  Google Scholar 

  37. Ott A., Breteler M.M.B., de Bruyne M.C.: Atrial fibrillation and dementia in a population based study. Stroke 28: 316–321, 1997.

    Article  CAS  PubMed  Google Scholar 

  38. Kalman J., Juhasz A., Csaszar A., Kanka A., Rimanoczy A., Janka Z., Rasko I.: Increased apolipoprotein E4 allele frequency is associated with vascular dementia in the Hungarian population. Acta Neurol. Scand. 98: 166–168, 1998.

    Article  CAS  PubMed  Google Scholar 

  39. Noguchi S., Murakami K., Yamada N.: Apolipoprotein E genotype and Alzheimer’s disease. Lancet 342: 737–741, 1993.

    Article  CAS  PubMed  Google Scholar 

  40. Nagy Z.S., Esiri M.M., Joachim C., Jobst K.A., Morris J.H., King E.M., Hindley N.J., McDonald B., Litchfield S., Barnetson L., Smith A.D.: Comparison of pathological diagnostic criteria for Alzheimer disease. Alzheimer Dis. Assoc. Disord. 12: 182–189, 1998.

    Article  CAS  PubMed  Google Scholar 

  41. Morris J.C., Storandt M., McKeel D.W., Rubin E.H., Price J.L., Grant E.A., Berg L.: Cerebral amyloid deposition and diffuse plaques in “normal” aging: evidence for presympto-matic and very mild Alzheimer’s disease. Neurology 46: 707–719, 1996.

    Article  CAS  PubMed  Google Scholar 

  42. Haroutunian V., Perl D.P., Purohit D.P., Marin D., Khan K., Lantz M., Davis K.L., Mohs R.C.: Regional distribution of neuritic plaques in the non demented elderly and subjects with very mild Alzheimer disease. Arch. Neurol. 55: 1185–1191, 1998.

    Article  CAS  PubMed  Google Scholar 

  43. Ellis R.J., Olichney J.M., Thal L.J., Mirra S.S., Morris J.C., Beekly D., Heyman A.: Cerebral amyloid angiopathy in the brains of patients with Alzheimer’s disease: the CERAD experience. Part XV. Neurology 46: 1592–1596, 1996.

    Article  CAS  PubMed  Google Scholar 

  44. Kalaria R.N., Hedera P.: β-amyloid vasoactivity in Alzheimer’s disease. Lancet 347: 1492–1493, 1996 (letter).

    Article  CAS  PubMed  Google Scholar 

  45. de la Torre J.C., Mussivand T.: Can disturbed brain microcir-culation cause Alzheimer’s disease? Neurol. Res. 15: 146–153, 1993.

    PubMed  Google Scholar 

  46. Sutton E.T., Hallermann G.R., Thomas T.: β-Amyloid induced endothelial necrosis and inhibition of nitric oxide production. Exp. Cell Res. 230: 368–376, 1997.

    Article  CAS  PubMed  Google Scholar 

  47. Olichney Y.M., Hansen L.A., Hofstetter C.R.: Cerebral infarction in Alzheimer’s disease is associated with severe amyloid angiopathy and hypertension. Arch. Neurol. 52: 703–708, 1995.

    Article  Google Scholar 

  48. Iwamoto N., Nishiyama E., Ohwada J.: Distribution of amyloid deposits in the cerebral white matter of the Alzheimer’s disease brain: relationship to blood vessels. Acta Neu-ropathol. 93: 334–340, 1997.

    CAS  Google Scholar 

  49. Brillian M., Hughes L., Anderson D., Ghobrial M., Elble R.: Rarefied white matter in patients with Alzheimer disease. Alzheimer Dis. Assoc. Disord. 9: 39–46, 1995.

    Article  Google Scholar 

  50. Golomb J., Kluger A., Gianutsos J., Ferris S.H., de Leon M.J., George A.E.: Non specific leukoencephalopathy associated with aging. Neuroimaging Clin. J. Am. 5: 33–44, 1995.

    CAS  Google Scholar 

  51. George A.E., de Leon M.J., Gentes C.I., Miller J., London E., Budzilovich G.N.: Leukoencephalopathy in normal and pathological ageing. Am. J. Neuroradiol. 7: 561–566, 1986.

    CAS  PubMed  Google Scholar 

  52. Wallin A., Blennow K., Uhlemann C., Langstrom F., Gottfries C.G.: White matter low attenuations on CT in Alzheimer’s disease and vascular dementia; diagnostic and pathogenetic aspects. Acta Neurol. Scand. 80: 518–523, 1989.

    Article  CAS  PubMed  Google Scholar 

  53. Inzitari D., Diaz F., Fox A., Hachinski V.C., Steingart A., Lau C.: Vascular risk factors and leukoaraiosis. Arch. Neurol. 44: 42–47, 1987.

    Article  CAS  PubMed  Google Scholar 

  54. Amar K., Wilkock G.: Vascular dementia. BMJ 312: 227–231, 1996.

    Article  CAS  PubMed  Google Scholar 

  55. Blennow K., Wallin A., Uhlemann C., Gottfries C.G.: White-matter lesions on CT in Alzheimer patients: relation to clinical symptomatology and vascular factors. Acta Neurol. Scand. 83: 187–193, 1991.

    Article  CAS  PubMed  Google Scholar 

  56. Furuta A., Nobuyoshi I., Nischihara Y., Horie A.: Medullary arteries in aging and dementia. Stroke 22: 442–446, 1991.

    Article  CAS  PubMed  Google Scholar 

  57. Roman G.C.: Senile dementia of the Binswanger type: a vascular form of dementia in the elderly. JAMA 258: 1782–1788, 1987.

    Article  CAS  PubMed  Google Scholar 

  58. Pantoni L., Garcia J.H.: Pathogenesis of leukoaraiosis: a review. Stroke 28: 652–659, 1997.

    Article  CAS  PubMed  Google Scholar 

  59. Brun A., Englund E.: A white matter disorder in dementia of the Alzheimer type: a pathoanatomical study. Ann. Neurol. 19: 253–262, 1986.

    Article  CAS  PubMed  Google Scholar 

  60. Tumimoto H., Akiguchi I., Suenaga T., Nishimura M., Wakita H., Nakamura S., Kimura J.: Alterations of the blood-brain barrier and glial cells in white-matter lesions in cerebrov-ascular and Alzheimer’s disease patients. Stroke 27: 2069–2074, 1996.

    Article  Google Scholar 

  61. Hann J., Rooss R.A., Algra P.R.: Hereditary cerebral haemorrhage with amyloidosis-Dutch type. Magnetic resonance imaging findings in 7 cases. Brain 113: 1251–1267, 1990.

    Article  Google Scholar 

  62. Erkinjuntti T., Benavente O., Eliasziw M.: Diffuse vacuoliza-tion (spongiosis) and arteriosclerosis in the frontal white matter occurs in vascular dementia. Arch. Neurol. 53: 325–332, 1996.

    Article  CAS  PubMed  Google Scholar 

  63. Steward R.: Cardiovascular factors in Alzheimer’s disease. J. Neurol. Neurosurg. Psychiatry 65: 143–147, 1998.

    Article  Google Scholar 

  64. Breteler M.M.B., Van Swieten J.C., Bots M.L., Grobbee D.E., Claus J.J., Van Den Hout J.H.W., Van Harskamp F., Tanghe H.L.J., De Jong P.T.V.M., Van Gijn J., Hofman A.: Cerebral white matter lesions, vascular risk factors, and cognitive function in a population-based study. The Rotterdam Study. Neurology 44: 1246–1252, 1994.

    Article  CAS  PubMed  Google Scholar 

  65. Smowdon D.A., Greiner L.H., Mortimer J.A., Riley K.P., Greiner P.A., Markesbery W.R.: Brain infarction and the clinical expression of Alzheimer disease. The Nun Study. JAMA 277: 813–817, 1997.

    Article  Google Scholar 

  66. Sparks D.L., Scheff S.W., Liu H.: Increased incidence of neurofibrillary tangles in non-demented individuals with hypertension. J. Neurol. Sci. 131: 162–169, 1995.

    Article  CAS  PubMed  Google Scholar 

  67. Strassburger T.L., Lee H.C., Daly E.M., Szezepanic J., Krasuski J.S., Mentis M.J., Salerno J.A., DeCarli C., Shapiro M.B., Alexander G.E.: Interactive effects of age and hypertension on volume of brain structures. Stroke 28: 1410–1417, 1997.

    Article  CAS  PubMed  Google Scholar 

  68. Brun A., Gustafson L., Samulsson S.M., Ericsson C.: Neuropathology of late life. Dementia 3: 125–130, 1992.

    Google Scholar 

  69. Hulette C., Nochlin D., McKeel D.: Clinical-neuropathologic findings in multi-infarct dementia: a report of six autopsied cases. Neurology 48: 668–672, 1997.

    Article  CAS  PubMed  Google Scholar 

  70. Desmond D.W.: Vascular dementia: a construct in evolution. Cerebrovasc. Brain Metab. Rev. 8: 296–325, 1996.

    CAS  PubMed  Google Scholar 

  71. Nolan K.A., Lino M.M., Seligmann A.W., Blass J.P.: Absence of vascular dementia in an autopsy series from a dementia clinic. J. Am. Geriatr. Soc. 46: 597–604, 1998.

    CAS  PubMed  Google Scholar 

  72. Nyenhuis D.L., Gorelick P.B.: Vascular dementia: a contemporary review of epidemiology, diagnosis, prevention and treatment. J. Am. Geriatr. Soc. 46: 1437–1448, 1998.

    CAS  PubMed  Google Scholar 

  73. Hall E.D., Osteveen J.A., Dunn E.: Increased amyloid protein precursor and apolipoprotein E immunoreactivity in the selectively vulnerable hippocampus following transient forebrain ischemia in gerbils. Exp. Neurol. 135: 17–27, 1995.

    Article  CAS  PubMed  Google Scholar 

  74. Pluta R., Barcikowsa M., Janusezewki S.: Evidence of blood-brain barrier permeability/leakage for circulating human Alzheimer’s β-amyloid (1-42) peptide. Neuroreport 7: 1261–1265, 1996.

    Article  CAS  PubMed  Google Scholar 

  75. Sasaki N., Fakatsu R., Tsuzuki K., Yoshida T., Fujii N., Koike T., Wakayama I., Yanagihara R., Garruto R., Amano N., Makita Z.: Advanced glycation end products in Alzheimer’s disease and other neurodegenerative disease. Am. J. Pathol. 153: 1149–1155, 1998.

    Article  CAS  PubMed  Google Scholar 

  76. Forette F., Seux M.L., Staessen J.A., Thijs L., Birkenhager W.H., Babarskiene M.R., Babeanu S., Bossini A., Gil-Extremera B., Girerd X., Laks T., Lilov E., Moisseyev V., Tuomileto J., Vanhanen H., Webster J., Yodfat Y., Fagard R.: Prevention of dementia in randomised double-blind placebo-controlled Systolic Hypertension in Europe (Syst-Eur) trial. Lancet 352: 1347–1351, 1998.

    Article  CAS  PubMed  Google Scholar 

  77. Shep Cooperative Research Group: 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). JAMA 265: 3255–3264, 1991.

    Article  Google Scholar 

  78. Parnetti L., Senin U., Mecocci P.: Cognitive enhancement therapy for Alzheimer’s disease: the way forward. Drugs 53: 752–768, 1997.

    Article  CAS  PubMed  Google Scholar 

  79. Gould R.J., Murphy K.M., Snyder S.H.: Autoradiographic localization of calcium channel antagonist receptors in rat brain with (3H) nitrendipine. Brain Res. 330: 217–223, 1985.

    Article  CAS  PubMed  Google Scholar 

  80. Barrett-Connor E.: Rethinking estrogen in the brain. J. Am. Geriatr. Soc. 46: 918–920, 1998.

    CAS  PubMed  Google Scholar 

  81. Yaffe K., Grady D., Pressman A., Cummings S.: Serum estrogen levels, cognitive performance, and risk of cognitive decline in older community women. J. Am. Geriatr. Soc. 46: 816–821, 1998.

    CAS  PubMed  Google Scholar 

  82. Trabucchi M.: Le demenze. UTET, Milano, 1998.

    Google Scholar 

  83. McGeer P.L., Schulzer M., McGeer E.G.: Arthritis and anti-inflammatory agents as possible protective factors for Alzheimer’s disease: a review of 17 epidemiologic studies. Neurology 47: 425–432, 1996.

    Article  CAS  PubMed  Google Scholar 

  84. Rich J.B., Rasmusson D.X., Folstein M.F.: Non-steroidal anti-inflammatory drugs in Alzheimer’s disease. Neurology 45: 51–55, 1995.

    Article  CAS  PubMed  Google Scholar 

  85. Steward W.F., Kawas C., Corrada M.: Risk of Alzheimer’s disease and duration of NSAID use. Neurology 48: 626–632, 1997.

    Article  Google Scholar 

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  1. Department of Medicine and Aging, “G. D’Annunzio” University, Chieti, Italy

    A. Di Iorio, M. Zito, M. Lupinetti & G. Abate M.D.

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  1. A. Di Iorio
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Di Iorio, A., Zito, M., Lupinetti, M. et al. Are vascular factors involved in Alzheimer’s disease? Facts and theories. Aging Clin Exp Res 11, 345–352 (1999). https://doi.org/10.1007/BF03339811

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