Nothing Special   »   [go: up one dir, main page]
Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Epidemiology of Alzheimer disease

Nature Reviews Neurology volume 7, pages 137–152 (2011)Cite this article

Subjects

Abstract

The global prevalence of dementia is estimated to be as high as 24 million, and is predicted to double every 20 years through to 2040, leading to a costly burden of disease. Alzheimer disease (AD) is the leading cause of dementia and is characterized by a progressive decline in cognitive function, which typically begins with deterioration in memory. Before death, individuals with this disorder have usually become dependent on caregivers. The neuropathological hallmarks of the AD brain are diffuse and neuritic extracellular amyloid plaques—which are frequently surrounded by dystrophic neurites—and intracellular neurofibrillary tangles. These hallmark pathologies are often accompanied by the presence of reactive microgliosis and the loss of neurons, white matter and synapses. The etiological mechanisms underlying the neuropathological changes in AD remain unclear, but are probably affected by both environmental and genetic factors. Here, we provide an overview of the criteria used in the diagnosis of AD, highlighting how this disease is related to, but distinct from, normal aging. We also summarize current information relating to AD prevalence, incidence and risk factors, and review the biomarkers that may be used for risk assessment and in diagnosis.

Key Points

  • The unprecedented level of aging occurring in developed nations will lead to an enormous burden of Alzheimer disease (AD)

  • The primary pathological hallmarks in AD brain tissue—diffuse and neuritic extracellular amyloid plaques and intracellular neurofibrillary tangles—are well known, but the underlying etiologies of these pathologies remain unclear

  • The diagnosis of AD in living patients is based on clinical examination—no definite diagnostic test is currently available—but may be supported by the use of clinical biomarkers

  • AD heritability varies from 58–79% depending on age at onset; however, only a portion of the likely substantial genetic contribution to this disease has been determined

  • Several nongenetic factors (including recognized vascular risk factors) have been associated with AD, but the underlying mechanisms linked to these factors are uncertain

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Potential mechanisms linking vascular risk factors and cognitive impairment.
Figure 2: T1-weighted MRI scan of a patient with a clinical diagnosis of late-onset AD.
Figure 3: Changes revealed by PET in the AD brain.

Similar content being viewed by others

References

  1. Alzheimer's Association. 2010 Alzheimer's disease facts and figures. Alzheimers Dement. 6, 158–194 (2010).

  2. McKhann, G. et al. 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).

    CAS  PubMed  Google Scholar 

  3. Ferri, C. P. et al. Global prevalence of dementia: a Delphi consensus study. Lancet 366, 2112–2117 (2005).

    PubMed  PubMed Central  Google Scholar 

  4. Pendlebury, S. T. & Rothwell, P. M. Prevalence, incidence, and factors associated with pre-stroke and post-stroke dementia: a systematic review and meta-analysis. Lancet Neurol. 8, 1006–1018 (2009).

    PubMed  Google Scholar 

  5. Cheung, Z. H., Gong, K. & Ip, N. Y. Cyclin-dependent kinase 5 supports neuronal survival through phosphorylation of Bcl-2. J. Neurosci. 28, 4872–4877 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Weishaupt, J. H. et al. Inhibition of CDK5 is protective in necrotic and apoptotic paradigms of neuronal cell death and prevents mitochondrial dysfunction. Mol. Cell. Neurosci. 24, 489–502 (2003).

    CAS  PubMed  Google Scholar 

  7. Wen, Y. et al. Cdk5 is involved in NFT-like tauopathy induced by transient cerebral ischemia in female rats. Biochim. Biophys. Acta 1772, 473–483 (2007).

    CAS  PubMed  Google Scholar 

  8. Kivipelto, M. et al. Midlife vascular risk factors and late-life mild cognitive impairment: a population-based study. Neurology 56, 1683–1689 (2001).

    CAS  PubMed  Google Scholar 

  9. Launer, L. J., Masaki, K., Petrovitch, H., Foley, D. & Havlik, R. J. The association between midlife blood pressure levels and late-life cognitive function. The Honolulu–Asia Aging Study. JAMA 274, 1846–1851 (1995).

    CAS  PubMed  Google Scholar 

  10. Swan, G. E., Carmelli, D. & Larue, A. Systolic blood pressure tracking over 25 to 30 years and cognitive performance in older adults. Stroke 29, 2334–2340 (1998).

    CAS  PubMed  Google Scholar 

  11. Whitmer, R. A., Sidney, S., Selby, J., Johnston, S. C. & Yaffe, K. Midlife cardiovascular risk factors and risk of dementia in late life. Neurology 64, 277–281 (2005).

    CAS  PubMed  Google Scholar 

  12. Glynn, R. J. et al. Current and remote blood pressure and cognitive decline. JAMA 281, 438–445 (1999).

    CAS  PubMed  Google Scholar 

  13. Knopman, D. et al. Cardiovascular risk factors and cognitive decline in middle-aged adults. Neurology 56, 42–48 (2001).

    CAS  PubMed  Google Scholar 

  14. Posner, H. B. et al. The relationship of hypertension in the elderly to AD, vascular dementia, and cognitive function. Neurology 58, 1175–1181 (2002).

    CAS  PubMed  Google Scholar 

  15. Skoog, I. et al. 15-year longitudinal study of blood pressure and dementia. Lancet 347, 1141–1145 (1996).

    CAS  PubMed  Google Scholar 

  16. Kalaria, R. N. Vascular basis for brain degeneration: faltering controls and risk factors for dementia. Nutr. Rev. 68 (Suppl. 2), S74–S87 (2010).

    PubMed  Google Scholar 

  17. Deane, R., Wu, Z. & Zlokovic, B. V. RAGE (yin) versus LRP (yang) balance regulates Alzheimer amyloid β-peptide clearance through transport across the blood–brain barrier. Stroke 35, 2628–2631 (2004).

    CAS  PubMed  Google Scholar 

  18. Forette, F. et al. The prevention of dementia with antihypertensive treatment: new evidence from the Systolic Hypertension in Europe (Syst-Eur.) study. Arch. Intern. Med. 162, 2046–2052 (2002).

    PubMed  Google Scholar 

  19. Tzourio, C. 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. 163, 1069–1075 (2003).

    CAS  PubMed  Google Scholar 

  20. Starr, J. M., Whalley, L. J. & Deary, I. J. The effects of antihypertensive treatment on cognitive function: results from the HOPE study. J. Am. Geriatr. Soc. 44, 411–415 (1996).

    CAS  PubMed  Google Scholar 

  21. Prince, M. J., Bird, A. S., Blizard, R. A. & Mann, A. H. 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 312, 801–805 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. [No authors listed] 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 265, 3255–3264 (1991).

  23. Lithell, H. et al. The Study on Cognition and Prognosis in the Elderly (SCOPE): principal results of a randomized double-blind intervention trial. J. Hypertens. 21, 875–886 (2003).

    CAS  PubMed  Google Scholar 

  24. Peters, R. et al. Association of depression with subsequent mortality, cardiovascular morbidity and incident dementia in people aged 80 and over and suffering from hypertension. Data from the Hypertension in the Very Elderly Trial (HYVET). Age Ageing 39, 439–445 (2010).

    PubMed  Google Scholar 

  25. Leibson, C. L. et al. The risk of dementia among persons with diabetes mellitus: a population-based cohort study. Ann. N. Y. Acad. Sci. 826, 422–427 (1997).

    CAS  PubMed  Google Scholar 

  26. Luchsinger, J. A., Tang, M. X., Stern, Y., Shea, S. & Mayeux, R. Diabetes mellitus and risk of Alzheimer's disease and dementia with stroke in a multiethnic cohort. Am. J. Epidemiol. 154, 635–641 (2001).

    CAS  PubMed  Google Scholar 

  27. Ott, A. et al. Diabetes mellitus and the risk of dementia: The Rotterdam Study. Neurology 53, 1937–1942 (1999).

    CAS  PubMed  Google Scholar 

  28. Craft, S. Insulin resistance and Alzheimer's disease pathogenesis: potential mechanisms and implications for treatment. Curr. Alzheimer Res. 4, 147–152 (2007).

    CAS  PubMed  Google Scholar 

  29. Cook, D. G. et al. Reduced hippocampal insulin-degrading enzyme in late-onset Alzheimer's disease is associated with the apolipoprotein E-ɛ4 allele. Am. J. Pathol. 162, 313–319 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Yamagishi, S., Nakamura, K., Inoue, H., Kikuchi, S. & Takeuchi, M. Serum or cerebrospinal fluid levels of glyceraldehyde-derived advanced glycation end products (AGEs) may be a promising biomarker for early detection of Alzheimer's disease. Med. Hypotheses 64, 1205–1207 (2005).

    CAS  PubMed  Google Scholar 

  31. Yan, S. D. et al. RAGE and amyloid-β peptide neurotoxicity in Alzheimer's disease. Nature 382, 685–691 (1996).

    CAS  PubMed  Google Scholar 

  32. Harvey, J., Solovyova, N. & Irving, A. Leptin and its role in hippocampal synaptic plasticity. Prog. Lipid Res. 45, 369–378 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Li, X. L. et al. Impairment of long-term potentiation and spatial memory in leptin receptor-deficient rodents. Neuroscience 113, 607–615 (2002).

    CAS  PubMed  Google Scholar 

  34. Lieb, W. et al. Association of plasma leptin levels with incident Alzheimer disease and MRI measures of brain aging. JAMA 302, 2565–2572 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Profenno, L. A, Porsteinsson, A. P. & Faraone, S. V. Meta-analysis of Alzheimer's disease risk with obesity, diabetes, and related disorders. Biol. Psychiatry 67, 505–512 (2010).

    PubMed  Google Scholar 

  36. Janson, J. et al. Increased risk of type 2 diabetes in Alzheimer disease. Diabetes 53, 474–481 (2004).

    CAS  PubMed  Google Scholar 

  37. Peila, R., Rodriguez, B. L. & Launer, L. J. Type 2 diabetes, APOE gene, and the risk for dementia and related pathologies: the Honolulu–Asia Aging Study. Diabetes 51, 1256–1262 (2002).

    CAS  PubMed  Google Scholar 

  38. Arvanitakis, Z. et al. Diabetes is related to cerebral infarction but not to AD pathology in older persons. Neurology 67, 1960–1965 (2006).

    CAS  PubMed  Google Scholar 

  39. Reger, M. A. et al. Effects of intranasal insulin on cognition in memory-impaired older adults: modulation by APOE genotype. Neurobiol. Aging 27, 451–458 (2006).

    CAS  PubMed  Google Scholar 

  40. Watson, G. S. et al. Preserved cognition in patients with early Alzheimer disease and amnestic mild cognitive impairment during treatment with rosiglitazone: a preliminary study. Am. J. Geriatr. Psychiatry 13, 950–958 (2005).

    PubMed  Google Scholar 

  41. Risner, M. E. et al. Efficacy of rosiglitazone in a genetically defined population with mild-to-moderate Alzheimer's disease. Pharmacogenomics J. 6, 246–254 (2006).

    CAS  PubMed  Google Scholar 

  42. Sato, T. et al. Efficacy of PPAR-γ agonist pioglitazone in mild Alzheimer disease. Neurobiol. Aging doi:10.1016/j.neurobiolaging.2009.10.009.

    CAS  PubMed  Google Scholar 

  43. Jiang, Q., Heneka, M. & Landreth, G. E. The role of peroxisome proliferator-activated receptor-gamma (PPARγ) in Alzheimer's disease: therapeutic implications. CNS Drugs 22, 1–14 (2008).

    CAS  PubMed  Google Scholar 

  44. Grundman, M., Corey-Bloom, J., Jernigan, T., Archibald, S. & Thal, L. J. Low body weight in Alzheimer's disease is associated with mesial temporal cortex atrophy. Neurology 46, 1585–1591 (1996).

    CAS  PubMed  Google Scholar 

  45. White, H., Pieper, C. & Schmader, K. The association of weight change in Alzheimer's disease with severity of disease and mortality: a longitudinal analysis. J. Am. Geriatr. Soc. 46, 1223–1227 (1998).

    CAS  PubMed  Google Scholar 

  46. Gustafson, D., Rothenberg, E., Blennow, K., Steen, B. & Skoog, I. An 18-year follow-up of overweight and risk of Alzheimer disease. Arch. Intern. Med. 163, 1524–1528 (2003).

    PubMed  Google Scholar 

  47. Razay, G. & Vreugdenhil, A. Obesity in middle age and future risk of dementia: midlife obesity increases risk of future dementia. BMJ 331, 455 (2005).

    PubMed  PubMed Central  Google Scholar 

  48. Stewart, R. et al. A 32-year prospective study of change in body weight and incident dementia: the Honolulu–Asia Aging Study. Arch. Neurol. 62, 55–60 (2005).

    PubMed  Google Scholar 

  49. Gustafson, D. R. et al. Adiposity indicators and dementia over 32 years in Sweden. Neurology 73, 1559–1566 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Whitmer, R. A. et al. Central obesity and increased risk of dementia more than three decades later. Neurology 71, 1057–1064 (2008).

    CAS  PubMed  Google Scholar 

  51. Muckle, T. J. & Roy., J. R. High-density lipoprotein cholesterol in differential diagnosis of senile dementia. Lancet 1, 1191–1193 (1985).

    CAS  PubMed  Google Scholar 

  52. Kuo, Y. M. et al. Elevated low-density lipoprotein in Alzheimer's disease correlates with brain Aβ 1–42 levels. Biochem. Biophys. Res. Commun. 252, 711–715 (1998).

    CAS  PubMed  Google Scholar 

  53. Michikawa, M. Cholesterol paradox: is high total or low HDL cholesterol level a risk for Alzheimer's disease? J. Neurosci. Res. 72, 141–146 (2003).

    CAS  PubMed  Google Scholar 

  54. Wieringa, G. E. et al. Apolipoprotein E genotypes and serum lipid levels in Alzheimer's disease and multi-infarct dementia. Int. J. Geriatr. Psychiatry 12, 359–362 (1997).

    CAS  PubMed  Google Scholar 

  55. van Exel, E. et al. Association between high-density lipoprotein and cognitive impairment in the oldest old. Ann. Neurol. 51, 716–721 (2002).

    CAS  PubMed  Google Scholar 

  56. Lesser, G. et al. Elevated serum total and LDL cholesterol in very old patients with Alzheimer's disease. Dement. Geriatr. Cogn. Disord. 12, 138–145 (2001).

    CAS  PubMed  Google Scholar 

  57. Burns, M. & Duff, K. Cholesterol in Alzheimer's disease and tauopathy. Ann. N. Y. Acad. Sci. 977, 367–375 (2002).

    CAS  PubMed  Google Scholar 

  58. Jones, R. W. et al. The Atorvastatin/Donepezil in Alzheimer's Disease Study (LEADe): design and baseline characteristics. Alzheimers Dement. 4, 145–153 (2008).

    CAS  PubMed  Google Scholar 

  59. Simons, M. et al. Treatment with simvastatin in normocholesterolemic patients with Alzheimer's disease: a 26-week randomized, placebo-controlled, double-blind trial. Ann. Neurol. 52, 346–350 (2002).

    CAS  PubMed  Google Scholar 

  60. Sparks, D. L. et al. Circulating cholesterol levels, apolipoprotein E genotype and dementia severity influence the benefit of atorvastatin treatment in Alzheimer's disease: results of the Alzheimer's Disease Cholesterol-Lowering Treatment (ADCLT) trial. Acta Neurol. Scand. Suppl. 185, 3–7 (2006).

    CAS  PubMed  Google Scholar 

  61. Sano, M. Multi-center, randomized, double-blind, placebo-controlled trial of simvatatin to slow the progression of Alzheimer's disease. Alzheimers Dement. 4 (Suppl. 2), T200 (2008).

    Google Scholar 

  62. Raffaitin, C. et al. Metabolic syndrome and risk for incident Alzheimer's disease or vascular dementia: the Three-City Study. Diabetes Care 32, 169–174 (2009).

    PubMed  PubMed Central  Google Scholar 

  63. Solfrizzi, V. et al. Metabolic syndrome and the risk of vascular dementia: the Italian Longitudinal Study on Ageing. J. Neurol. Neurosurg. Psychiatry 81, 433–440 (2010).

    PubMed  Google Scholar 

  64. Yaffe, K., Weston, A. L., Blackwell, T. & Krueger, K. A. The metabolic syndrome and development of cognitive impairment among older women. Arch. Neurol. 66, 324–328 (2009).

    PubMed  PubMed Central  Google Scholar 

  65. Tyas, S. L. Are tobacco and alcohol use related to Alzheimer's disease? A critical assessment of the evidence and its implications. Addict. Biol. 1, 237–254 (1996).

    CAS  PubMed  Google Scholar 

  66. Brenner, D. E. et al. Relationship between cigarette smoking and Alzheimer's disease in a population-based case–control study. Neurology 43, 293–300 (1993).

    CAS  PubMed  Google Scholar 

  67. Ferini-Strambi, L., Smirne, S., Garancini, P., Pinto, P. & Franceschi, M. Clinical and epidemiological aspects of Alzheimer's disease with presenile onset: a case control study. Neuroepidemiology 9, 39–49 (1990).

    CAS  PubMed  Google Scholar 

  68. Merchant, C. et al. The influence of smoking on the risk of Alzheimer's disease. Neurology 52, 1408–1412 (1999).

    CAS  PubMed  Google Scholar 

  69. Launer, L. J. et al. Rates and risk factors for dementia and Alzheimer's disease: results from EURODEM pooled analyses. EURODEM Incidence Research Group and Work Groups. European Studies of Dementia. Neurology 52, 78–84 (1999).

    CAS  PubMed  Google Scholar 

  70. Ott, A. et al. Smoking and risk of dementia and Alzheimer's disease in a population-based cohort study: the Rotterdam Study. Lancet 351, 1840–1843 (1998).

    CAS  PubMed  Google Scholar 

  71. Doll, R., Peto, R., Boreham, J. & Sutherland, I. Smoking and dementia in male British doctors: prospective study. BMJ 320, 1097–1102 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Hebert, L. E. et al. Relation of smoking and alcohol consumption to incident Alzheimer's disease. Am. J. Epidemiol. 135, 347–355 (1992).

    CAS  PubMed  Google Scholar 

  73. Cataldo, J. K., Prochaska, J. J. & Glantz, S. A. Cigarette smoking is a risk factor for Alzheimer's disease: an analysis controlling for tobacco industry affiliation. J. Alzheimers Dis. 19, 465–480 (2010).

    PubMed  PubMed Central  Google Scholar 

  74. Traber, M. G., van der Vliet, A., Reznick, A. Z. & Cross, C. E. Tobacco-related diseases. Is there a role for antioxidant micronutrient supplementation? Clin. Chest Med. 21, 173–187 (2000).

    CAS  PubMed  Google Scholar 

  75. Kellar, K. J. & Wonnacott, S. in Nicotine Psychopharmacology: Molecular, Cellular, and Behavioral Aspects (eds Wonnacott, S., Russell, M. A. & Stolerman, I. P) 341–373 (Oxford University Press, Oxford, 1990).

    Google Scholar 

  76. Jorm, A. F. History of depression as a risk factor for dementia: an updated review. Aust. NZ J. Psychiatry 35, 776–781 (2001).

    CAS  Google Scholar 

  77. Barnes, D. E., Alexopoulos, G. S., Lopez, O. L., Williamson, J. D. & Yaffe, K. Depressive symptoms, vascular disease, and mild cognitive impairment: findings from the Cardiovascular Health Study. Arch. Gen. Psychiatry 63, 273–279 (2006).

    PubMed  Google Scholar 

  78. Becker, J. T. et al. Depressed mood is not a risk factor for incident dementia in a community-based cohort. Am. J. Geriatr. Psychiatry 17, 653–663 (2009).

    PubMed  PubMed Central  Google Scholar 

  79. Panza, F. et al. Impact of depressive symptoms on the rate of progression to dementia in patients affected by mild cognitive impairment. The Italian Longitudinal Study on Aging. Int. J. Geriatr. Psychiatry 23, 726–734 (2008).

    PubMed  Google Scholar 

  80. Aleisa, A. M., Alzoubi, K. H., Gerges, N. Z. & Alkadhi, K. A. Chronic psychosocial stress-induced impairment of hippocampal LTP: possible role of BDNF. Neurobiol. Dis. 22, 453–462 (2006).

    CAS  PubMed  Google Scholar 

  81. Mayeux, R. et al. Synergistic effects of traumatic head injury and apolipoprotein-epsilon 4 in patients with Alzheimer's disease. Neurology 45, 555–557 (1995).

    CAS  PubMed  Google Scholar 

  82. Rasmusson, D. X., Brandt, J., Martin, D. B. & Folstein, M. F. Head injury as a risk factor in Alzheimer's disease. Brain Inj. 9, 213–219 (1995).

    CAS  PubMed  Google Scholar 

  83. Schofield, P. W. et al. Alzheimer's disease after remote head injury: an incidence study. J. Neurol. Neurosurg. Psychiatry 62, 119–124 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Fleminger, S., Oliver, D. L., Lovestone, S., Rabe-Hesketh, S. & Giora, A. Head injury as a risk factor for Alzheimer's disease: the evidence 10 years on; a partial replication. J. Neurol. Neurosurg. Psychiatry 74, 857–862 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Mortimer, J. A. et al. Head trauma as a risk factor for Alzheimer's disease: a collaborative re-analysis of case–control studies. EURODEM Risk Factors Research Group. Int. J. Epidemiol. 20 (Suppl. 2), S28–S35 (1991).

    PubMed  Google Scholar 

  86. Guo, Z. et al. Head injury and the risk of AD in the MIRAGE study. Neurology 54, 1316–1323 (2000).

    CAS  PubMed  Google Scholar 

  87. Mehta, K. M. et al. Head trauma and risk of dementia and Alzheimer's disease: the Rotterdam Study. Neurology 53, 1959–1962 (1999).

    CAS  PubMed  Google Scholar 

  88. Plassman, B. L. et al. Documented head injury in early adulthood and risk of Alzheimer's disease and other dementias. Neurology 55, 1158–1166 (2000).

    CAS  PubMed  Google Scholar 

  89. Hartman, R. E. et al. Apolipoprotein E4 influences amyloid deposition but not cell loss after traumatic brain injury in a mouse model of Alzheimer's disease. J. Neurosci. 22, 10083–10087 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Franz, G. et al. Amyloid β 1–42 and tau in cerebrospinal fluid after severe traumatic brain injury. Neurology 60, 1457–1461 (2003).

    CAS  PubMed  Google Scholar 

  91. Morris, M. C. et al. Dietary intake of antioxidant nutrients and the risk of incident Alzheimer disease in a biracial community study. JAMA 287, 3230–3237 (2002).

    CAS  PubMed  Google Scholar 

  92. Engelhart, M. J. et al. Dietary intake of antioxidants and risk of Alzheimer disease. JAMA 287, 3223–3229 (2002).

    CAS  PubMed  Google Scholar 

  93. Masaki, K. H. et al. Association of vitamin E and C supplement use with cognitive function and dementia in elderly men. Neurology 54, 1265–1272 (2000).

    CAS  PubMed  Google Scholar 

  94. Laurin, D., Masaki, K. H., Foley, D. J., White, L. R. & Launer, L. J. Midlife dietary intake of antioxidants and risk of late-life incident dementia: the Honolulu–Asia Aging Study. Am. J. Epidemiol. 159, 959–967 (2004).

    PubMed  Google Scholar 

  95. Luchsinger, J. A., Tang, M. X., Shea, S. & Mayeux, R. Antioxidant vitamin intake and risk of Alzheimer disease. Arch. Neurol. 60, 203–208 (2003).

    PubMed  Google Scholar 

  96. Huang, T. L. et al. Benefits of fatty fish on dementia risk are stronger for those without APOE ɛ4. Neurology 65, 1409–1414 (2005).

    CAS  PubMed  Google Scholar 

  97. Kalmijn, S. et al. Dietary fat intake and the risk of incident dementia in the Rotterdam Study. Ann. Neurol. 42, 776–782 (1997).

    CAS  PubMed  Google Scholar 

  98. Schaefer, E. J. et al. Plasma phosphatidylcholine docosahexaenoic acid content and risk of dementia and Alzheimer disease: the Framingham Heart Study. Arch. Neurol. 63, 1545–1550 (2006).

    PubMed  Google Scholar 

  99. Roberts, R. O. et al. Polyunsaturated fatty acids and reduced odds of MCI: the Mayo Clinic Study of Aging. J. Alzheimers Dis. 21, 853–865.

    CAS  PubMed  Google Scholar 

  100. Solfrizzi, V. et al. Dietary intake of unsaturated fatty acids and age-related cognitive decline: a 8.5-year follow-up of the Italian Longitudinal Study on Aging. Neurobiol. Aging 27, 1694–1704 (2006).

    CAS  PubMed  Google Scholar 

  101. Engelhart, M. J. et al. Diet and risk of dementia: does fat matter?: The Rotterdam Study. Neurology 59, 1915–1921 (2002).

    CAS  PubMed  Google Scholar 

  102. Scarmeas, N., Stern, Y., Tang, M. X., Mayeux, R. & Luchsinger, J. A. Mediterranean diet and risk for Alzheimer's disease. Ann. Neurol. 59, 912–921 (2006).

    PubMed  PubMed Central  Google Scholar 

  103. Scarmeas, N. et al. Mediterranean diet and mild cognitive impairment. Arch. Neurol. 66, 216–225 (2009).

    PubMed  PubMed Central  Google Scholar 

  104. Scarmeas, N. et al. Physical activity, diet, and risk of Alzheimer disease. JAMA 302, 627–637 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Scarmeas, N., Stern, Y., Mayeux, R. & Luchsinger, J. A. Mediterranean diet, Alzheimer disease, and vascular mediation. Arch. Neurol. 63, 1709–1717 (2006).

    PubMed  PubMed Central  Google Scholar 

  106. Feart, C. et al. Adherence to a Mediterranean diet, cognitive decline, and risk of dementia. JAMA 302, 638–648 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Anstey, K. J., Mack, H. A. & Cherbuin, N. Alcohol consumption as a risk factor for dementia and cognitive decline: meta-analysis of prospective studies. Am. J. Geriatr. Psychiatry 17, 542–555 (2009).

    PubMed  Google Scholar 

  108. Kang, J. H., Cook, N., Manson, J., Buring, J. E. & Grodstein, F. A randomized trial of vitamin E supplementation and cognitive function in women. Arch. Intern. Med. 166, 2462–2468 (2006).

    CAS  PubMed  Google Scholar 

  109. Yaffe, K., Clemons, T. E., McBee, W. L. & Lindblad, A. S. Impact of antioxidants, zinc, and copper on cognition in the elderly: a randomized, controlled trial. Neurology 63, 1705–1707 (2004).

    CAS  PubMed  Google Scholar 

  110. Petersen, R. C. et al. Vitamin E and donepezil for the treatment of mild cognitive impairment. N. Engl. J. Med. 352, 2379–2388 (2005).

    CAS  PubMed  Google Scholar 

  111. Sano, M. et al. A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer's disease. The Alzheimer's Disease Cooperative Study. N. Engl. J. Med. 336, 1216–1222 (1997).

    CAS  PubMed  Google Scholar 

  112. Chiu, C. C. et al. The effects of omega-3 fatty acids monotherapy in Alzheimer's disease and mild cognitive impairment: a preliminary randomized double-blind placebo-controlled study. Prog. Neuropsychopharmacol. Biol. Psychiatry 32, 1538–1544 (2008).

    CAS  PubMed  Google Scholar 

  113. Freund-Levi, Y. et al. Effects of omega-3 fatty acids on inflammatory markers in cerebrospinal fluid and plasma in Alzheimer's disease: the OmegAD study. Dement. Geriatr. Cogn. Disord. 27, 481–490 (2009).

    CAS  PubMed  Google Scholar 

  114. Nagano, S. et al. Peroxidase activity of cyclooxygenase-2 (COX-2) cross-links β-amyloid (Aβ) and generates Aβ–COX-2 hetero-oligomers that are increased in Alzheimer's disease. J. Biol. Chem. 279, 14673–14678 (2004).

    CAS  PubMed  Google Scholar 

  115. Butterfield, D. A., Castegna, A., Drake, J., Scapagnini, G. & Calabrese, V. Vitamin E and neurodegenerative disorders associated with oxidative stress. Nutr. Neurosci. 5, 229–239 (2002).

    CAS  PubMed  Google Scholar 

  116. Pitchumoni, S. S. & Doraiswamy, P. M. Current status of antioxidant therapy for Alzheimer's Disease. J. Am. Geriatr. Soc. 46, 1566–1572 (1998).

    CAS  PubMed  Google Scholar 

  117. Weisburger, J. H. Vitamin C and prevention of nitrosamine formation. Lancet 2, 607 (1977).

    CAS  PubMed  Google Scholar 

  118. Pardo, B., Mena, M. A., Fahn, S. & Garcia de Yebenes, J. Ascorbic acid protects against levodopa-induced neurotoxicity on a catecholamine-rich human neuroblastoma cell line. Mov. Disord. 8, 278–284 (1993).

    CAS  PubMed  Google Scholar 

  119. Voko, Z., Hollander, M., Hofman, A., Koudstaal, P. J. & Breteler, M. M. Dietary antioxidants and the risk of ischemic stroke: the Rotterdam Study. Neurology 61, 1273–1275 (2003).

    CAS  PubMed  Google Scholar 

  120. Calder, P. C. Polyunsaturated fatty acids, inflammation, and immunity. Lipids 36, 1007–1024 (2001).

    CAS  PubMed  Google Scholar 

  121. Yehuda, S., Rabinovitz, S., Carasso, R. L. & Mostofsky, D. I. The role of polyunsaturated fatty acids in restoring the aging neuronal membrane. Neurobiol. Aging 23, 843–853 (2002).

    CAS  PubMed  Google Scholar 

  122. Abbott, R. D. et al. Walking and dementia in physically capable elderly men. JAMA 292, 1447–1453 (2004).

    CAS  PubMed  Google Scholar 

  123. Fratiglioni, L., Paillard-Borg, S. & Winblad, B. An active and socially integrated lifestyle in late life might protect against dementia. Lancet Neurol. 3, 343–353 (2004).

    PubMed  Google Scholar 

  124. Scarmeas, N., Levy, G., Tang, M. X., Manly, J. & Stern, Y. Influence of leisure activity on the incidence of Alzheimer's disease. Neurology 57, 2236–2242 (2001).

    CAS  PubMed  Google Scholar 

  125. Verghese, J. et al. Leisure activities and the risk of dementia in the elderly. N. Engl. J. Med. 348, 2508–2516 (2003).

    PubMed  Google Scholar 

  126. Rovio, S. et al. Leisure-time physical activity at midlife and the risk of dementia and Alzheimer's disease. Lancet Neurol. 4, 705–711 (2005).

    PubMed  Google Scholar 

  127. Churchill, J. D. et al. Exercise, experience and the aging brain. Neurobiol. Aging 23, 941–955 (2002).

    PubMed  Google Scholar 

  128. Colcombe, S. & Kramer, A. F. Fitness effects on the cognitive function of older adults: a meta-analytic study. Psychol. Sci. 14, 125–130 (2003).

    PubMed  Google Scholar 

  129. Dishman, R. K. et al. Neurobiology of exercise. Obesity 14, 345–356 (2006).

    CAS  PubMed  Google Scholar 

  130. Emery, C. F., Schein, R. L., Hauck, E. R. & MacIntyre, N. R. Psychological and cognitive outcomes of a randomized trial of exercise among patients with chronic obstructive pulmonary disease. Health Psychol. 17, 232–240 (1998).

    CAS  PubMed  Google Scholar 

  131. Fabre, C., Chamari, K., Mucci, P., Masse-Biron, J. & Prefaut, C. Improvement of cognitive function by mental and/or individualized aerobic training in healthy elderly subjects. Int. J. Sports Med. 23, 415–421 (2002).

    CAS  PubMed  Google Scholar 

  132. Kramer, A. F., Erickson, K. I. & Colcombe, S. J. Exercise, cognition, and the aging brain. J. Appl. Physiol. 101, 1237–1242 (2006).

    PubMed  Google Scholar 

  133. Lautenschlager, N. T. et al. Effect of physical activity on cognitive function in older adults at risk for Alzheimer disease: a randomized trial. JAMA 300, 1027–1037 (2008).

    CAS  PubMed  Google Scholar 

  134. Angevaren, M., Aufdemkampe, G., Verhaar, H. J., Aleman, A. & Vanhees, L. Physical activity and enhanced fitness to improve cognitive function in older people without known cognitive impairment. Cochrane Database of Systematic Reviews, Issue 3. Art. No.: CD005381. doi:10.1002/14651858. CD005381.pub3 (2008).

  135. Carlson, M. C. et al. Midlife activity predicts risk of dementia in older male twin pairs. Alzheimers Dement. 4, 324–331 (2008).

    PubMed  PubMed Central  Google Scholar 

  136. Fratiglioni, L. & Wang, H. X. Brain reserve hypothesis in dementia. J. Alzheimers Dis. 12, 11–22 (2007).

    PubMed  Google Scholar 

  137. Acevedo, A. & Loewenstein, D. A. Nonpharmacological cognitive interventions in aging and dementia. J. Geriatr. Psychiatry Neurol. 20, 239–249 (2007).

    PubMed  Google Scholar 

  138. Ball, K. et al. Effects of cognitive training interventions with older adults: a randomized controlled trial. JAMA 288, 2271–2281 (2002).

    PubMed  PubMed Central  Google Scholar 

  139. Unverzagt, F. W. et al. Effect of memory impairment on training outcomes in ACTIVE. J. Int. Neuropsychol. Soc. 13, 953–960 (2007).

    PubMed  PubMed Central  Google Scholar 

  140. Alzheimer Disease Mutation Database. Alzheimer Disease & Frontotemporal Dementia Mutation Database [online], (2010).

  141. De Strooper, B. et al. Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature 391, 387–390 (1998).

    CAS  PubMed  Google Scholar 

  142. Scheuner, D. et al. Secreted amyloid β-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease. Nat. Med. 2, 864–870 (1996).

    CAS  PubMed  Google Scholar 

  143. Green, R. C. et al. Risk of dementia among white and African American relatives of patients with Alzheimer disease. JAMA 287, 329–336 (2002).

    PubMed  Google Scholar 

  144. Gatz, M. et al. Role of genes and environments for explaining Alzheimer disease. Arch. Gen. Psychiatry 63, 168–174 (2006).

    PubMed  Google Scholar 

  145. Corder, E. H. et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 261, 921–923 (1993).

    CAS  PubMed  Google Scholar 

  146. Kurz, A. et al. Apolipoprotein E type 4 allele and Alzheimer's disease: effect on age at onset and relative risk in different age groups. J. Neurol. 243, 452–456 (1996).

    CAS  PubMed  Google Scholar 

  147. Poirier, J. et al. Apolipoprotein E polymorphism and Alzheimer's disease. Lancet 342, 697–699 (1993).

    CAS  PubMed  Google Scholar 

  148. Farlow, M. R. et al. Impact of APOE in mild cognitive impairment. Neurology 63, 1898–1901 (2004).

    CAS  PubMed  Google Scholar 

  149. Myers, R. H. et al. Apolipoprotein E ɛ4 association with dementia in a population-based study: the Framingham study. Neurology 46, 673–677 (1996).

    CAS  PubMed  Google Scholar 

  150. Daw, E. W. et al. The number of trait loci in late-onset Alzheimer disease. Am. J. Hum. Genet. 66, 196–204 (2000).

    CAS  PubMed  Google Scholar 

  151. Rogaeva, E. et al. The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease. Nature Genet. 39, 168–177 (2007).

    CAS  PubMed  Google Scholar 

  152. Reitz, C. et al. Meta-analysis of the association between variants in SORL1 and Alzheimer's disease. Arch. Neurol. 68, 99–106 (2011).

    PubMed  PubMed Central  Google Scholar 

  153. Reitz, C. et al. SORCS1 alters APP processing and variants may increase Alzheimer's disease risk. Ann. Neurol. doi:10.1002/ana.22308.

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Lane, R. et al. Diabetes-associated SorCS1 regulates Alzheimer's amyloid-β metabolism: evidence for involvement of SorL1 and the retromer complex. J. Neurosci. 30, 13110–13115 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. Beecham, G. W. et al. Genome-wide association study implicates a chromosome 12 risk locus for late-onset Alzheimer disease. Am. J. Hum. Genet. 84, 35–43 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Bertram, L., McQueen, M. B., Mullin, K., Blacker, D. & Tanzi, R. E. Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database. Nat. Genet. 39, 17–23 (2007).

    CAS  PubMed  Google Scholar 

  157. Carrasquillo, M. M. et al. Genetic variation in PCDH11X is associated with susceptibility to late-onset Alzheimer's disease. Nat. Genet. 41, 192–198 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  158. Reiman, E. M. et al. GAB2 alleles modify Alzheimer's risk in APOE ɛ4 carriers. Neuron 54, 713–720 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. Potkin, S. G. et al. Hippocampal atrophy as a quantitative trait in a genome-wide association study identifying novel susceptibility genes for Alzheimer's disease. PLoS One 4, e6501 (2009).

    PubMed  PubMed Central  Google Scholar 

  160. Harold, D. et al. Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease. Nat. Genet. 41, 1088–1093 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  161. Lambert, J. C. et al. Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease. Nat. Genet. 41, 1094–1099 (2009).

    CAS  PubMed  Google Scholar 

  162. Bertrand, P., Poirier, J., Oda, T., Finch, C. E. & Pasinetti, G. M. Association of apolipoprotein E genotype with brain levels of apolipoprotein E and apolipoprotein J (clusterin) in Alzheimer disease. Brain Res. Mol. Brain Res. 33, 174–178 (1995).

    CAS  PubMed  Google Scholar 

  163. Wyss-Coray, T. et al. Prominent neurodegeneration and increased plaque formation in complement-inhibited Alzheimer's mice. Proc. Natl Acad. Sci. USA 99, 10837–10842 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  164. Baig, S. et al. Distribution and expression of picalm in Alzheimer disease. J. Neuropathol. Exp. Neurol. 69, 1071–1077 (2010).

    CAS  PubMed  Google Scholar 

  165. Seshadri, S. et al. Genome-wide analysis of genetic loci associated with Alzheimer disease. JAMA 303, 1832–1840 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. Wigge, P. et al. Amphiphysin heterodimers: potential role in clathrin-mediated endocytosis. Mol. Biol. Cell 8, 2003–2015 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  167. Kelly, B. L. & Ferreira, A. Beta-amyloid disrupted synaptic vesicle endocytosis in cultured hippocampal neurons. Neuroscience 147, 60–70 (2007).

    CAS  PubMed  Google Scholar 

  168. Yang, S. et al. Comparative proteomic analysis of brains of naturally aging mice. Neuroscience 154, 1107–1120 (2008).

    CAS  PubMed  Google Scholar 

  169. Drewes, G., Ebneth, A., Preuss, U., Mandelkow, E. M. & Mandelkow, E. MARK, a novel family of protein kinases that phosphorylate microtubule-associated proteins and trigger microtubule disruption. Cell 89, 297–308 (1997).

    CAS  PubMed  Google Scholar 

  170. Starcevic, M. & Dell'Angelica, E. C. Identification of snapin and three novel proteins (BLOS1, BLOS2, and BLOS3/reduced pigmentation) as subunits of biogenesis of lysosome-related organelles complex-1 (BLOC-1). J. Biol. Chem. 279, 28393–28401 (2004).

    CAS  PubMed  Google Scholar 

  171. Morris, D. W. et al. Dysbindin (DTNBP1) and the biogenesis of lysosome-related organelles complex 1 (BLOC-1): main and epistatic gene effects are potential contributors to schizophrenia susceptibility. Biol. Psychiatry 63, 24–31 (2008).

    CAS  PubMed  Google Scholar 

  172. Hansson, O. et al. Prediction of Alzheimer's disease using the CSF Aβ42/Aβ40 ratio in patients with mild cognitive impairment. Dement. Geriatr. Cogn. Disord. 23, 316–320 (2007).

    CAS  PubMed  Google Scholar 

  173. Ewers, M. et al. Multicenter assessment of CSF-phosphorylated tau for the prediction of conversion of MCI. Neurology 69, 2205–2212 (2007).

    CAS  PubMed  Google Scholar 

  174. Andersson, C. et al. Differential CSF biomarker levels in APOE-ɛ4-positive and -negative patients with memory impairment. Dement. Geriatr. Cogn. Disord. 23, 87–95 (2007).

    CAS  PubMed  Google Scholar 

  175. Hoglund, K. et al. Prediction of Alzheimer's disease using a cerebrospinal fluid pattern of C-terminally truncated β-amyloid peptides. Neurodegener. Dis. 5, 268–276 (2008).

    CAS  PubMed  Google Scholar 

  176. Fagan, A. M. et al. Inverse relation between in vivo amyloid imaging load and cerebrospinal fluid Aβ42 in humans. Ann. Neurol. 59, 512–519 (2006).

    CAS  PubMed  Google Scholar 

  177. Buerger, K. et al. CSF phosphorylated tau protein correlates with neocortical neurofibrillary pathology in Alzheimer's disease. Brain 129, 3035–3041 (2006).

    PubMed  Google Scholar 

  178. Buerger, K. et al. No correlation between CSF tau protein phosphorylated at threonine 181 with neocortical neurofibrillary pathology in Alzheimer's disease. Brain 130, e82 (2007).

    PubMed  Google Scholar 

  179. Engelborghs, S. et al. No association of CSF biomarkers with APOEɛ4, plaque and tangle burden in definite Alzheimer's disease. Brain 130, 2320–2326 (2007).

    PubMed  Google Scholar 

  180. Fukumoto, H. et al. Age but not diagnosis is the main predictor of plasma amyloid β-protein levels. Arch. Neurol. 60, 958–964 (2003).

    PubMed  Google Scholar 

  181. Shafaati, M., Solomon, A., Kivipelto, M., Bjorkhem, I. & Leoni, V. Levels of ApoE in cerebrospinal fluid are correlated with Tau and 24S-hydroxycholesterol in patients with cognitive disorders. Neurosci. Lett. 425, 78–82 (2007).

    CAS  PubMed  Google Scholar 

  182. Schmand, B., Huizenga, H. M. & van Gool, W. A. Meta-analysis of CSF and MRI biomarkers for detecting preclinical Alzheimer's disease. Psychol. Med. 40, 135–145 (2010).

    CAS  PubMed  Google Scholar 

  183. Kosaka, T. et al. The beta APP717 Alzheimer mutation increases the percentage of plasma amyloid-beta protein ending at A beta42(43). Neurology 48, 741–745 (1997).

    CAS  PubMed  Google Scholar 

  184. Schupf, N. et al. Elevated plasma amyloid β-peptide 1–42 and onset of dementia in adults with Down syndrome. Neurosci. Lett. 301, 199–203 (2001).

    CAS  PubMed  Google Scholar 

  185. Mayeux, R. et al. Plasma Aβ40 and Aβ42 and Alzheimer's disease: relation to age, mortality, and risk. Neurology 61, 1185–1190 (2003).

    CAS  PubMed  Google Scholar 

  186. van Oijen, M., Hofman, A., Soares, H. D., Koudstaal, P. J. & Breteler, M. M. Plasma Aβ1–40 and Aβ1–42 and the risk of dementia: a prospective case–cohort study. Lancet Neurol. 5, 655–660 (2006).

    CAS  PubMed  Google Scholar 

  187. Lopez, O. L. et al. Plasma amyloid levels and the risk of AD in normal subjects in the Cardiovascular Health Study. Neurology 70, 1664–1671 (2008).

    CAS  PubMed  Google Scholar 

  188. Lui, J. K. et al. Plasma amyloid-β as a biomarker in Alzheimer's disease: the AIBL study of aging. J. Alzheimers Dis. 20, 1233–1242 (2010).

    CAS  PubMed  Google Scholar 

  189. Schupf, N. et al. Peripheral Aβ subspecies as risk biomarkers of Alzheimer's disease. Proc. Natl Acad. Sci. USA 105, 14052–14057 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  190. Teipel, S. J. et al. Relation of corpus callosum and hippocampal size to age in nondemented adults with Down's syndrome. Am. J. Psychiatry 160, 1870–1878 (2003).

    PubMed  Google Scholar 

  191. Karas, G. et al. Precuneus atrophy in early-onset Alzheimer's disease: a morphometric structural MRI study. Neuroradiology 49, 967–976 (2007).

    PubMed  Google Scholar 

  192. Krasuski, J. S. et al. Volumes of medial temporal lobe structures in patients with Alzheimer's disease and mild cognitive impairment (and in healthy controls). Biol. Psychiatry 43, 60–68 (1998).

    CAS  PubMed  Google Scholar 

  193. Mungas, D. et al. Longitudinal volumetric MRI change and rate of cognitive decline. Neurology 65, 565–571 (2005).

    CAS  PubMed  Google Scholar 

  194. Apostolova, L. G. et al. Conversion of mild cognitive impairment to Alzheimer disease predicted by hippocampal atrophy maps. Arch. Neurol. 63, 693–699 (2006).

    PubMed  Google Scholar 

  195. Likeman, M. et al. Visual assessment of atrophy on magnetic resonance imaging in the diagnosis of pathologically confirmed young-onset dementias. Arch. Neurol. 62, 1410–1415 (2005).

    PubMed  Google Scholar 

  196. Chetelat, G. et al. Using voxel-based morphometry to map the structural changes associated with rapid conversion in MCI: a longitudinal MRI study. Neuroimage 27, 934–946 (2005).

    CAS  PubMed  Google Scholar 

  197. Rombouts, S. A. et al. Functional MR imaging in Alzheimer's disease during memory encoding. AJNR Am. J. Neuroradiol. 21, 1869–1875 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  198. Small, G. W. et al. Current and future uses of neuroimaging for cognitively impaired patients. Lancet Neurol. 7, 161–172 (2008).

    PubMed  PubMed Central  Google Scholar 

  199. Silverman, D. H. et al. Positron emission tomography in evaluation of dementia: regional brain metabolism and long-term outcome. JAMA 286, 2120–2127 (2001).

    CAS  PubMed  Google Scholar 

  200. O'Brien, J. T. Role of imaging techniques in the diagnosis of dementia. Br. J. Radiol. 80, S71–S77 (2007).

    PubMed  Google Scholar 

  201. Klunk, W. E. et al. Imaging brain amyloid in Alzheimer's disease with Pittsburgh Compound-B. Ann. Neurol. 55, 306–319 (2004).

    CAS  PubMed  Google Scholar 

  202. Engler, H. et al. Two-year follow-up of amyloid deposition in patients with Alzheimer's disease. Brain 129, 2856–2866 (2006).

    PubMed  Google Scholar 

  203. Frisoni, G. B. et al. In vivo mapping of amyloid toxicity in Alzheimer disease. Neurology 72, 1504–1511 (2009).

    CAS  PubMed  Google Scholar 

  204. Tolboom, N. et al. Differential association of [11C]PIB and [18F]FDDNP binding with cognitive impairment. Neurology 73, 2079–2085 (2009).

    CAS  PubMed  Google Scholar 

  205. Katzman, R. Editorial: the prevalence and malignancy of Alzheimer disease. A major killer. Arch. Neurol. 33, 217–218 (1976).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the NIH and the National Institute on Aging (grants R37-AG15473 and P01-AG07232), as well as funding from The Blanchette Hooker Rockefeller Foundation and The Charles S. Robertson Gift from the Banbury Fund (R. Mayeux), and a Paul B. Beeson Career Development Award (K23AG034550) to C. Reitz.

Laurie Barclay, freelance writer and reviewer, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the MedscapeCME-accredited continuing medical education activity associated with this article.

Author information

Authors and Affiliations

  1. Gertrude H. Sergievsky Center, Columbia University Medical Center, 630 West 168th Street, New York, 10032, NY, USA

    Christiane Reitz & Richard Mayeux

  2. Department of Public Health and Primary Care, Institute of Public Health, University Forvie Site, Robinson Way, Cambridge, CB2 0SR, UK

    Carol Brayne

Authors
  1. Christiane Reitz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Carol Brayne
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Richard Mayeux
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

C. Reitz, C. Brayne and R. Mayeux researched the data for the article, provided substantial contributions to discussions of the content, and contributed equally to writing the article and to review and/or editing of the manuscript before submission.

Corresponding author

Correspondence to Richard Mayeux.

Ethics declarations

Competing interests

R. Mayeux has received grant support from the NIH. The other authors declare no competing interests.

Supplementary information

Supplementary Figure 1

Incidence rates of Alzheimer disease (per 100 person-years) across studies. (DOC 99 kb)

Supplementary Table 1

Cerebrospinal fluid biomarkers in AD (DOC 20 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Reitz, C., Brayne, C. & Mayeux, R. Epidemiology of Alzheimer disease. Nat Rev Neurol 7, 137–152 (2011). https://doi.org/10.1038/nrneurol.2011.2

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrneurol.2011.2

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing