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Risk factors for cognitive decline and dementia

Author
Eric B Larson, MD, MPH
Section Editor
Steven T DeKosky, MD, FAAN, FACP, FANA
Deputy Editor
April F Eichler, MD, MPH

INTRODUCTION

Dementia is a disorder that is characterized by impairment of cognition, typically involving memory and at least one other cognitive domain (language, visuospatial, executive function). These must represent a decline from previous level of function and be severe enough to interfere with daily function and independence. As the global population ages, dementia prevalence is expected to rise substantially over the next several decades, especially in low- to middle-income countries.

Two major reports released in 2017 review the literature on potentially modifiable risk factors for dementia and highlight strengths and weaknesses in the available data to support the impact of risk factor modification on dementia incidence [1,2]. While the overall evidence is generally of low quality and does not support any single intervention as effective in delaying or preventing dementia, there is optimism that intensive risk factor modification, especially during midlife (age 45 to 65 years), has the potential to delay or prevent a substantial number of dementia cases worldwide. In support of this, large population-based studies indicate that the incidence of dementia has declined in high-income countries over the last several decades [3-8].

The Lancet Commission estimates that approximately 35 percent of dementia cases are attributable to a combination of nine potentially modifiable risk factors [1]:

Low educational attainment

Midlife hypertension

                                   
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Literature review current through: Sep 2017. | This topic last updated: Sep 19, 2017.
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References
Top
  1. Livingston G, Sommerlad A, Orgeta V, et al. Dementia prevention, intervention, and care. Lancet 2017.
  2. Kane RL, Bulter M, Fink HA, et al. Interventions to prevent age-related cognitive decline, mild cognitive impairment, and clinical Alzheimer's-type dementia: Comparative effectiveness review No. 188. AHQR Pub. No. 17-EHC008-EF, Agency for Healthcare Research and Quality, Rockville, MD 2017.
  3. Satizabal CL, Beiser AS, Chouraki V, et al. Incidence of Dementia over Three Decades in the Framingham Heart Study. N Engl J Med 2016; 374:523.
  4. Schrijvers EM, Verhaaren BF, Koudstaal PJ, et al. Is dementia incidence declining?: Trends in dementia incidence since 1990 in the Rotterdam Study. Neurology 2012; 78:1456.
  5. Rocca WA, Petersen RC, Knopman DS, et al. Trends in the incidence and prevalence of Alzheimer's disease, dementia, and cognitive impairment in the United States. Alzheimers Dement 2011; 7:80.
  6. Matthews FE, Arthur A, Barnes LE, et al. A two-decade comparison of prevalence of dementia in individuals aged 65 years and older from three geographical areas of England: results of the Cognitive Function and Ageing Study I and II. Lancet 2013; 382:1405.
  7. Qiu C, von Strauss E, Bäckman L, et al. Twenty-year changes in dementia occurrence suggest decreasing incidence in central Stockholm, Sweden. Neurology 2013; 80:1888.
  8. Langa KM, Larson EB, Crimmins EM, et al. A Comparison of the Prevalence of Dementia in the United States in 2000 and 2012. JAMA Intern Med 2017; 177:51.
  9. Niu H, Álvarez-Álvarez I, Guillén-Grima F, Aguinaga-Ontoso I. Prevalence and incidence of Alzheimer's disease in Europe: A meta-analysis. Neurologia 2017; 32:523.
  10. Carone M, Asgharian M, Jewell NP. Estimating the lifetime risk of dementia in the Canadian elderly population using cross-sectional cohort survival data. J Am Stat Assoc 2014; 109:24.
  11. Corrada MM, Brookmeyer R, Berlau D, et al. Prevalence of dementia after age 90: results from the 90+ study. Neurology 2008; 71:337.
  12. Corrada MM, Brookmeyer R, Paganini-Hill A, et al. Dementia incidence continues to increase with age in the oldest old: the 90+ study. Ann Neurol 2010; 67:114.
  13. Larson EB, Langa KM. The rising tide of dementia worldwide. Lancet 2008; 372:430.
  14. Chan KY, Wang W, Wu JJ, et al. Epidemiology of Alzheimer's disease and other forms of dementia in China, 1990-2010: a systematic review and analysis. Lancet 2013; 381:2016.
  15. Mercy L, Hodges JR, Dawson K, et al. Incidence of early-onset dementias in Cambridgeshire, United Kingdom. Neurology 2008; 71:1496.
  16. Garre-Olmo J, Genís Batlle D, del Mar Fernández M, et al. Incidence and subtypes of early-onset dementia in a geographically defined general population. Neurology 2010; 75:1249.
  17. Kelley BJ, Boeve BF, Josephs KA. Young-onset dementia: demographic and etiologic characteristics of 235 patients. Arch Neurol 2008; 65:1502.
  18. Green RC, Cupples LA, Go R, et al. Risk of dementia among white and African American relatives of patients with Alzheimer disease. JAMA 2002; 287:329.
  19. Wolters FJ, van der Lee SJ, Koudstaal PJ, et al. Parental family history of dementia in relation to subclinical brain disease and dementia risk. Neurology 2017.
  20. Pendlebury ST, Rothwell PM. Prevalence, incidence, and factors associated with pre-stroke and post-stroke dementia: a systematic review and meta-analysis. Lancet Neurol 2009; 8:1006.
  21. Gottesman RF, Hillis AE. Predictors and assessment of cognitive dysfunction resulting from ischaemic stroke. Lancet Neurol 2010; 9:895.
  22. Levine DA, Galecki AT, Langa KM, et al. Trajectory of Cognitive Decline After Incident Stroke. JAMA 2015; 314:41.
  23. Moulin S, Labreuche J, Bombois S, et al. Dementia risk after spontaneous intracerebral haemorrhage: a prospective cohort study. Lancet Neurol 2016; 15:820.
  24. Biffi A, Bailey D, Anderson CD, et al. Risk Factors Associated With Early vs Delayed Dementia After Intracerebral Hemorrhage. JAMA Neurol 2016; 73:969.
  25. Akoudad S, Wolters FJ, Viswanathan A, et al. Association of Cerebral Microbleeds With Cognitive Decline and Dementia. JAMA Neurol 2016; 73:934.
  26. Debette S, Seshadri S, Beiser A, et al. Midlife vascular risk factor exposure accelerates structural brain aging and cognitive decline. Neurology 2011; 77:461.
  27. Yaffe K, Vittinghoff E, Pletcher MJ, et al. Early adult to midlife cardiovascular risk factors and cognitive function. Circulation 2014; 129:1560.
  28. Gottesman RF, Schneider AL, Albert M, et al. Midlife hypertension and 20-year cognitive change: the atherosclerosis risk in communities neurocognitive study. JAMA Neurol 2014; 71:1218.
  29. Gottesman RF, Albert MS, Alonso A, et al. Associations Between Midlife Vascular Risk Factors and 25-Year Incident Dementia in the Atherosclerosis Risk in Communities (ARIC) Cohort. JAMA Neurol 2017; 74:1246.
  30. Luchsinger JA, Reitz C, Honig LS, et al. Aggregation of vascular risk factors and risk of incident Alzheimer disease. Neurology 2005; 65:545.
  31. Unverzagt FW, McClure LA, Wadley VG, et al. Vascular risk factors and cognitive impairment in a stroke-free cohort. Neurology 2011; 77:1729.
  32. Irie F, Fitzpatrick AL, Lopez OL, et al. Enhanced risk for Alzheimer disease in persons with type 2 diabetes and APOE epsilon4: the Cardiovascular Health Study Cognition Study. Arch Neurol 2008; 65:89.
  33. Verdelho A, Madureira S, Moleiro C, et al. White matter changes and diabetes predict cognitive decline in the elderly: the LADIS study. Neurology 2010; 75:160.
  34. Ahtiluoto S, Polvikoski T, Peltonen M, et al. Diabetes, Alzheimer disease, and vascular dementia: a population-based neuropathologic study. Neurology 2010; 75:1195.
  35. Ohara T, Doi Y, Ninomiya T, et al. Glucose tolerance status and risk of dementia in the community: the Hisayama study. Neurology 2011; 77:1126.
  36. Rawlings AM, Sharrett AR, Schneider AL, et al. Diabetes in midlife and cognitive change over 20 years: a cohort study. Ann Intern Med 2014; 161:785.
  37. Katon W, Pedersen HS, Ribe AR, et al. Effect of depression and diabetes mellitus on the risk for dementia: a national population-based cohort study. JAMA Psychiatry 2015; 72:612.
  38. Ng TP, Feng L, Nyunt MS, et al. Metabolic Syndrome and the Risk of Mild Cognitive Impairment and Progression to Dementia: Follow-up of the Singapore Longitudinal Ageing Study Cohort. JAMA Neurol 2016; 73:456.
  39. Li W, Risacher SL, Huang E, et al. Type 2 diabetes mellitus is associated with brain atrophy and hypometabolism in the ADNI cohort. Neurology 2016; 87:595.
  40. Biessels GJ, Staekenborg S, Brunner E, et al. Risk of dementia in diabetes mellitus: a systematic review. Lancet Neurol 2006; 5:64.
  41. Crane PK, Walker R, Hubbard RA, et al. Glucose levels and risk of dementia. N Engl J Med 2013; 369:540.
  42. Kerti L, Witte AV, Winkler A, et al. Higher glucose levels associated with lower memory and reduced hippocampal microstructure. Neurology 2013; 81:1746.
  43. Avadhani R, Fowler K, Barbato C, et al. Glycemia and cognitive function in metabolic syndrome and coronary heart disease. Am J Med 2015; 128:46.
  44. Munshi M, Grande L, Hayes M, et al. Cognitive dysfunction is associated with poor diabetes control in older adults. Diabetes Care 2006; 29:1794.
  45. Whitmer RA, Karter AJ, Yaffe K, et al. Hypoglycemic episodes and risk of dementia in older patients with type 2 diabetes mellitus. JAMA 2009; 301:1565.
  46. Launer LJ, Miller ME, Williamson JD, et al. Effects of intensive glucose lowering on brain structure and function in people with type 2 diabetes (ACCORD MIND): a randomised open-label substudy. Lancet Neurol 2011; 10:969.
  47. Lovestone S. Diabetes and dementia: is the brain another site of end-organ damage? Neurology 1999; 53:1907.
  48. Biessels GJ, De Leeuw FE, Lindeboom J, et al. Increased cortical atrophy in patients with Alzheimer's disease and type 2 diabetes mellitus. J Neurol Neurosurg Psychiatry 2006; 77:304.
  49. Arvanitakis Z, Schneider JA, Wilson RS, et al. Diabetes is related to cerebral infarction but not to AD pathology in older persons. Neurology 2006; 67:1960.
  50. Sonnen JA, Larson EB, Brickell K, et al. Different patterns of cerebral injury in dementia with or without diabetes. Arch Neurol 2009; 66:315.
  51. Cherbuin N, Sachdev P, Anstey KJ. Higher normal fasting plasma glucose is associated with hippocampal atrophy: The PATH Study. Neurology 2012; 79:1019.
  52. Whitmer RA, Sidney S, Selby J, et al. Midlife cardiovascular risk factors and risk of dementia in late life. Neurology 2005; 64:277.
  53. Alonso A, Mosley TH Jr, Gottesman RF, et al. Risk of dementia hospitalisation associated with cardiovascular risk factors in midlife and older age: the Atherosclerosis Risk in Communities (ARIC) study. J Neurol Neurosurg Psychiatry 2009; 80:1194.
  54. Solomon A, Kåreholt I, Ngandu T, et al. Serum cholesterol changes after midlife and late-life cognition: twenty-one-year follow-up study. Neurology 2007; 68:751.
  55. Shepardson NE, Shankar GM, Selkoe DJ. Cholesterol level and statin use in Alzheimer disease: I. Review of epidemiological and preclinical studies. Arch Neurol 2011; 68:1239.
  56. Moroney JT, Tang MX, Berglund L, et al. Low-density lipoprotein cholesterol and the risk of dementia with stroke. JAMA 1999; 282:254.
  57. Reitz C, Tang MX, Luchsinger J, Mayeux R. Relation of plasma lipids to Alzheimer disease and vascular dementia. Arch Neurol 2004; 61:705.
  58. Dufouil C, Richard F, Fiévet N, et al. APOE genotype, cholesterol level, lipid-lowering treatment, and dementia: the Three-City Study. Neurology 2005; 64:1531.
  59. Tan ZS, Seshadri S, Beiser A, et al. Plasma total cholesterol level as a risk factor for Alzheimer disease: the Framingham Study. Arch Intern Med 2003; 163:1053.
  60. Reitz C, Luchsinger J, Tang MX, et al. Impact of plasma lipids and time on memory performance in healthy elderly without dementia. Neurology 2005; 64:1378.
  61. Li G, Shofer JB, Kukull WA, et al. Serum cholesterol and risk of Alzheimer disease: a community-based cohort study. Neurology 2005; 65:1045.
  62. Xiong GL, Plassman BL, Helms MJ, Steffens DC. Vascular risk factors and cognitive decline among elderly male twins. Neurology 2006; 67:1586.
  63. Mielke MM, Zandi PP, Shao H, et al. The 32-year relationship between cholesterol and dementia from midlife to late life. Neurology 2010; 75:1888.
  64. Mielke MM, Zandi PP, Sjögren M, et al. High total cholesterol levels in late life associated with a reduced risk of dementia. Neurology 2005; 64:1689.
  65. Stewart R, White LR, Xue QL, Launer LJ. Twenty-six-year change in total cholesterol levels and incident dementia: the Honolulu-Asia Aging Study. Arch Neurol 2007; 64:103.
  66. Verdelho A, Madureira S, Ferro JM, et al. Differential impact of cerebral white matter changes, diabetes, hypertension and stroke on cognitive performance among non-disabled elderly. The LADIS study. J Neurol Neurosurg Psychiatry 2007; 78:1325.
  67. Elias MF, Wolf PA, D'Agostino RB, et al. Untreated blood pressure level is inversely related to cognitive functioning: the Framingham Study. Am J Epidemiol 1993; 138:353.
  68. Skoog I, Lernfelt B, Landahl S, et al. 15-year longitudinal study of blood pressure and dementia. Lancet 1996; 347:1141.
  69. Kilander L, Nyman H, Boberg M, et al. Hypertension is related to cognitive impairment: a 20-year follow-up of 999 men. Hypertension 1998; 31:780.
  70. Tzourio C, Dufouil C, Ducimetière P, Alpérovitch A. Cognitive decline in individuals with high blood pressure: a longitudinal study in the elderly. EVA Study Group. Epidemiology of Vascular Aging. Neurology 1999; 53:1948.
  71. Freitag MH, Peila R, Masaki K, et al. Midlife pulse pressure and incidence of dementia: the Honolulu-Asia Aging Study. Stroke 2006; 37:33.
  72. Obisesan TO, Obisesan OA, Martins S, et al. High blood pressure, hypertension, and high pulse pressure are associated with poorer cognitive function in persons aged 60 and older: the Third National Health and Nutrition Examination Survey. J Am Geriatr Soc 2008; 56:501.
  73. Tsivgoulis G, Alexandrov AV, Wadley VG, et al. Association of higher diastolic blood pressure levels with cognitive impairment. Neurology 2009; 73:589.
  74. Elkins JS, Yaffe K, Cauley JA, et al. Pre-existing hypertension and the impact of stroke on cognitive function. Ann Neurol 2005; 58:68.
  75. Wang LY, Larson EB, Sonnen JA, et al. Blood pressure and brain injury in older adults: findings from a community-based autopsy study. J Am Geriatr Soc 2009; 57:1975.
  76. Beason-Held LL, Moghekar A, Zonderman AB, et al. Longitudinal changes in cerebral blood flow in the older hypertensive brain. Stroke 2007; 38:1766.
  77. Razay G, Vreugdenhil A, Wilcock G. The metabolic syndrome and Alzheimer disease. Arch Neurol 2007; 64:93.
  78. Kalmijn S, Foley D, White L, et al. Metabolic cardiovascular syndrome and risk of dementia in Japanese-American elderly men. The Honolulu-Asia aging study. Arterioscler Thromb Vasc Biol 2000; 20:2255.
  79. Yaffe K, Weston AL, Blackwell T, Krueger KA. The metabolic syndrome and development of cognitive impairment among older women. Arch Neurol 2009; 66:324.
  80. Solfrizzi V, Scafato E, Capurso C, et al. Metabolic syndrome and the risk of vascular dementia: the Italian Longitudinal Study on Ageing. J Neurol Neurosurg Psychiatry 2010; 81:433.
  81. Vanhanen M, Koivisto K, Moilanen L, et al. Association of metabolic syndrome with Alzheimer disease: a population-based study. Neurology 2006; 67:843.
  82. Raffaitin C, Féart C, Le Goff M, et al. Metabolic syndrome and cognitive decline in French elders: the Three-City Study. Neurology 2011; 76:518.
  83. Singh-Manoux A, Czernichow S, Elbaz A, et al. Obesity phenotypes in midlife and cognition in early old age: the Whitehall II cohort study. Neurology 2012; 79:755.
  84. Yaffe K, Kanaya A, Lindquist K, et al. The metabolic syndrome, inflammation, and risk of cognitive decline. JAMA 2004; 292:2237.
  85. van den Berg E, Biessels GJ, de Craen AJ, et al. The metabolic syndrome is associated with decelerated cognitive decline in the oldest old. Neurology 2007; 69:979.
  86. Luchsinger JA, Patel B, Tang MX, et al. Measures of adiposity and dementia risk in elderly persons. Arch Neurol 2007; 64:392.
  87. Whitmer RA, Gunderson EP, Barrett-Connor E, et al. Obesity in middle age and future risk of dementia: a 27 year longitudinal population based study. BMJ 2005; 330:1360.
  88. Kivipelto M, Ngandu T, Fratiglioni L, et al. Obesity and vascular risk factors at midlife and the risk of dementia and Alzheimer disease. Arch Neurol 2005; 62:1556.
  89. Rosengren A, Skoog I, Gustafson D, Wilhelmsen L. Body mass index, other cardiovascular risk factors, and hospitalization for dementia. Arch Intern Med 2005; 165:321.
  90. Gustafson D, Rothenberg E, Blennow K, et al. An 18-year follow-up of overweight and risk of Alzheimer disease. Arch Intern Med 2003; 163:1524.
  91. Whitmer RA, Gustafson DR, Barrett-Connor E, et al. Central obesity and increased risk of dementia more than three decades later. Neurology 2008; 71:1057.
  92. Gustafson DR, Bäckman K, Waern M, et al. Adiposity indicators and dementia over 32 years in Sweden. Neurology 2009; 73:1559.
  93. Xu WL, Atti AR, Gatz M, et al. Midlife overweight and obesity increase late-life dementia risk: a population-based twin study. Neurology 2011; 76:1568.
  94. Cournot M, Marquié JC, Ansiau D, et al. Relation between body mass index and cognitive function in healthy middle-aged men and women. Neurology 2006; 67:1208.
  95. Albanese E, Davis B, Jonsson PV, et al. Overweight and Obesity in Midlife and Brain Structure and Dementia 26 Years Later: The AGES-Reykjavik Study. Am J Epidemiol 2015; 181:672.
  96. Alhurani RE, Vassilaki M, Aakre JA, et al. Decline in Weight and Incident Mild Cognitive Impairment: Mayo Clinic Study of Aging. JAMA Neurol 2016; 73:439.
  97. Stewart R, Masaki K, Xue QL, et al. A 32-year prospective study of change in body weight and incident dementia: the Honolulu-Asia Aging Study. Arch Neurol 2005; 62:55.
  98. Buchman AS, Wilson RS, Bienias JL, et al. Change in body mass index and risk of incident Alzheimer disease. Neurology 2005; 65:892.
  99. Nourhashémi F, Deschamps V, Larrieu S, et al. Body mass index and incidence of dementia: the PAQUID study. Neurology 2003; 60:117.
  100. Johnson DK, Wilkins CH, Morris JC. Accelerated weight loss may precede diagnosis in Alzheimer disease. Arch Neurol 2006; 63:1312.
  101. Knopman DS, Edland SD, Cha RH, et al. Incident dementia in women is preceded by weight loss by at least a decade. Neurology 2007; 69:739.
  102. Hughes TF, Borenstein AR, Schofield E, et al. Association between late-life body mass index and dementia: The Kame Project. Neurology 2009; 72:1741.
  103. Vidoni ED, Townley RA, Honea RA, et al. Alzheimer disease biomarkers are associated with body mass index. Neurology 2011; 77:1913.
  104. Burns JM, Johnson DK, Watts A, et al. Reduced lean mass in early Alzheimer disease and its association with brain atrophy. Arch Neurol 2010; 67:428.
  105. Almeida OP, Hulse GK, Lawrence D, Flicker L. Smoking as a risk factor for Alzheimer's disease: contrasting evidence from a systematic review of case-control and cohort studies. Addiction 2002; 97:15.
  106. Tyas SL, White LR, Petrovitch H, et al. Mid-life smoking and late-life dementia: the Honolulu-Asia Aging Study. Neurobiol Aging 2003; 24:589.
  107. Sabia S, Marmot M, Dufouil C, Singh-Manoux A. Smoking history and cognitive function in middle age from the Whitehall II study. Arch Intern Med 2008; 168:1165.
  108. Rusanen M, Kivipelto M, Quesenberry CP Jr, et al. Heavy smoking in midlife and long-term risk of Alzheimer disease and vascular dementia. Arch Intern Med 2011; 171:333.
  109. Yamada M, Kasagi F, Sasaki H, et al. Association between dementia and midlife risk factors: the Radiation Effects Research Foundation Adult Health Study. J Am Geriatr Soc 2003; 51:410.
  110. Chen R, Wilson K, Chen Y, et al. Association between environmental tobacco smoke exposure and dementia syndromes. Occup Environ Med 2013; 70:63.
  111. Llewellyn DJ, Lang IA, Langa KM, et al. Exposure to secondhand smoke and cognitive impairment in non-smokers: national cross sectional study with cotinine measurement. BMJ 2009; 338:b462.
  112. Barnes DE, Haight TJ, Mehta KM, et al. Secondhand smoke, vascular disease, and dementia incidence: findings from the cardiovascular health cognition study. Am J Epidemiol 2010; 171:292.
  113. Anstey KJ, von Sanden C, Salim A, O'Kearney R. Smoking as a risk factor for dementia and cognitive decline: a meta-analysis of prospective studies. Am J Epidemiol 2007; 166:367.
  114. Reitz C, Luchsinger J, Tang MX, Mayeux R. Effect of smoking and time on cognitive function in the elderly without dementia. Neurology 2005; 65:870.
  115. Ott A, Slooter AJ, Hofman A, et al. Smoking and risk of dementia and Alzheimer's disease in a population-based cohort study: the Rotterdam Study. Lancet 1998; 351:1840.
  116. Reitz C, den Heijer T, van Duijn C, et al. Relation between smoking and risk of dementia and Alzheimer disease: the Rotterdam Study. Neurology 2007; 69:998.
  117. Poirier J, Delisle MC, Quirion R, et al. Apolipoprotein E4 allele as a predictor of cholinergic deficits and treatment outcome in Alzheimer disease. Proc Natl Acad Sci U S A 1995; 92:12260.
  118. Haring B, Leng X, Robinson J, et al. Cardiovascular disease and cognitive decline in postmenopausal women: results from the Women's Health Initiative Memory Study. J Am Heart Assoc 2013; 2:e000369.
  119. van Oijen M, de Jong FJ, Witteman JC, et al. Atherosclerosis and risk for dementia. Ann Neurol 2007; 61:403.
  120. Wendell CR, Zonderman AB, Metter EJ, et al. Carotid intimal medial thickness predicts cognitive decline among adults without clinical vascular disease. Stroke 2009; 40:3180.
  121. Wendell CR, Waldstein SR, Ferrucci L, et al. Carotid atherosclerosis and prospective risk of dementia. Stroke 2012; 43:3319.
  122. Bos D, Ikram MA, Elias-Smale SE, et al. Calcification in major vessel beds relates to vascular brain disease. Arterioscler Thromb Vasc Biol 2011; 31:2331.
  123. Vidal JS, Sigurdsson S, Jonsdottir MK, et al. Coronary artery calcium, brain function and structure: the AGES-Reykjavik Study. Stroke 2010; 41:891.
  124. Reis JP, Launer LJ, Terry JG, et al. Subclinical atherosclerotic calcification and cognitive functioning in middle-aged adults: the CARDIA study. Atherosclerosis 2013; 231:72.
  125. Kuller LH, Lopez OL, Mackey RH, et al. Subclinical Cardiovascular Disease and Death, Dementia, and Coronary Heart Disease in Patients 80+ Years. J Am Coll Cardiol 2016; 67:1013.
  126. Baker ML, Marino Larsen EK, Kuller LH, et al. Retinal microvascular signs, cognitive function, and dementia in older persons: the Cardiovascular Health Study. Stroke 2007; 38:2041.
  127. Lesage SR, Mosley TH, Wong TY, et al. Retinal microvascular abnormalities and cognitive decline: the ARIC 14-year follow-up study. Neurology 2009; 73:862.
  128. de Jong FJ, Schrijvers EM, Ikram MK, et al. Retinal vascular caliber and risk of dementia: the Rotterdam study. Neurology 2011; 76:816.
  129. Haan M, Espeland MA, Klein BE, et al. Cognitive function and retinal and ischemic brain changes: the Women's Health Initiative. Neurology 2012; 78:942.
  130. Schrijvers EM, Buitendijk GH, Ikram MK, et al. Retinopathy and risk of dementia: the Rotterdam Study. Neurology 2012; 79:365.
  131. Dolan H, Crain B, Troncoso J, et al. Atherosclerosis, dementia, and Alzheimer disease in the Baltimore Longitudinal Study of Aging cohort. Ann Neurol 2010; 68:231.
  132. Abbott RD, White LR, Ross GW, et al. Walking and dementia in physically capable elderly men. JAMA 2004; 292:1447.
  133. Weuve J, Kang JH, Manson JE, et al. Physical activity, including walking, and cognitive function in older women. JAMA 2004; 292:1454.
  134. Barnes LL, Mendes de Leon CF, Wilson RS, et al. Social resources and cognitive decline in a population of older African Americans and whites. Neurology 2004; 63:2322.
  135. Barnes DE, Yaffe K, Satariano WA, Tager IB. A longitudinal study of cardiorespiratory fitness and cognitive function in healthy older adults. J Am Geriatr Soc 2003; 51:459.
  136. Rovio S, Kåreholt I, Helkala EL, et al. Leisure-time physical activity at midlife and the risk of dementia and Alzheimer's disease. Lancet Neurol 2005; 4:705.
  137. Larson EB, Wang L, Bowen JD, et al. Exercise is associated with reduced risk for incident dementia among persons 65 years of age and older. Ann Intern Med 2006; 144:73.
  138. Verghese J, LeValley A, Derby C, et al. Leisure activities and the risk of amnestic mild cognitive impairment in the elderly. Neurology 2006; 66:821.
  139. Bennett DA, Schneider JA, Tang Y, et al. The effect of social networks on the relation between Alzheimer's disease pathology and level of cognitive function in old people: a longitudinal cohort study. Lancet Neurol 2006; 5:406.
  140. Deary IJ, Whalley LJ, Batty GD, Starr JM. Physical fitness and lifetime cognitive change. Neurology 2006; 67:1195.
  141. Wilson RS, Scherr PA, Schneider JA, et al. Relation of cognitive activity to risk of developing Alzheimer disease. Neurology 2007; 69:1911.
  142. Ravaglia G, Forti P, Lucicesare A, et al. Physical activity and dementia risk in the elderly: findings from a prospective Italian study. Neurology 2008; 70:1786.
  143. Burns JM, Cronk BB, Anderson HS, et al. Cardiorespiratory fitness and brain atrophy in early Alzheimer disease. Neurology 2008; 71:210.
  144. Scarmeas N, Luchsinger JA, Schupf N, et al. Physical activity, diet, and risk of Alzheimer disease. JAMA 2009; 302:627.
  145. Akbaraly TN, Portet F, Fustinoni S, et al. Leisure activities and the risk of dementia in the elderly: results from the Three-City Study. Neurology 2009; 73:854.
  146. Vercambre MN, Grodstein F, Manson JE, et al. Physical activity and cognition in women with vascular conditions. Arch Intern Med 2011; 171:1244.
  147. Middleton LE, Manini TM, Simonsick EM, et al. Activity energy expenditure and incident cognitive impairment in older adults. Arch Intern Med 2011; 171:1251.
  148. Buchman AS, Boyle PA, Yu L, et al. Total daily physical activity and the risk of AD and cognitive decline in older adults. Neurology 2012; 78:1323.
  149. Wilson RS, Segawa E, Boyle PA, Bennett DA. Influence of late-life cognitive activity on cognitive health. Neurology 2012; 78:1123.
  150. Verdelho A, Madureira S, Ferro JM, et al. Physical activity prevents progression for cognitive impairment and vascular dementia: results from the LADIS (Leukoaraiosis and Disability) study. Stroke 2012; 43:3331.
  151. Liang KY, Mintun MA, Fagan AM, et al. Exercise and Alzheimer's disease biomarkers in cognitively normal older adults. Ann Neurol 2010; 68:311.
  152. Nyberg J, Åberg MA, Schiöler L, et al. Cardiovascular and cognitive fitness at age 18 and risk of early-onset dementia. Brain 2014; 137:1514.
  153. Krell-Roesch J, Vemuri P, Pink A, et al. Association Between Mentally Stimulating Activities in Late Life and the Outcome of Incident Mild Cognitive Impairment, With an Analysis of the APOE ε4 Genotype. JAMA Neurol 2017; 74:332.
  154. Defina LF, Willis BL, Radford NB, et al. The association between midlife cardiorespiratory fitness levels and later-life dementia: a cohort study. Ann Intern Med 2013; 158:162.
  155. Fratiglioni L, Paillard-Borg S, Winblad B. An active and socially integrated lifestyle in late life might protect against dementia. Lancet Neurol 2004; 3:343.
  156. Stern Y, Gurland B, Tatemichi TK, et al. Influence of education and occupation on the incidence of Alzheimer's disease. JAMA 1994; 271:1004.
  157. Evans DA, Hebert LE, Beckett LA, et al. Education and other measures of socioeconomic status and risk of incident Alzheimer disease in a defined population of older persons. Arch Neurol 1997; 54:1399.
  158. Prince M, Acosta D, Ferri CP, et al. Dementia incidence and mortality in middle-income countries, and associations with indicators of cognitive reserve: a 10/66 Dementia Research Group population-based cohort study. Lancet 2012; 380:50.
  159. Ngandu T, von Strauss E, Helkala EL, et al. Education and dementia: what lies behind the association? Neurology 2007; 69:1442.
  160. Fotenos AF, Mintun MA, Snyder AZ, et al. Brain volume decline in aging: evidence for a relation between socioeconomic status, preclinical Alzheimer disease, and reserve. Arch Neurol 2008; 65:113.
  161. Yaffe K, Weston A, Graff-Radford NR, et al. Association of plasma beta-amyloid level and cognitive reserve with subsequent cognitive decline. JAMA 2011; 305:261.
  162. Bennett DA, Wilson RS, Schneider JA, et al. Education modifies the relation of AD pathology to level of cognitive function in older persons. Neurology 2003; 60:1909.
  163. Boyle PA, Wilson RS, Schneider JA, et al. Processing resources reduce the effect of Alzheimer pathology on other cognitive systems. Neurology 2008; 70:1534.
  164. Roe CM, Xiong C, Miller JP, Morris JC. Education and Alzheimer disease without dementia: support for the cognitive reserve hypothesis. Neurology 2007; 68:223.
  165. Perneczky R, Drzezga A, Diehl-Schmid J, et al. Schooling mediates brain reserve in Alzheimer's disease: findings of fluoro-deoxy-glucose-positron emission tomography. J Neurol Neurosurg Psychiatry 2006; 77:1060.
  166. Garibotto V, Borroni B, Kalbe E, et al. Education and occupation as proxies for reserve in aMCI converters and AD: FDG-PET evidence. Neurology 2008; 71:1342.
  167. Roe CM, Mintun MA, D'Angelo G, et al. Alzheimer disease and cognitive reserve: variation of education effect with carbon 11-labeled Pittsburgh Compound B uptake. Arch Neurol 2008; 65:1467.
  168. Rentz DM, Locascio JJ, Becker JA, et al. Cognition, reserve, and amyloid deposition in normal aging. Ann Neurol 2010; 67:353.
  169. Iacono D, Markesbery WR, Gross M, et al. The Nun study: clinically silent AD, neuronal hypertrophy, and linguistic skills in early life. Neurology 2009; 73:665.
  170. Iacono D, O'Brien R, Resnick SM, et al. Neuronal hypertrophy in asymptomatic Alzheimer disease. J Neuropathol Exp Neurol 2008; 67:578.
  171. Wilson RS, Li Y, Aggarwal NT, et al. Education and the course of cognitive decline in Alzheimer disease. Neurology 2004; 63:1198.
  172. Hall CB, Derby C, LeValley A, et al. Education delays accelerated decline on a memory test in persons who develop dementia. Neurology 2007; 69:1657.
  173. Singh-Manoux A, Marmot MG, Glymour M, et al. Does cognitive reserve shape cognitive decline? Ann Neurol 2011; 70:296.
  174. Sofi F, Valecchi D, Bacci D, et al. Physical activity and risk of cognitive decline: a meta-analysis of prospective studies. J Intern Med 2011; 269:107.
  175. Santangeli P, Di Biase L, Bai R, et al. Atrial fibrillation and the risk of incident dementia: a meta-analysis. Heart Rhythm 2012; 9:1761.
  176. Dublin S, Anderson ML, Haneuse SJ, et al. Atrial fibrillation and risk of dementia: a prospective cohort study. J Am Geriatr Soc 2011; 59:1369.
  177. Thacker EL, McKnight B, Psaty BM, et al. Atrial fibrillation and cognitive decline: a longitudinal cohort study. Neurology 2013; 81:119.
  178. Marzona I, O'Donnell M, Teo K, et al. Increased risk of cognitive and functional decline in patients with atrial fibrillation: results of the ONTARGET and TRANSCEND studies. CMAJ 2012; 184:E329.
  179. de Bruijn RF, Heeringa J, Wolters FJ, et al. Association Between Atrial Fibrillation and Dementia in the General Population. JAMA Neurol 2015; 72:1288.
  180. Kalantarian S, Stern TA, Mansour M, Ruskin JN. Cognitive impairment associated with atrial fibrillation: a meta-analysis. Ann Intern Med 2013; 158:338.
  181. Deckers K, Camerino I, van Boxtel MP, et al. Dementia risk in renal dysfunction: A systematic review and meta-analysis of prospective studies. Neurology 2017; 88:198.
  182. Green RC, Cupples LA, Kurz A, et al. Depression as a risk factor for Alzheimer disease: the MIRAGE Study. Arch Neurol 2003; 60:753.
  183. Ownby RL, Crocco E, Acevedo A, et al. Depression and risk for Alzheimer disease: systematic review, meta-analysis, and metaregression analysis. Arch Gen Psychiatry 2006; 63:530.
  184. Geerlings MI, den Heijer T, Koudstaal PJ, et al. History of depression, depressive symptoms, and medial temporal lobe atrophy and the risk of Alzheimer disease. Neurology 2008; 70:1258.
  185. Köhler S, van Boxtel MP, van Os J, et al. Depressive symptoms and cognitive decline in community-dwelling older adults. J Am Geriatr Soc 2010; 58:873.
  186. Saczynski JS, Beiser A, Seshadri S, et al. Depressive symptoms and risk of dementia: the Framingham Heart Study. Neurology 2010; 75:35.
  187. Dotson VM, Beydoun MA, Zonderman AB. Recurrent depressive symptoms and the incidence of dementia and mild cognitive impairment. Neurology 2010; 75:27.
  188. Diniz BS, Butters MA, Albert SM, et al. Late-life depression and risk of vascular dementia and Alzheimer's disease: systematic review and meta-analysis of community-based cohort studies. Br J Psychiatry 2013; 202:329.
  189. Singh-Manoux A, Dugravot A, Fournier A, et al. Trajectories of Depressive Symptoms Before Diagnosis of Dementia: A 28-Year Follow-up Study. JAMA Psychiatry 2017; 74:712.
  190. Verghese J, Lipton RB, Hall CB, et al. Abnormality of gait as a predictor of non-Alzheimer's dementia. N Engl J Med 2002; 347:1761.
  191. Verghese J, Wang C, Lipton RB, Holtzer R. Motoric cognitive risk syndrome and the risk of dementia. J Gerontol A Biol Sci Med Sci 2013; 68:412.
  192. Mez J, Daneshvar DH, Kiernan PT, et al. Clinicopathological Evaluation of Chronic Traumatic Encephalopathy in Players of American Football. JAMA 2017; 318:360.
  193. Giza CC, Kutcher JS, Ashwal S, et al. Summary of evidence-based guideline update: evaluation and management of concussion in sports: report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology 2013; 80:2250.
  194. Washington PM, Villapol S, Burns MP. Polypathology and dementia after brain trauma: Does brain injury trigger distinct neurodegenerative diseases, or should they be classified together as traumatic encephalopathy? Exp Neurol 2016; 275 Pt 3:381.
  195. Institute of Medicine. Long-term consequences of traumatic brain injury, Volume 7. National Academies Press; Gulf War and Health, Washington, DC, 2009.
  196. Crane PK, Gibbons LE, Dams-O'Connor K, et al. Association of Traumatic Brain Injury With Late-Life Neurodegenerative Conditions and Neuropathologic Findings. JAMA Neurol 2016; 73:1062.
  197. Lin FR, Metter EJ, O'Brien RJ, et al. Hearing loss and incident dementia. Arch Neurol 2011; 68:214.
  198. Lin FR, Yaffe K, Xia J, et al. Hearing loss and cognitive decline in older adults. JAMA Intern Med 2013; 173:293.
  199. Fritze T, Teipel S, Óvári A, et al. Hearing Impairment Affects Dementia Incidence. An Analysis Based on Longitudinal Health Claims Data in Germany. PLoS One 2016; 11:e0156876.
  200. Gurgel RK, Ward PD, Schwartz S, et al. Relationship of hearing loss and dementia: a prospective, population-based study. Otol Neurotol 2014; 35:775.
  201. Amieva H, Ouvrard C, Giulioli C, et al. Self-Reported Hearing Loss, Hearing Aids, and Cognitive Decline in Elderly Adults: A 25-Year Study. J Am Geriatr Soc 2015; 63:2099.
  202. Golub JS, Luchsinger JA, Manly JJ, et al. Observed Hearing Loss and Incident Dementia in a Multiethnic Cohort. J Am Geriatr Soc 2017; 65:1691.
  203. Gates GA, Anderson ML, McCurry SM, et al. Central auditory dysfunction as a harbinger of Alzheimer dementia. Arch Otolaryngol Head Neck Surg 2011; 137:390.
  204. Gates GA, Gibbons LE, McCurry SM, et al. Executive dysfunction and presbycusis in older persons with and without memory loss and dementia. Cogn Behav Neurol 2010; 23:218.
  205. Gates GA, Anderson ML, Feeney MP, et al. Central auditory dysfunction in older persons with memory impairment or Alzheimer dementia. Arch Otolaryngol Head Neck Surg 2008; 134:771.
  206. Seshadri S, Beiser A, Selhub J, et al. Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. N Engl J Med 2002; 346:476.
  207. Kalmijn S, Launer LJ, Lindemans J, et al. Total homocysteine and cognitive decline in a community-based sample of elderly subjects: the Rotterdam Study. Am J Epidemiol 1999; 150:283.
  208. Wright CB, Lee HS, Paik MC, et al. Total homocysteine and cognition in a tri-ethnic cohort: the Northern Manhattan Study. Neurology 2004; 63:254.
  209. Garcia A, Zanibbi K. Homocysteine and cognitive function in elderly people. CMAJ 2004; 171:897.
  210. Kado DM, Karlamangla AS, Huang MH, et al. Homocysteine versus the vitamins folate, B6, and B12 as predictors of cognitive function and decline in older high-functioning adults: MacArthur Studies of Successful Aging. Am J Med 2005; 118:161.
  211. Irizarry MC, Gurol ME, Raju S, et al. Association of homocysteine with plasma amyloid beta protein in aging and neurodegenerative disease. Neurology 2005; 65:1402.
  212. Nurk E, Refsum H, Tell GS, et al. Plasma total homocysteine and memory in the elderly: the Hordaland Homocysteine Study. Ann Neurol 2005; 58:847.
  213. Elkins JS, Johnston SC, Ziv E, et al. Methylenetetrahydrofolate reductase C677T polymorphism and cognitive function in older women. Am J Epidemiol 2007; 166:672.
  214. Hooshmand B, Solomon A, Kåreholt I, et al. Homocysteine and holotranscobalamin and the risk of Alzheimer disease: a longitudinal study. Neurology 2010; 75:1408.
  215. Ford AH, Flicker L, Alfonso H, et al. Plasma homocysteine and MTHFRC677T polymorphism as risk factors for incident dementia. J Neurol Neurosurg Psychiatry 2012; 83:70.
  216. Selhub J, Jacques PF, Bostom AG, et al. Relationship between plasma homocysteine, vitamin status and extracranial carotid-artery stenosis in the Framingham Study population. J Nutr 1996; 126:1258S.
  217. Hassan A, Hunt BJ, O'Sullivan M, et al. Homocysteine is a risk factor for cerebral small vessel disease, acting via endothelial dysfunction. Brain 2004; 127:212.
  218. Kim JM, Stewart R, Kim SW, et al. Changes in folate, vitamin B12 and homocysteine associated with incident dementia. J Neurol Neurosurg Psychiatry 2008; 79:864.
  219. Iwashyna TJ, Ely EW, Smith DM, Langa KM. Long-term cognitive impairment and functional disability among survivors of severe sepsis. JAMA 2010; 304:1787.
  220. Ehlenbach WJ, Hough CL, Crane PK, et al. Association between acute care and critical illness hospitalization and cognitive function in older adults. JAMA 2010; 303:763.
  221. Wilson RS, Hebert LE, Scherr PA, et al. Cognitive decline after hospitalization in a community population of older persons. Neurology 2012; 78:950.
  222. Song X, Mitnitski A, Rockwood K. Nontraditional risk factors combine to predict Alzheimer disease and dementia. Neurology 2011; 77:227.
  223. Montlahuc C, Soumaré A, Dufouil C, et al. Self-rated health and risk of incident dementia: a community-based elderly cohort, the 3C study. Neurology 2011; 77:1457.
  224. Tannenbaum C, Paquette A, Hilmer S, et al. A systematic review of amnestic and non-amnestic mild cognitive impairment induced by anticholinergic, antihistamine, GABAergic and opioid drugs. Drugs Aging 2012; 29:639.
  225. Billioti de Gage S, Moride Y, Ducruet T, et al. Benzodiazepine use and risk of Alzheimer's disease: case-control study. BMJ 2014; 349:g5205.
  226. Gray SL, Anderson ML, Dublin S, et al. Cumulative use of strong anticholinergics and incident dementia: a prospective cohort study. JAMA Intern Med 2015; 175:401.
  227. Billioti de Gage S, Bégaud B, Bazin F, et al. Benzodiazepine use and risk of dementia: prospective population based study. BMJ 2012; 345:e6231.
  228. Imfeld P, Bodmer M, Jick SS, Meier CR. Benzodiazepine Use and Risk of Developing Alzheimer's Disease or Vascular Dementia: A Case-Control Analysis. Drug Saf 2015; 38:909.
  229. Gray SL, Dublin S, Yu O, et al. Benzodiazepine use and risk of incident dementia or cognitive decline: prospective population based study. BMJ 2016; 352:i90.
  230. Risacher SL, McDonald BC, Tallman EF, et al. Association Between Anticholinergic Medication Use and Cognition, Brain Metabolism, and Brain Atrophy in Cognitively Normal Older Adults. JAMA Neurol 2016; 73:721.
  231. Yaffe K, Laffan AM, Harrison SL, et al. Sleep-disordered breathing, hypoxia, and risk of mild cognitive impairment and dementia in older women. JAMA 2011; 306:613.
  232. Spira AP, Blackwell T, Stone KL, et al. Sleep-disordered breathing and cognition in older women. J Am Geriatr Soc 2008; 56:45.
  233. Blackwell T, Yaffe K, Laffan A, et al. Associations between sleep-disordered breathing, nocturnal hypoxemia, and subsequent cognitive decline in older community-dwelling men: the Osteoporotic Fractures in Men Sleep Study. J Am Geriatr Soc 2015; 63:453.
  234. Ju Y, Lopez O, Redline S, Stein P. Obstructive sleep apnea increases risk of incident dementia in community-dwelling older adults. Neurology 2013; 80:P03.098.
  235. Osorio RS, Gumb T, Pirraglia E, et al. Sleep-disordered breathing advances cognitive decline in the elderly. Neurology 2015; 84:1964.
  236. Haba-Rubio J, Marti-Soler H, Tobback N, et al. Sleep characteristics and cognitive impairment in the general population: The HypnoLaus study. Neurology 2017; 88:463.
  237. Ramos AR, Tarraf W, Rundek T, et al. Obstructive sleep apnea and neurocognitive function in a Hispanic/Latino population. Neurology 2015; 84:391.
  238. Ramos AR, Gardener H, Rundek T, et al. Sleep disturbances and cognitive decline in the Northern Manhattan Study. Neurology 2016; 87:1511.
  239. Yun CH, Lee HY, Lee SK, et al. Amyloid Burden in Obstructive Sleep Apnea. J Alzheimers Dis 2017; 59:21.
  240. Liguori C, Mercuri NB, Izzi F, et al. Obstructive Sleep Apnea is Associated With Early but Possibly Modifiable Alzheimer's Disease Biomarkers Changes. Sleep 2017; 40.
  241. Pase MP, Himali JJ, Grima NA, et al. Sleep architecture and the risk of incident dementia in the community. Neurology 2017; 89:1244.
  242. Killin LO, Starr JM, Shiue IJ, Russ TC. Environmental risk factors for dementia: a systematic review. BMC Geriatr 2016; 16:175.
  243. Campdelacreu J. Parkinson disease and Alzheimer disease: environmental risk factors. Neurologia 2014; 29:541.
  244. Power MC, Adar SD, Yanosky JD, Weuve J. Exposure to air pollution as a potential contributor to cognitive function, cognitive decline, brain imaging, and dementia: A systematic review of epidemiologic research. Neurotoxicology 2016; 56:235.
  245. Peters R, Peters J, Booth A, Mudway I. Is air pollution associated with increased risk of cognitive decline? A systematic review. Age Ageing 2015; 44:755.
  246. Chen H, Kwong JC, Copes R, et al. Living near major roads and the incidence of dementia, Parkinson's disease, and multiple sclerosis: a population-based cohort study. Lancet 2017; 389:718.
  247. Fuller-Thomson E, Jopling SA. Exposure to lead in petrol and increased incidence of dementia. Lancet 2017; 389:2371.
  248. Laidlaw MAS, Poropat AE, Ball A, Mielke HW. Exposure to lead in petrol and increased incidence of dementia. Lancet 2017; 389:2371.
  249. Cacciottolo M, Wang X, Driscoll I, et al. Particulate air pollutants, APOE alleles and their contributions to cognitive impairment in older women and to amyloidogenesis in experimental models. Transl Psychiatry 2017; 7:e1022.
  250. Balion C, Griffith LE, Strifler L, et al. Vitamin D, cognition, and dementia: a systematic review and meta-analysis. Neurology 2012; 79:1397.
  251. Buell JS, Dawson-Hughes B, Scott TM, et al. 25-Hydroxyvitamin D, dementia, and cerebrovascular pathology in elders receiving home services. Neurology 2010; 74:18.
  252. Annweiler C, Schott AM, Rolland Y, et al. Dietary intake of vitamin D and cognition in older women: a large population-based study. Neurology 2010; 75:1810.
  253. Annweiler C, Schott AM, Allali G, et al. Association of vitamin D deficiency with cognitive impairment in older women: cross-sectional study. Neurology 2010; 74:27.
  254. Mokry LE, Ross S, Morris JA, et al. Genetically decreased vitamin D and risk of Alzheimer disease. Neurology 2016; 87:2567.
  255. Slinin Y, Paudel ML, Taylor BC, et al. 25-Hydroxyvitamin D levels and cognitive performance and decline in elderly men. Neurology 2010; 74:33.
  256. Llewellyn DJ, Lang IA, Langa KM, et al. Vitamin D and risk of cognitive decline in elderly persons. Arch Intern Med 2010; 170:1135.
  257. Littlejohns TJ, Henley WE, Lang IA, et al. Vitamin D and the risk of dementia and Alzheimer disease. Neurology 2014; 83:920.