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  • Review Article
  • Published:

Depression and risk of developing dementia

Abstract

Depression is highly common throughout the life course and dementia is common in late life. Depression has been linked with dementia, and growing evidence implies that the timing of depression may be important in defining the nature of this association. In particular, earlier-life depression (or depressive symptoms) has consistently been associated with a more than twofold increase in dementia risk. By contrast, studies of late-life depression and dementia risk have been conflicting; most support an association, yet the nature of this association (for example, if depression is a prodrome or consequence of, or risk factor for dementia) remains unclear. The likely biological mechanisms linking depression to dementia include vascular disease, alterations in glucocorticoid steroid levels and hippocampal atrophy, increased deposition of amyloid-β plaques, inflammatory changes, and deficits of nerve growth factors. Treatment strategies for depression could interfere with these pathways and alter the risk of dementia. Given the projected increase in dementia incidence in the coming decades, understanding whether treatment for depression alone, or combined with other regimens, improves cognition is of critical importance. In this Review, we summarize and analyze current evidence linking late-life and earlier-life depression and dementia, and discuss the primary underlying mechanisms and implications for treatment.

Key Points

  • Depression is common throughout the life course, while dementia is very common in late life

  • Late-life depression or depressive symptoms may be associated with dementia, but inconsistencies across studies exist

  • Current research supports the association between earlier-life depression—or depressive symptoms—and dementia; however, more studies are needed to examine depression occurrence over the life course

  • Vascular disease, glucocorticoid steroid levels, hippocampal atrophy, increased deposition of amyloid-β plaques, inflammatory changes, and deficits of nerve growth factors or neurotrophins are likely to underlie depression and dementia

  • A patient presenting with early-life or late-life depression or depressive symptoms, especially if chronic, should be screened and monitored for cognitive deficits over the long term

  • Determining whether treatment of depression alone or combined with other regimens would delay or prevent dementia is critical

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Figure 1: Proposed predominant pathways linking depression to the onset of dementia.

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References

  1. Kessler, R. C. et al. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch. Gen. Psychiatry 62, 593–602 (2005).

    Article  PubMed  Google Scholar 

  2. Jorm, A. F. & Jolley, D. The incidence of dementia: a meta-analysis. Neurology 51, 728–733 (1998).

    Article  CAS  PubMed  Google Scholar 

  3. Corrada, M. M., Brookmeyer, R., Berlau, D., Paganini-Hill, A. & Kawas, C. H. Prevalence of dementia after age 90: results from the 90+ study. Neurology 71, 337–343 (2008).

    Article  CAS  PubMed  Google Scholar 

  4. Yaffe, K. et al. Mild cognitive impairment, dementia and subtypes among oldest old women. Arch. Neurol. (in press).

  5. US Census Bureau Newsroom. An older and more diverse nation by midcentury. US Census Bureau [online], (2008).

  6. Park, J. H. et al. Depression in vascular dementia is quantitatively and qualitatively different from depression in Alzheimer's disease. Dement. Geriatr. Cogn. Disord. 23, 67–73 (2007).

    Article  CAS  PubMed  Google Scholar 

  7. Ballard, C., Bannister, C., Solis, M., Oyebode, F. & Wilcock, G. The prevalence, associations and symptoms of depression amongst dementia sufferers. J. Affect. Disord. 36, 135–144 (1996).

    Article  CAS  PubMed  Google Scholar 

  8. Ballard, C. et al. Anxiety, depression and psychosis in vascular dementia: prevalence and associations. J. Affect. Disord. 59, 97–106 (2000).

    Article  CAS  PubMed  Google Scholar 

  9. Steffens, D. C. & Potter, G. G. Geriatric depression and cognitive impairment. Psychol. Med. 38, 163–175 (2008).

    Article  CAS  PubMed  Google Scholar 

  10. Korczyn, A. D. & Halperin, I. Depression and dementia. J. Neurol. Sci. 283, 139–142 (2009).

    Article  PubMed  Google Scholar 

  11. Caraci, F., Copani, A., Nicoletti, F. & Drago, F. Depression and Alzheimer's disease: neurobiological links and common pharmacological targets. Eur. J. Pharmacol. 626, 64–71 (2010).

    Article  CAS  PubMed  Google Scholar 

  12. Saczynski, J. S. et al. Depressive symptoms and risk of dementia: the Framingham Heart Study. Neurology 75, 35–41 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Andersen, K., Lolk, A., Kragh-Sørensen, P., Petersen, N. E. & Green, A. Depression and the risk of Alzheimer disease. Epidemiology 16, 233–238 (2005).

    Article  PubMed  Google Scholar 

  14. Gatz, J. L., Tyas, S. L., St John, P. & Montgomery, P. Do depressive symptoms predict Alzheimer's disease and dementia? J. Gerontol. A Biol. Sci. Med. Sci. 60, 744–747 (2005).

    Article  PubMed  Google Scholar 

  15. Chen, R. et al. Severity of depression and risk for subsequent dementia: cohort studies in China and the UK. Br. J. Psychiatry 193, 373–377 (2008).

    Article  PubMed  Google Scholar 

  16. Byers, A. L., Covinsky, K. E., Barnes, D. E. & Yaffe, K. Dysthymia and depression increase risk of dementia and mortality among older veterans. Am. J. Geriatr. Psychiatry (in press).

  17. Hébert, R. et al. Vascular dementia: incidence and risk factors in the Canadian study of health and aging. Stroke 31, 1487–1493 (2000).

    Article  PubMed  Google Scholar 

  18. Wilson, R. S. et al. Depressive symptoms, cognitive decline, and risk of AD in older persons. Neurology 59, 364–370 (2002).

    Article  PubMed  Google Scholar 

  19. Fuhrer, R., Dufouil, C. & Dartigues, J. F. Exploring sex differences in the relationship between depressive symptoms and dementia incidence: prospective results from the PAQUID Study. J. Am. Geriatr. Soc. 51, 1055–1063 (2003).

    Article  PubMed  Google Scholar 

  20. Irie, F. et al. Apolipoprotein E ɛ4 allele genotype and the effect of depressive symptoms on the risk of dementia in men: the Honolulu–Asia Aging Study. Arch. Gen. Psychiatry 65, 906–912 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  21. Geerlings, M. I. et al. Depressive symptoms and risk of Alzheimer's disease in more highly educated older people. J. Am. Geriatr. Soc. 48, 1092–1097 (2000).

    Article  CAS  PubMed  Google Scholar 

  22. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  23. Lindsay, J. et al. Risk factors for Alzheimer's disease: a prospective analysis from the Canadian Study of Health and Aging. Am. J. Epidemiol. 156, 445–453 (2002).

    Article  PubMed  Google Scholar 

  24. Cankurtaran, M. et al. Risk factors and type of dementia: vascular or Alzheimer? Arch. Gerontol. Geriatr. 47, 25–34 (2008).

    Article  PubMed  Google Scholar 

  25. Zalsman, G. et al. Increased risk for dementia in elderly psychiatric inpatients with late-onset major depression. J. Nerv. Ment. Dis. 188, 242–243 (2000).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  27. Ownby, R. L. et al. Depression and risk for Alzheimer Disease: systematic review, meta-analysis, and metaregression analysis. Arch. Gen. Psychiatry 63, 530–538 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  28. Geerlings, M. I., den Heijer, T., Koudstaal, P. J., Hofman, A. & Breteler, M. M. History of depression, depressive symptoms, and medial temporal lobe atrophy and the risk of Alzheimer disease. Neurology 70, 1258–1264 (2008).

    Article  CAS  PubMed  Google Scholar 

  29. Dal Forno, G. et al. Depressive symptoms, sex, and risk for Alzheimer's disease. Ann. Neurol. 57, 381–387 (2005).

    Article  PubMed  Google Scholar 

  30. Dotson, V. M., Beydoun, M. A. & Zonderman, A. B. Recurrent depressive symptoms and the incidence of dementia and mild cognitive impairment. Neurology 75, 27–34 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  31. Barnes, D. E. et al. Mid-life versus late-life depression and risk of dementia: differential effects for vascular dementia and Alzheimer's disease [abstract]. Alzheimers Dement. 6 (Suppl. 1), S109 (2010).

    Google Scholar 

  32. Green, R. C. et al. Depression as a risk factor for Alzheimer disease: the MIRAGE Study. Arch. Neurol. 60, 753–759 (2003).

    Article  PubMed  Google Scholar 

  33. Alexopoulos, G. S. et al. “Vascular depression” hypothesis. Arch. Gen. Psychiatry 54, 915–922 (1997).

    Article  CAS  PubMed  Google Scholar 

  34. Krishnan, K. R. R., Hays, J. C. & Blazer, D. G. MRI-defined vascular depression. Am. J. Psychiatry 154, 497–500 (1997).

    Article  CAS  PubMed  Google Scholar 

  35. Alexopoulos, G. S. Depression in the elderly. Lancet 365, 1961–1970 (2005).

    Article  PubMed  Google Scholar 

  36. Alexopoulos, G. S. Vascular disease, depression, and dementia. J. Am. Geriatr. Soc. 51, 1178–1180 (2003).

    Article  PubMed  Google Scholar 

  37. Camus, V., Kraehenbuhl, H., Preisig, M., Bula, C. J. & Waeber, G. Geriatric depression and vascular diseases: what are the links? J. Affect. Disord. 81, 1–16 (2004).

    Article  PubMed  Google Scholar 

  38. Rao, R. Cerebrovascular disease and late life depression: an age old association revisited. Int. J. Geriatr. Psychiatry 15, 419–433 (2000).

    Article  CAS  PubMed  Google Scholar 

  39. de Groot, J. C. et al. Cerebral white matter lesions and depressive symptoms in elderly adults. Arch. Gen. Psychiatry 57, 1071–1076 (2000).

    Article  CAS  PubMed  Google Scholar 

  40. Thomas, A. J., Perry, R., Barber, R., Kalaria, R. N. & O'Brien, J. T. Pathologies and pathological mechanisms for white matter hyperintensities in depression. Ann. NY Acad. Sci. 977, 333–339 (2002).

    Article  PubMed  Google Scholar 

  41. Thomas, A. J., Kalaria, R. N. & O'Brien, J. T. Depression and vascular disease: what is the relationship? J. Affect. Disord. 79, 81–95 (2004).

    Article  PubMed  Google Scholar 

  42. Butters, M. A. et al. Pathways linking late-life depression to persistent cognitive impairment and dementia. Dialogues Clin. Neurosci. 10, 345–357 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  43. Liebetrau, M., Steen, B. & Skoog, I. Depression as a risk factor for the incidence of first-ever stroke in 85-year-olds. Stroke 39, 1960–1965 (2008).

    Article  PubMed  Google Scholar 

  44. Herrmann, L. L., Le Masurier, M. & Ebmeier, K. P. White matter hyperintensities in late life depression: a systematic review. J. Neurol. Neurosurg. Psychiatry 79, 619–624 (2008).

    Article  CAS  PubMed  Google Scholar 

  45. Steffens, D. C. et al. Cerebrovascular disease and evolution of depressive symptoms in the Cardiovascular Health Study. Stroke 33, 1636–1644 (2002).

    Article  PubMed  Google Scholar 

  46. Teodorczuk, A. et al. White matter changes and late-life depressive symptoms: longitudinal study. Br. J. Psychiatry 191, 212–217 (2007).

    Article  CAS  PubMed  Google Scholar 

  47. Flicker, L. Vascular factors in geriatric psychiatry: time to take a serious look. Curr. Opin. Psychiatry 21, 551–554 (2008).

    Article  PubMed  Google Scholar 

  48. Flicker, L. Cardiovascular risk factors, cerebrovascular disease burden, and healthy brain aging. Clin. Geriatr. Med. 26, 17–27 (2010).

    Article  PubMed  Google Scholar 

  49. Alexopoulos, G. S. The vascular depression hypothesis: 10 years later. Biol. Psychiatry 60, 1304–1305 (2006).

    Article  PubMed  Google Scholar 

  50. Sheline, Y. I. et al. Regional white matter hyperintensity burden in automated segmentation distinguishes late-life depressed subjects from comparison subjects matched for vascular risk factors. Am. J. Psychiatry 165, 524–532 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  51. Sapolsky, R. M., Krey, L. C. & McEwen, B. S. The neuroendocrinology of stress and aging: the glucocorticoid cascade hypothesis. Endocr. Rev. 7, 284–301 (1986).

    Article  CAS  PubMed  Google Scholar 

  52. Sierksma, A. S., van den Hove, D. L., Steinbusch, H. W. & Prickaerts, J. Major depression, cognitive dysfunction and Alzheimer's disease: is there a link? Eur. J. Pharmacol. 626, 72–82 (2010).

    Article  CAS  PubMed  Google Scholar 

  53. Wolkowitz, O. M., Epel, E. S., Reus, V. I. & Mellon, S. H. Depression gets old fast: do stress and depression accelerate cell aging? Depress. Anxiety 27, 327–338 (2010).

    Article  CAS  PubMed  Google Scholar 

  54. Rothman, S. M. & Mattson, M. P. Adverse stress, hippocampal networks, and Alzheimer's disease. Neuromolecular Med. 12, 56–70 (2010).

    Article  CAS  PubMed  Google Scholar 

  55. van de Pol, L. A. et al. Hippocampal atrophy in Alzheimer disease: age matters. Neurology 66, 236–238 (2006).

    Article  CAS  PubMed  Google Scholar 

  56. O'Brien, J. T., Lloyd, A., McKeith, I., Gholkar, A. & Ferrier, N. A longitudinal study of hippocampal volume, cortisol levels, and cognition in older depressed subjects. Am. J. Psychiatry 161, 2081–2090 (2004).

    Article  PubMed  Google Scholar 

  57. Videbech, P. & Ravnkilde, B. Hippocampal volume and depression: a meta-analysis of MRI studies. Am. J. Psychiatry 161, 1957–1966 (2004).

    Article  PubMed  Google Scholar 

  58. Colla, M. et al. Hippocampal volume reduction and HPA-system activity in major depression. J. Psychiatr. Res. 41, 553–560 (2007).

    Article  PubMed  Google Scholar 

  59. Cereseto, M. et al. Chronic treatment with high doses of corticosterone decreases cytoskeletal proteins in the rat hippocampus. Eur. J. Neurosci. 24, 3354–3364 (2006).

    Article  PubMed  Google Scholar 

  60. Park, C. R., Zoladz, P. R., Conrad, C. D., Fleshner, M. & Diamond, D. M. Acute predator stress impairs the consolidation and retrieval of hippocampus-dependent memory in male and female rats. Learn. Mem. 15, 271–280 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  61. Kim, J. J., Song, E. Y. & Kosten, T. A. Stress effects in the hippocampus: synaptic plasticity and memory. Stress 9, 1–11 (2006).

    Article  CAS  PubMed  Google Scholar 

  62. Pittenger, C. & Duman, R. S. Stress, depression, and neuroplasticity: a convergence of mechanisms. Neuropsychopharmacology 33, 88–109 (2008).

    Article  CAS  PubMed  Google Scholar 

  63. Caspi, A. et al. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 301, 386–389 (2003).

    Article  CAS  PubMed  Google Scholar 

  64. Charney, D. S. & Manji, H. K. Life stress, genes, and depression: multiple pathways lead to increased risk and new opportunities for intervention. Sci. STKE 225, re5 (2004).

    Google Scholar 

  65. Wolkowitz, O. M., Burke, H., Epel, E. S. & Reus, V. I. Glucocorticoids. Mood, memory, and mechanisms. Ann. NY Acad. Sci. 1179, 19–40 (2009).

    Article  CAS  PubMed  Google Scholar 

  66. Swaab, D. F., Bao, A. M. & Lucassen, P. J. The stress system in the human brain in depression and neurodegeneration. Ageing Res. Rev. 4, 141–194 (2005).

    Article  CAS  PubMed  Google Scholar 

  67. Hickie, I. et al. Reduced hippocampal volumes and memory loss in patients with early- and late-onset depression. Br. J. Psychiatry 186, 197–202 (2005).

    Article  PubMed  Google Scholar 

  68. Steffens, D. C., McQuoid, D. R., Payne, M. E. & Potter, G. G. Change in hippocampal volume on magnetic resonance imaging and cognitive decline among older depressed and nondepressed subjects in the neurocognitive outcomes of depression in the elderly study. Am. J. Geriatr. Psychiatry 19, 4–12 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  69. Steffens, D. C. et al. Hippocampal volume and incident dementia in geriatric depression. Am. J. Geriatr. Psychiatry 10, 62–71 (2002).

    Article  PubMed  Google Scholar 

  70. Hastings, R. S., Parsey, R. V., Oquendo, M. A., Arango, V. & Mann, J. J. Volumetric analysis of the prefrontal cortex, amygdala, and hippocampus in major depression. Neuropsychopharmacology 29, 952–959 (2004).

    Article  PubMed  Google Scholar 

  71. Sheline, Y. I., Gado, M. H. & Kraemer, H. C. Untreated depression and hippocampal volume loss. Am. J. Psychiatry 160, 1516–1518 (2003).

    Article  PubMed  Google Scholar 

  72. MacQueen, G. M. et al. Course of illness, hippocampal function, and hippocampal volume in major depression. Proc. Natl Acad. Sci. USA 100, 1387–1392 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Maes, M. et al. The inflammatory & neurodegenerative (I&ND) hypothesis of depression: leads for future research and new drug developments in depression. Metab. Brain Dis. 24, 27–53 (2009).

    Article  CAS  PubMed  Google Scholar 

  74. Knable, M. B., Barci, B. M., Webster, M. J., Meador-Woodruff, J. & Torrey, E. F. Molecular abnormalities of the hippocampus in severe psychiatric illness: postmortem findings from the Stanley Neuropathology Consortium. Mol. Psychiatry 9, 609–620 (2004).

    Article  CAS  PubMed  Google Scholar 

  75. Karege, F., Vaudan, G., Schwald, M., Perroud, N. & La Harpe, R. Neurotrophin levels in postmortem brains of suicide victims and the effects of antemortem diagnosis and psychotropic drugs. Brain Res. Mol. Brain Res. 136, 29–37 (2005).

    Article  CAS  PubMed  Google Scholar 

  76. Morishima-Kawashima, M. & Ihara, Y. Alzheimer's disease: β-amyloid protein and tau. J. Neurosci. Res. 70, 392–401 (2002).

    Article  CAS  PubMed  Google Scholar 

  77. Rapp, M. A. et al. Increased neurofibrillary tangles in patients with Alzheimer disease with comorbid depression. Am. J. Geriatr. Psychiatry 16, 168–174 (2008).

    Article  PubMed  Google Scholar 

  78. Rapp, M. A. et al. Increased hippocampal plaques and tangles in patients with Alzheimer disease with a lifetime history of major depression. Arch. Gen. Psychiatry 63, 161–167 (2006).

    Article  PubMed  Google Scholar 

  79. Hardy, J. & Selkoe, D. J. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297, 353–356 (2002).

    Article  CAS  PubMed  Google Scholar 

  80. Leinonen, V. et al. Amyloid and tau proteins in cortical brain biopsy and Alzheimer's disease. Ann. Neurol. 68, 446–453 (2010).

    Article  CAS  PubMed  Google Scholar 

  81. Green, K. N., Billings, L. M., Roozendaal, B., McGaugh, J. L. & LaFerla, F. M. Glucocorticoids increase amyloid-β and tau pathology in a mouse model of Alzheimer's disease. J. Neurosci. 26, 9047–9056 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Cho, S. & Hu, Y. Activation of 5-HT4 receptors inhibits secretion of beta-amyloid peptides and increases neuronal survival. Exp. Neurol. 203, 274–278 (2007).

    Article  CAS  PubMed  Google Scholar 

  83. Lezoualc'h, F. 5-HT4 receptor and Alzheimer's disease: the amyloid connection. Exp. Neurol. 205, 325–329 (2007).

    Article  CAS  PubMed  Google Scholar 

  84. Sun, X. et al. Amyloid-associated depression: a prodromal depression of Alzheimer disease? Arch. Gen. Psychiatry 65, 542–550 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Leonard, B. E. Inflammation, depression and dementia: are they connected? Neurochem. Res. 32, 1749–1756 (2007).

    Article  CAS  PubMed  Google Scholar 

  86. Rojo, L. E., Fernández, J. A., Maccioni, A. A., Jimenez, J. M. & Maccioni, R. B. Neuroinflammation: implications for the pathogenesis and molecular diagnosis of Alzheimer's disease. Arch. Med. Res. 39, 1–16 (2008).

    Article  CAS  PubMed  Google Scholar 

  87. Sorrells, S. F. & Sapolsky, R. M. An inflammatory review of glucocorticoid actions in the CNS. Brain Behav. Immun. 21, 259–272 (2007).

    Article  CAS  PubMed  Google Scholar 

  88. Yaffe, K. et al. Inflammatory markers and cognition in well-functioning African-American and white elders. Neurology 61, 76–80 (2003).

    Article  CAS  PubMed  Google Scholar 

  89. Maccioni, R. B., Rojo, L. E., Fernández, J. A. & Kuljis, R. O. The role of neuroimmunomodulation in Alzheimer's disease. Ann. NY Acad. Sci. 1153, 240–246 (2009).

    Article  CAS  PubMed  Google Scholar 

  90. Okello, A. et al. Microglial activation and amyloid deposition in mild cognitive impairment: a PET study. Neurology 72, 56–62 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Streit, W. J., Braak, H., Xue, Q. S. & Bechmann, I. Dystrophic (senescent) rather than activated microglial cells are associated with tau pathology and likely precede neurodegeneration in Alzheimer's disease. Acta Neuropathol. 118, 475–485 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  92. Fumagalli, F. et al. Neurotrophic factors in neurodegenerative disorders: potential for therapy. CNS Drugs 22, 1005–1019 (2008).

    Article  PubMed  Google Scholar 

  93. Krishnan, V. & Nestler, E. J. The molecular neurobiology of depression. Nature 455, 894–902 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Angelucci, F., Brenè, S. & Mathé, A. A. BDNF in schizophrenia, depression and corresponding animal models. Mol. Psychiatry 10, 345–352 (2005).

    Article  CAS  PubMed  Google Scholar 

  95. Murer, M. G., Yan, Q. & Raisman-Vozari, R. Brain-derived neurotrophic factor in the control human brain, and in Alzheimer's disease and Parkinson's disease. Prog. Neurobiol. 63, 71–124 (2001).

    Article  CAS  PubMed  Google Scholar 

  96. Cotman, C. W. The role of neurotrophins in brain aging: a perspective in honor of Regino Perez-Polo. Neurochem. Res. 30, 877–881 (2005).

    Article  CAS  PubMed  Google Scholar 

  97. Benjamin, S. et al. The brain-derived neurotrophic factor Val66Met polymorphism, hippocampal volume, and cognitive function in geriatric depression. Am. J. Geriatr. Psychiatry 18, 323–331 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  98. Jessen, F. et al. No association of the Val66Met polymorphism of the brain-derived neurotrophic factor with hippocampal volume in major depression. Psychiatr. Genet. 19, 99–101 (2009).

    Article  PubMed  Google Scholar 

  99. Cotman, C. W., Berchtold, N. C. & Christie, L. A. Exercise builds brain health: key roles of growth factor cascades and inflammation. Trends Neurosci. 30, 464–472 (2007).

    Article  CAS  PubMed  Google Scholar 

  100. Alzheimer's Disease International. World Alzheimer Report 2010: The Global Economic Impact of Dementia. Alzheimer's Association—World Alzheimer's Day [online], (2010).

  101. Herrera-Guzman, I. et al. Effects of selective serotonin reuptake and dual serotonergic–noradrenergic reuptake treatments on memory and mental processing speed in patients with major depressive disorder. J. Psychiatr. Res. 43, 855–863 (2009).

    Article  PubMed  Google Scholar 

  102. Mowla, A., Mosavinasab, M. & Pani, A. Does fluoxetine have any effect on the cognition of patients with mild cognitive impairment? A double-blind, placebo-controlled, clinical trial. J. Clin. Psychopharmacol. 27, 67–70 (2007).

    Article  CAS  PubMed  Google Scholar 

  103. Doraiswamy, P. M. et al. Does antidepressant therapy improve cognition in elderly depressed patients? Gerontol. A Biol. Sci. Med. Sci. 58, M1137–M1144 (2003).

    Article  Google Scholar 

  104. Areán, P. A. et al. Problem-solving therapy and supportive therapy in older adults with major depression and executive dysfunction. Am. J. Psychiatry 167, 1391–1398 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  105. Hashioka, S., McGeer, P. L., Monji, A. & Kanba, S. Anti-inflammatory effects of antidepressants: possibilities for preventives against Alzheimer's disease. Cent. Nerv. Syst. Agents Med. Chem. 9, 12–19 (2009).

    Article  CAS  PubMed  Google Scholar 

  106. Groves, J. O. Is it time to reassess the BDNF hypothesis of depression? Mol. Psychiatry 12, 1079–1088 (2007).

    Article  CAS  PubMed  Google Scholar 

  107. Hashimoto, K., Shimizu, E. & Iyo, M. Critical role of brain-derived neurotrophic factor in mood disorders. Brain Res. Brain Res. Rev. 45, 104–114 (2004).

    Article  CAS  PubMed  Google Scholar 

  108. Nebes, R. D. et al. Persistence of cognitive impairment in geriatric patients following antidepressant treatment: a randomized, double-blind clinical trial with nortriptyline and paroxetine. J. Psychiatr. Res. 37, 99–108 (2003).

    Article  PubMed  Google Scholar 

  109. Bhalla, R. K. et al. Persistence of neuropsychologic deficits in the remitted state of late-life depression. Am. J. Geriatr. Psychiatry 14, 419–427 (2006).

    Article  PubMed  Google Scholar 

  110. Devanand, D. P. et al. Sertraline treatment of elderly patients with depression and cognitive impairment. Int. J. Geriatr. Psychiatry 18, 123–130 (2003).

    Article  CAS  PubMed  Google Scholar 

  111. Modrego, P. J. & Ferrández, J. Depression in patients with mild cognitive impairment increases the risk of developing dementia of Alzheimer type: a prospective cohort study. Arch. Neurol. 61, 1290–1293 (2004).

    Article  PubMed  Google Scholar 

  112. Pelton, G. H. et al. Randomized double-blind placebo-controlled donepezil augmentation in antidepressant-treated elderly patients with depression and cognitive impairment: a pilot study. Int. J. Geriatr. Psychiatry 23, 670–676 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  113. Bragin, V. et al. Integrated treatment approach improves cognitive function in demented and clinically depressed patients. Am. J. Alzheimers Dis. Other Demen. 20, 21–26 (2005).

    Article  PubMed  Google Scholar 

  114. Lyketsos, C. G. & Lee, H. B. Diagnosis and treatment of depression in Alzheimer's disease. A practical update for the clinician. Dement. Geriatr. Cogn. Disord. 17, 55–64 (2004).

    Article  PubMed  Google Scholar 

  115. Lyketsos, C. G. et al. Treating depression in Alzheimer disease: efficacy and safety of sertraline therapy, and the benefits of depression reduction: the DIADS. Arch. Gen. Psychiatry 60, 737–746 (2003).

    Article  CAS  PubMed  Google Scholar 

  116. Bains, J., Birks, J. S. & Dening, T. R. The efficacy of antidepressants in the treatment of depression in dementia. Cochrane Database of Systematic Reviews. Issue 4. Art. No.: CD003944 doi:10.1002/14651858.CD003944 (2002).

  117. Weintraub, D. et al. Sertraline for the treatment of depression in Alzheimer disease: week-24 outcomes. Am. J. Geriatr. Psychiatry 18, 332–340 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  118. Rosenberg, P. B. et al. Sertraline for the treatment of depression in Alzheimer disease. Am. J. Geriatr Psychiatry 18, 136–145 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  119. Zweig, R. M. et al. The neuropathology of aminergic nuclei in Alzheimer's disease. Ann. Neurol. 24, 233–242 (1988).

    Article  CAS  PubMed  Google Scholar 

  120. Zubenko, G. S. Biological correlates of clinical heterogeneity in primary dementia. Neuropsychopharmacology 6, 77–93 (1992).

    CAS  PubMed  Google Scholar 

  121. Förstl, H. et al. Clinical and neuropathological correlates of depression in Alzheimer's disease. Psychol. Med. 22, 877–884 (1992).

    Article  PubMed  Google Scholar 

  122. Brookmeyer, R., Johnson, E., Ziegler-Graham, K. & Arrighi, H. M. Forecasting the global burden of Alzheimer's disease. Alzheimers Dement. 3, 186–191 (2007).

    Article  PubMed  Google Scholar 

  123. Copeland, J. R. M., Dewey, M. E. & Griffiths-Jones, H. M. Dementia and depression in elderly persons: AGECAT compared with DSMII and pervasive illness. Int. J. Geriatr. Psychiatry 5, 47–51 (1990).

    Article  Google Scholar 

  124. Radloff, L. S. The CES-D scale: a self-report depression scale for research in the general population. Appl. Psycho. Meas. 1, 385–401 (1977).

    Article  Google Scholar 

  125. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th edn (American Psychiatric Association, Washington, DC, 1994).

  126. Yesavage, J. A. et al. Development and validation of a geriatric depression screening scale. A preliminary report. J. Psychiatr. Res. 17, 37–49 (1982–1983).

    Article  PubMed  Google Scholar 

  127. Hooijer, C. et al. A standardized interview for the elderly (GMS): reliability studies comparing the Dutch language version with the original. Int. J. Geriatr. Psychiatry 6, 71–79 (1991).

    Article  Google Scholar 

  128. Copeland, J. R. et al. The Geriatric Mental State Examination in the 21st century. Int. J. Geriatr. Psychiatry 17, 729–732 (2002).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by the National Institute of Mental Health (grant K01 MH079093 to A. L. Byers and R01 MH086498 to K. Yaffe) and the National Institute on Aging (grant K24 AG031155 to K. Yaffe).

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A. L. Byers researched data for, and wrote, the article. A. L. Byers and K. Yaffe made equal contributions to discussions, reviewing and editing the article.

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Byers, A., Yaffe, K. Depression and risk of developing dementia. Nat Rev Neurol 7, 323–331 (2011). https://doi.org/10.1038/nrneurol.2011.60

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