Review Article

Depression and risk of developing dementia

  • Nature Reviews Neurology volume 7, pages 323331 (2011)
  • doi:10.1038/nrneurol.2011.60
  • Download Citation
Published:

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.

  • Subscribe to Nature Reviews Neurology for full access:

    $199

    Subscribe

Additional access options:

Already a subscriber?  Log in  now or  Register  for online access.

References

  1. 1.

    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).

  2. 2.

    & The incidence of dementia: a meta-analysis. Neurology 51, 728–733 (1998).

  3. 3.

    , , , & Prevalence of dementia after age 90: results from the 90+ study. Neurology 71, 337–343 (2008).

  4. 4.

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

  5. 5.

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

  6. 6.

    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).

  7. 7.

    , , , & The prevalence, associations and symptoms of depression amongst dementia sufferers. J. Affect. Disord. 36, 135–144 (1996).

  8. 8.

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

  9. 9.

    & Geriatric depression and cognitive impairment. Psychol. Med. 38, 163–175 (2008).

  10. 10.

    & Depression and dementia. J. Neurol. Sci. 283, 139–142 (2009).

  11. 11.

    , , & Depression and Alzheimer's disease: neurobiological links and common pharmacological targets. Eur. J. Pharmacol. 626, 64–71 (2010).

  12. 12.

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

  13. 13.

    , , , & Depression and the risk of Alzheimer disease. Epidemiology 16, 233–238 (2005).

  14. 14.

    , , & Do depressive symptoms predict Alzheimer's disease and dementia? J. Gerontol. A Biol. Sci. Med. Sci. 60, 744–747 (2005).

  15. 15.

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

  16. 16.

    , , & Dysthymia and depression increase risk of dementia and mortality among older veterans. Am. J. Geriatr. Psychiatry (in press).

  17. 17.

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

  18. 18.

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

  19. 19.

    , & 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).

  20. 20.

    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).

  21. 21.

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

  22. 22.

    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).

  23. 23.

    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).

  24. 24.

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

  25. 25.

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

  26. 26.

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

  27. 27.

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

  28. 28.

    , , , & History of depression, depressive symptoms, and medial temporal lobe atrophy and the risk of Alzheimer disease. Neurology 70, 1258–1264 (2008).

  29. 29.

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

  30. 30.

    , & Recurrent depressive symptoms and the incidence of dementia and mild cognitive impairment. Neurology 75, 27–34 (2010).

  31. 31.

    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).

  32. 32.

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

  33. 33.

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

  34. 34.

    , & MRI-defined vascular depression. Am. J. Psychiatry 154, 497–500 (1997).

  35. 35.

    Depression in the elderly. Lancet 365, 1961–1970 (2005).

  36. 36.

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

  37. 37.

    , , , & Geriatric depression and vascular diseases: what are the links? J. Affect. Disord. 81, 1–16 (2004).

  38. 38.

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

  39. 39.

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

  40. 40.

    , , , & Pathologies and pathological mechanisms for white matter hyperintensities in depression. Ann. NY Acad. Sci. 977, 333–339 (2002).

  41. 41.

    , & Depression and vascular disease: what is the relationship? J. Affect. Disord. 79, 81–95 (2004).

  42. 42.

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

  43. 43.

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

  44. 44.

    , & White matter hyperintensities in late life depression: a systematic review. J. Neurol. Neurosurg. Psychiatry 79, 619–624 (2008).

  45. 45.

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

  46. 46.

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

  47. 47.

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

  48. 48.

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

  49. 49.

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

  50. 50.

    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).

  51. 51.

    , & The neuroendocrinology of stress and aging: the glucocorticoid cascade hypothesis. Endocr. Rev. 7, 284–301 (1986).

  52. 52.

    , , & Major depression, cognitive dysfunction and Alzheimer's disease: is there a link? Eur. J. Pharmacol. 626, 72–82 (2010).

  53. 53.

    , , & Depression gets old fast: do stress and depression accelerate cell aging? Depress. Anxiety 27, 327–338 (2010).

  54. 54.

    & Adverse stress, hippocampal networks, and Alzheimer's disease. Neuromolecular Med. 12, 56–70 (2010).

  55. 55.

    et al. Hippocampal atrophy in Alzheimer disease: age matters. Neurology 66, 236–238 (2006).

  56. 56.

    , , , & A longitudinal study of hippocampal volume, cortisol levels, and cognition in older depressed subjects. Am. J. Psychiatry 161, 2081–2090 (2004).

  57. 57.

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

  58. 58.

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

  59. 59.

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

  60. 60.

    , , , & Acute predator stress impairs the consolidation and retrieval of hippocampus-dependent memory in male and female rats. Learn. Mem. 15, 271–280 (2008).

  61. 61.

    , & Stress effects in the hippocampus: synaptic plasticity and memory. Stress 9, 1–11 (2006).

  62. 62.

    & Stress, depression, and neuroplasticity: a convergence of mechanisms. Neuropsychopharmacology 33, 88–109 (2008).

  63. 63.

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

  64. 64.

    & Life stress, genes, and depression: multiple pathways lead to increased risk and new opportunities for intervention. Sci. STKE 225, re5 (2004).

  65. 65.

    , , & Glucocorticoids. Mood, memory, and mechanisms. Ann. NY Acad. Sci. 1179, 19–40 (2009).

  66. 66.

    , & The stress system in the human brain in depression and neurodegeneration. Ageing Res. Rev. 4, 141–194 (2005).

  67. 67.

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

  68. 68.

    , , & 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).

  69. 69.

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

  70. 70.

    , , , & Volumetric analysis of the prefrontal cortex, amygdala, and hippocampus in major depression. Neuropsychopharmacology 29, 952–959 (2004).

  71. 71.

    , & Untreated depression and hippocampal volume loss. Am. J. Psychiatry 160, 1516–1518 (2003).

  72. 72.

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

  73. 73.

    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).

  74. 74.

    , , , & Molecular abnormalities of the hippocampus in severe psychiatric illness: postmortem findings from the Stanley Neuropathology Consortium. Mol. Psychiatry 9, 609–620 (2004).

  75. 75.

    , , , & 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).

  76. 76.

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

  77. 77.

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

  78. 78.

    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).

  79. 79.

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

  80. 80.

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

  81. 81.

    , , , & Glucocorticoids increase amyloid-β and tau pathology in a mouse model of Alzheimer's disease. J. Neurosci. 26, 9047–9056 (2006).

  82. 82.

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

  83. 83.

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

  84. 84.

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

  85. 85.

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

  86. 86.

    , , , & Neuroinflammation: implications for the pathogenesis and molecular diagnosis of Alzheimer's disease. Arch. Med. Res. 39, 1–16 (2008).

  87. 87.

    & An inflammatory review of glucocorticoid actions in the CNS. Brain Behav. Immun. 21, 259–272 (2007).

  88. 88.

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

  89. 89.

    , , & The role of neuroimmunomodulation in Alzheimer's disease. Ann. NY Acad. Sci. 1153, 240–246 (2009).

  90. 90.

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

  91. 91.

    , , & 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).

  92. 92.

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

  93. 93.

    & The molecular neurobiology of depression. Nature 455, 894–902 (2008).

  94. 94.

    , & BDNF in schizophrenia, depression and corresponding animal models. Mol. Psychiatry 10, 345–352 (2005).

  95. 95.

    , & Brain-derived neurotrophic factor in the control human brain, and in Alzheimer's disease and Parkinson's disease. Prog. Neurobiol. 63, 71–124 (2001).

  96. 96.

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

  97. 97.

    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).

  98. 98.

    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).

  99. 99.

    , & Exercise builds brain health: key roles of growth factor cascades and inflammation. Trends Neurosci. 30, 464–472 (2007).

  100. 100.

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

  101. 101.

    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).

  102. 102.

    , & 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).

  103. 103.

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

  104. 104.

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

  105. 105.

    , , & Anti-inflammatory effects of antidepressants: possibilities for preventives against Alzheimer's disease. Cent. Nerv. Syst. Agents Med. Chem. 9, 12–19 (2009).

  106. 106.

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

  107. 107.

    , & Critical role of brain-derived neurotrophic factor in mood disorders. Brain Res. Brain Res. Rev. 45, 104–114 (2004).

  108. 108.

    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).

  109. 109.

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

  110. 110.

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

  111. 111.

    & 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).

  112. 112.

    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).

  113. 113.

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

  114. 114.

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

  115. 115.

    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).

  116. 116.

    , & 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. 117.

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

  118. 118.

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

  119. 119.

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

  120. 120.

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

  121. 121.

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

  122. 122.

    , , & Forecasting the global burden of Alzheimer's disease. Alzheimers Dement. 3, 186–191 (2007).

  123. 123.

    , & Dementia and depression in elderly persons: AGECAT compared with DSMII and pervasive illness. Int. J. Geriatr. Psychiatry 5, 47–51 (1990).

  124. 124.

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

  125. 125.

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

  126. 126.

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

  127. 127.

    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).

  128. 128.

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

Download references

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).

Author information

Affiliations

  1. Department of Psychiatry, University of California, San Francisco and San Francisco Veterans Affairs Medical Center, 4150 Clement Street (116H), San Francisco, CA 94121, USA

    • Amy L. Byers
    •  & Kristine Yaffe

Authors

  1. Search for Amy L. Byers in:

  2. Search for Kristine Yaffe in:

Contributions

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.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Amy L. Byers.