Skip to main content Accessibility help

Cross-sectional and prospective inter-relationships between depressive symptoms, vascular disease and cognition in older adults

  • Louise Mewton (a1), Simone Reppermund (a2) (a3), John Crawford (a2), David Bunce (a2) (a4), Wei Wen (a2) (a5) and Perminder Sachdev (a2) (a5)...



It has been proposed that vascular disease is the mechanism linking depression and cognition, but prospective studies have not supported this hypothesis. This study aims to investigate the inter-relationships between depressive symptoms, cognition and cerebrovascular disease using a well-characterised prospective cohort.


Data came from waves 1 (2005–2007) and 2 (2007–2009) of the Sydney Memory and Ageing Study (n = 462; mean age = 78.3 years).


At wave 1, there was an association between depressive symptoms and white matter hyperintensity (WMH) volume [b = 0.016, t(414) = 2.34, p = 0.020]. Both depressive symptoms [b = −0.058, t(413) = −2.64, p = 0.009] and WMH volume [b = −0.011, t(413) = −3.77, p < 0.001], but not stroke/transient ischaemic attack (TIA) [b = −0.328, t(413) = −1.90, p = 0.058], were independently associated with lower cognition. Prospectively, cerebrovascular disease was not found to predict increasing depressive symptoms [stroke/TIA: b = −0.349, t(374.7) = −0.76, p = 0.448; WMH volume: b = 0.007, t(376.3) = 0.875, p = 0.382]. Depressive symptoms predicted increasing WMH severity [b = 0.012, t(265.9) = −3.291, p = 0.001], but not incident stroke/TIA (odds ratio = 0.995; CI 0.949–1.043; p = 0.820). When examined in separate models, depressive symptoms [b = −0.027, t(373.5) = −2.16, p = 0.032] and a history of stroke/TIA [b = −0.460, t(361.2) = −4.45, p < 0.001], but not WMH volume [b = 0.001, t(362.3) = −0.520, p = 0.603], predicted declines in cognition. When investigated in a combined model, a history of stroke/TIA remained a predictor of cognitive decline [b = −0.443, t(360.6) = −4.28, p < 0.001], whilst depressive symptoms did not [b = −0.012, t(359.7) = −0.96, p = 0.336].


This study is contrasted with previous prospective studies which indicate that depressive symptoms predict cognitive decline independently of vascular disease. Future research should focus on further exploring the vascular mechanisms underpinning the relationship between depressive symptoms and cognition.


Corresponding author

Author for correspondence: Louise Mewton, E-mail:,


Hide All
Alexopoulos, GS, Meyers, BS, Young, RC, Campbell, S, Silbersweig, D and Charlson, M (1997 a) ‘Vascular depression’ hypothesis. Archives of General Psychiatry 54, 915.
Alexopoulos, GS, Meyers, BS, Young, RC, Kakuma, T, Silbersweig, D and Charlson, M (1997 b) Clinically defined vascular depression. American Journal of Psychiatry 154, 562565.
Alexopoulos, GS, Meyers, BS, Young, RC, Kalayam, B, Kakuma, T, Gabrielle, M, Sirey, JA and Hull, J (2000) Executive dysfunction and long-term outcomes of geriatric depression. Archives of General Psychiatry 57, 285290.
Alexopoulos, GS, Kiosses, DN, Murphy, C and Heo, M (2004) Executive dysfunction, heart disease burden, and remission of geriatric depression. Neuropsychopharmacology 29, 22782284.
Alexopoulos, GS, Raue, PJ, Kiosses, DN, Mackin, RS, Kanellopoulos, D, Mcculloch, C and Areán, PA (2011) Problem-solving therapy and supportive therapy in older adults with major depression and executive dysfunction: effect on disability. Archives of General Psychiatry 68, 3341.
Areán, PA, Raue, P, Mackin, RS, Kanellopoulos, D, Mcculloch, C and Alexopoulos, GS (2010) Problem-solving therapy and supportive therapy in older adults with major depression and executive dysfunction. American Journal of Psychiatry 167, 13911398.
Ayerbe, L, Ayis, S, Wolfe, CD and Rudd, AG (2013) Natural history, predictors and outcomes of depression after stroke: systematic review and meta-analysis. The British Journal of Psychiatry 202, 1421.
Baldwin, R, Jeffries, S, Jackson, A, Sutcliffe, C, Thacker, N, Scott, M and Burns, A (2004) Treatment response in late-onset depression: relationship to neuropsychological, neuroradiological and vascular risk factors. Psychological Medicine 34, 125136.
Barch, DM, D'Angelo, G, Pieper, C, Wilkins, CH, Welsh-Bohmer, K, Taylor, W, Garcia, KS, Gersing, K, Doraiswamy, PM and Sheline, YI (2012) Cognitive improvement following treatment in late-life depression: relationship to vascular risk and age of onset. The American Journal of Geriatric Psychiatry 20, 682690.
Barnes, DE and Yaffe, K (2011) The projected effect of risk factor reduction on Alzheimer's disease prevalence. The Lancet Neurology 10, 819828.
Barnes, DE, Alexopoulos, GS, Lopez, OL, Williamson, JD and Yaffe, K (2006) Depressive symptoms, vascular disease, and mild cognitive impairment: findings from the Cardiovascular Health Study. Archives of General Psychiatry 63, 273279.
Beekman, A, Deeg, D, Braam, A, Smit, J and Van Tilburg, W (1997) Consequences of major and minor depression in later life: a study of disability, well-being and service utilization. Psychological Medicine 27, 13971409.
Benton, AL (1967) Problems of test construction in the field of aphasia. Cortex 3, 3258.
Benton, AL, Sivan, AB and Spreen, O (1966) Der Benton Test, 7th Edn. Bern: Huber.
Brickman, AM, Muraskin, J and Zimmerman, ME (2009) Structural neuroimaging in Alzheimer's disease: do white matter hyperintensities matter? Dialogues in Clinical Neuroscience 11, 181.
Brink, T (1982) Geriatric depression and hypochondriasis: incidence, interaction, assessment and treatment. Psychotherapy: Theory, Research & Practice 19, 506.
Bunce, D, Batterham, PJ, Christensen, H and Mackinnon, AJ (2014) Causal associations between depression symptoms and cognition in a community-based cohort of older adults. The American Journal of Geriatric Psychiatry 22, 15831591.
Butters, MA, Becker, JT, Nebes, RD, Zmuda, MD, Mulsant, BH, Pollock, BG and Reynolds, CF III (2000) Changes in cognitive functioning following treatment of late-life depression. American Journal of Psychiatry 157, 19491954.
Butters, MA, Whyte, EM, Nebes, RD, Begley, AE, Dew, MA, Mulsant, BH, Zmuda, MD, Bhalla, R, Meltzer, CC and Pollock, BG (2004) The nature and determinants of neuropsychological functioning in late-life depression. Archives of General Psychiatry 61, 587595.
Byers, AL and Yaffe, K (2011) Depression and risk of developing dementia. Nature Reviews Neurology 7, 323331.
Debette, S and Markus, H (2010) The clinical importance of white matter hyperintensities on brain magnetic resonance imaging: systematic review and meta-analysis. The British Medical Journal 341, c3666.
Fang, J and Cheng, Q (2009) Etiological mechanisms of post-stroke depression: a review. Neurological Research 31, 904909.
Fastenau, PS, Denburg, NL and Mauer, BA (1998) Parallel short forms for the Boston Naming Test: psychometric properties and norms for older adults. Journal of Clinical and Experimental Neuropsychology 20, 828834.
Ferketich, AK, Schwartzbaum, JA, Frid, DJ and Moeschberger, ML (2000) Depression as an antecedent to heart disease among women and men in the NHANES I study. Archives of Internal Medicine 160, 12611268.
Ferrari, AJ, Charlson, FJ, Norman, RE, Patten, SB, Freedman, G, Murray, CJ, Vos, T and Whiteford, HA (2013) Burden of depressive disorders by country, sex, age, and year: findings from the global burden of disease study 2010. PLoS Medicine 10, e1001547.
Folstein, MF, Folstein, SE and Mchugh, PR (1975) ‘Mini-mental state’: a practical method for grading the cognitive state of patients for the clinician. Journal of Psychiatric Research 12, 189198.
Freiheit, EA, Hogan, DB, Eliasziw, M, Patten, SB, Demchuk, AM, Faris, P, Anderson, T, Galbraith, D, Parboosingh, JS and Ghali, WA (2012) A dynamic view of depressive symptoms and neurocognitive change among patients with coronary artery disease. Archives of General Psychiatry 69, 244255.
Goodkind, MS, Gallagher-Thompson, D, Thompson, LW, Kesler, SR, Anker, L, Flournoy, J, Berman, MP, Holland, JM and O'Hara, RM (2015) The impact of executive function on response to cognitive behavioral therapy in late-life depression. International Journal of Geriatric Psychiatry 31, 334339.
Gordon, WA and Hibbard, MR (1997) Poststroke depression: an examination of the literature. Archives of Physical Medicine and Rehabilitation 78, 658663.
Hackett, ML and Pickles, K (2014) Part I: frequency of depression after stroke: an updated systematic review and meta-analysis of observational studies. International Journal of Stroke 9, 10171025.
Herrmann, N, Mittmann, N, Silver, IL, Shulman, KI, Busto, UA, Shear, NH and Naranjo, CA (1996) A validation study of the Geriatric Depression Scale short form. International Journal of Geriatric Psychiatry 11, 457460.
Jorge, RE, Moser, DJ, Acion, L and Robinson, RG (2008) Treatment of vascular depression using repetitive transcranial magnetic stimulation. Archives of General Psychiatry 65, 268276.
Kalayam, B and Alexopoulos, GS (1999) Prefrontal dysfunction and treatment response in geriatric depression. Archives of General Psychiatry 56, 713718.
Kaplan, E, Goodglass, H and Weintraub, S (2001) The Boston Naming Test. Baltimore: Lippincott, Williams & Wilkins.
Khalaf, A, Edelman, K, Tudorascu, D, Andreescu, C, Reynolds, CF and Aizenstein, H (2015) White matter hyperintensity accumulation during treatment of late-life depression. Neuropsychopharmacology 40, 30273035.
Krishnan, K, Hays, JC and Blazer, DG (1997) MRI-defined vascular depression. American Journal of Psychiatry 154, 497501.
Leblanc, GG, Meschia, JF, Stuss, DT and Hachinski, V (2006) Genetics of vascular cognitive impairment. Stroke 37, 248255.
Liebetrau, M, Steen, B and Skoog, I (2008) Depression as a risk factor for the incidence of first-ever stroke in 85-year-olds. Stroke 39, 19601965.
Luchsinger, JA, Honig, LS, Tang, MX and Devanand, DP (2008) Depressive symptoms, vascular risk factors, and Alzheimer's disease. International Journal of Geriatric Psychiatry 23, 922928.
Lutz, W, Sanderson, W and Scherbov, S (2008) The coming acceleration of global population ageing. Nature 451, 716.
Mclennan, SN and Mathias, JL (2010) The depression-executive dysfunction (DED) syndrome and response to antidepressants: a meta-analytic review. International Journal of Geriatric Psychiatry 25, 933944.
Morimoto, SS, Gunning, FM, Murphy, CF, Kanellopoulos, D, Kelly, RE and Alexopoulos, GS (2011) Executive function and short-term remission of geriatric depression: the role of semantic strategy. The American Journal of Geriatric Psychiatry 19, 115122.
Murray, CJ, Vos, T, Lozano, R, Naghavi, M, Flaxman, AD, Michaud, C, Ezzati, M, Shibuya, K, Salomon, JA and Abdalla, S (2012) Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010. The Lancet 380, 21972223.
Nakano, Y, Baba, H, Maeshima, H, Kitajima, A, Sakai, Y, Baba, K, Suzuki, T, Mimura, M and Arai, H (2008) Executive dysfunction in medicated, remitted state of major depression. Journal of Affective Disorders 111, 4651.
Nebes, RD, Butters, M, Mulsant, B, Pollock, B, Zmuda, M, Houck, P and Reynolds, C (2000) Decreased working memory and processing speed mediate cognitive impairment in geriatric depression. Psychological Medicine 30, 679691.
Nebes, RD, Pollock, BG, Houck, PR, Butters, MA, Mulsant, BH, Zmuda, MD and Reynolds, CF (2003) Persistence of cognitive impairment in geriatric patients following antidepressant treatment: a randomized, double-blind clinical trial with nortriptyline and paroxetine. Journal of Psychiatric Research 37, 99108.
O'Brien, JT, Lloyd, A, Mckeith, I, Gholkar, A and Ferrier, N (2004) A longitudinal study of hippocampal volume, cortisol levels, and cognition in older depressed subjects. American Journal of Psychiatry 161, 20812090.
Pan, A, Sun, Q, Okereke, OI, Rexrode, KM and Hu, FB (2011) Depression and risk of stroke morbidity and mortality: a meta-analysis and systematic review. JAMA 306, 12411249.
Prince, M, Bryce, R, Albanese, E, Wimo, A, Ribeiro, W and Ferri, CP (2013) The global prevalence of dementia: a systematic review and metaanalysis. Alzheimer's & Dementia 9, 6375, e2.
Prince, MJ, Wu, F, Guo, Y, Robledo, LMG, O'Donnell, M, Sullivan, R and Yusuf, S (2015) The burden of disease in older people and implications for health policy and practice. The Lancet 385, 549562.
Prins, ND and Scheltens, P (2015) White matter hyperintensities, cognitive impairment and dementia: an update. Nature Reviews Neurology 11, 157166.
Prins, ND, Van Dijk, EJ, Den Heijer, T, Vermeer, SE, Jolles, J, Koudstaal, PJ, Hofman, A and Breteler, MM (2005) Cerebral small-vessel disease and decline in information processing speed, executive function and memory. Brain 128, 20342041.
Reitan, RM and Wolfson, D (1993) The Halstead-Reitan Neuropsychological Test Battery: Theory and Clinical Interpretation, 2nd Edn. Tucson, AZ: Neuropsychology Press.
Reppermund, S and Tsang, RSM (2016) The risk relationship between depression and CVD during ageing. In Baune, B and Tully, P (eds), Cardiovascular Diseases and Depression. Cham: Springer.
Reppermund, S, Brodaty, H, Crawford, J, Kochan, N, Slavin, M, Trollor, J, Draper, B and Sachdev, P (2011) The relationship of current depressive symptoms and past depression with cognitive impairment and instrumental activities of daily living in an elderly population: The Sydney Memory and Ageing Study. Journal of Psychiatric Research 45, 16001607.
Reppermund, S, Zhuang, L, Wen, W, Slavin, MJ, Trollor, JN, Brodaty, H and Sachdev, PS (2014) White matter integrity and late-life depression in community-dwelling individuals: diffusion tensor imaging study using tract-based spatial statistics. The British Journal of Psychiatry 205, 315320.
Rey, A (1964) L'Examen Clinique en Psychologie. Paris: Presses Universitaires de France.
Robinson, RG and Jorge, RE (2015) Post-stroke depression: a review. American Journal of Psychiatry 173, 221231.
Sachdev, PS, Brodaty, H, Reppermund, S, Kochan, NA, Trollor, JN, Draper, B, Slavin, MJ, Crawford, J, Kang, K and Broe, GA (2010) The Sydney Memory and Ageing Study (MAS): methodology and baseline medical and neuropsychiatric characteristics of an elderly epidemiological non-demented cohort of Australians aged 70–90 years. International Psychogeriatrics 22, 12481264.
Saczynski, JS, Beiser, A, Seshadri, S, Auerbach, S, Wolf, P and Au, R (2010) Depressive symptoms and risk of dementia The Framingham Heart Study. Neurology 75, 3541.
Salaycik, KJ, Kelly-Hayes, M, Beiser, A, Nguyen, A-H, Brady, SM, Kase, CS and Wolf, PA (2007) Depressive symptoms and risk of stroke. Stroke 38, 1621.
Sheline, YI, Pieper, CF, Barch, DM, Welsh-Boehmer, K, Mckinstry, RC, Macfall, JR, D'Angelo, G, Garcia, KS, Gersing, K and Wilkins, C (2010) Support for the vascular depression hypothesis in late-life depression: results of a 2-site, prospective, antidepressant treatment trial. Archives of General Psychiatry 67, 277285.
Sneed, JR and Culang-Reinlieb, ME (2011) The vascular depression hypothesis: an update. The American Journal of Geriatric Psychiatry 19, 99.
Sneed, JR, Culang-Reinlieb, ME, Brickman, AM, Gunning-Dixon, FM, Johnert, L, Garcon, E and Roose, SP (2011) MRI signal hyperintensities and failure to remit following antidepressant treatment. Journal of Affective Disorders 135, 315320.
Spreen, O and Bennett, D 1969 Neurosensory Centre Comprehensive Examination for Aphasia Manual (NCCEA). Victoria: University of Victoria.
Taylor, WD, Aizenstein, HJ and Alexopoulos, GS (2013) The vascular depression hypothesis: mechanisms linking vascular disease with depression. Molecular Psychiatry 18, 963974.
Valkanova, V and Ebmeier, KP (2013) Vascular risk factors and depression in later life: a systematic review and meta-analysis. Biological Psychiatry 73, 406413.
Van Agtmaal, MJ, Houben, AJ, Pouwer, F, Stehouwer, CD and Schram, MT (2017) Association of microvascular dysfunction with late-life depression: a systematic review and meta-analysis. JAMA Psychiatry 74, 729739.
Van Der Kooy, K, Van Hout, H, Marwijk, H, Marten, H, Stehouwer, C and Beekman, A (2007) Depression and the risk for cardiovascular diseases: systematic review and meta analysis. International Journal of Geriatric Psychiatry 22, 613626.
Van Sloten, TT, Sigurdsson, S, Van Buchem, MA, Phillips, CL, Jonsson, PV, Ding, J, Schram, MT, Harris, TB, Gudnason, V and Launer, LJ (2015) Cerebral small vessel disease and association with higher incidence of depressive symptoms in a general elderly population: the AGES-Reykjavik Study. American Journal of Psychiatry 172, 570578.
Van Uden, IW, Van Der Holst, HM, Van Leijsen, EM, Tuladhar, AM, Van Norden, AG, De Laat, KF, Claassen, JA, Van Dijk, EJ, Kessels, RP and Richard, E (2016) Late-onset depressive symptoms increase the risk of dementia in small vessel disease. Neurology 87, 11021109.
Vemuri, P, Lesnick, TG, Przybelski, SA, Knopman, DS, Preboske, GM, Kantarci, K, Raman, MR, Machulda, MM, Mielke, MM and Lowe, VJ (2015) Vascular and amyloid pathologies are independent predictors of cognitive decline in normal elderly. Brain 138, 761771.
Verdelho, A, Madureira, S, Moleiro, C, Ferro, JM, T O'Brien, J, Poggesi, A, Pantoni, L, Fazekas, F, Scheltens, P and Waldemar, G (2013) Depressive symptoms predict cognitive decline and dementia in older people independently of cerebral white matter changes: the LADIS study. Journal of Neurology, Neurosurgery & Psychiatry 84, 12501254.
Vermeer, SE, Prins, ND, Den Heijer, T, Hofman, A, Koudstaal, PJ and Breteler, MM (2003) Silent brain infarcts and the risk of dementia and cognitive decline. New England Journal of Medicine 348, 12151222.
Volkert, J, Schulz, H, Härter, M, Wlodarczyk, O and Andreas, S (2013) The prevalence of mental disorders in older people in Western countries – a meta-analysis. Ageing Research Reviews 12, 339353.
Wang, L, Leonards, CO, Sterzer, P and Ebinger, M (2014) White matter lesions and depression: a systematic review and meta-analysis. Journal of Psychiatric Research 56, 5664.
Wechsler, D 1981 WAIS-R Manual. New York: The Psychological Corporation.
Wechsler, D 1997 Wechsler Adult Intelligence Scale-III. San Antonio: The Psychological Corporation.
Weintraub, S, Salmon, D, Mercaldo, N, Ferris, S, Graff-Radford, NR, Chui, H, Cummings, J, Decarli, C, Foster, NL and Galasko, D (2009) The Alzheimer's disease centers’ uniform data set (UDS): the neuropsychological test battery. Alzheimer Disease and Associated Disorders 23, 91.
Wen, W, Sachdev, PS, Li, JJ, Chen, X and Anstey, KJ (2009) White matter hyperintensities in the forties: their prevalence and topography in an epidemiological sample aged 44–48. Human Brain Mapping 30, 11551167.
Whyte, EM and Mulsant, BH (2002) Post stroke depression: epidemiology, pathophysiology, and biological treatment. Biological Psychiatry 52, 253264.
Yesavage, JA, Brink, T, Rose, TL, Lum, O, Huang, V, Adey, M and Leirer, VO (1983) Development and validation of a geriatric depression screening scale: a preliminary report. Journal of Psychiatric Research 17, 3749.
Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Psychological Medicine
  • ISSN: 0033-2917
  • EISSN: 1469-8978
  • URL: /core/journals/psychological-medicine
Please enter your name
Please enter a valid email address
Who would you like to send this to? *



Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed