Accessibility / Report Error

Effects of stress hormones on the brain and cognition: Evidence from normal to pathological aging

Efeitos dos hormônios do estresse no cérebro e cognição: evidências do envelhecimento normal ao patológico

Juliana Nery de Souza-Talarico Marie-France Marin Shireen Sindi Sonia J. Lupien About the authors


Several studies have demonstrated a wide cognitive variability among aged individuals. One factor thought to be associated with this heterogeneity is exposure to chronic stress throughout life. Animal and human evidence demonstrates that glucocorticoids (GCs), the main class of stress hormones, are strongly linked to memory performance whereby elevated GC levels are associated with memory performance decline in both normal and pathological cognitive aging. Accordingly, it is believed that GCs may increase the brain's vulnerability to the effects of internal and external insults, and thus may play a role in the development of age-related cognitive disorders such as Alzheimer's disease (AD). The aim of this review article was to investigate the effects of GCs on normal and pathological cognitive aging by showing how these hormones interact with different brain structures involved in cognitive abilities, subsequently worsen memory performance, and increase the risk for developing dementia.

Key words:
glucocorticoids; memory; aging; Alzheimer's disease


Vários estudos têm demonstrado uma ampla variabilidade cognitiva entre indivíduos idosos. Um dos fatores que tem sido associado com esta heterogeneidade é a exposição crônica ao estresse ao longo da vida. Evidências em humanos em animais têm mostrado que os glicocorticóides (GCs), principal classe de hormônios do estresse, estão fortemente associados com o desempenho da memória, sendo que concentrações elevadas de GCs está correlacionada com declínio da memória no envelhecimento cognitivo normal e patológico. Consequentemente, alguns autores têm proposto que os GCs podem aumentar a vulnerabilidade do cérebro aos efeitos de insultos internos e externos desempenhando, portanto, papel importante no desenvolvimento de transtornos cognitivos associados à idade como a doença de Alzheimer (AD). Este artigo de revisão discute os efeitos dos GCs no envelhecimento cognitivo normal e patológico demonstrando como estes hormônios interagem com diferentes estruturas cerebrais envolvidas em habilidades cognitivas e subsequentemente pioram o desempenho da memória e aumentam o risco para o desenvolvimento de demência.

glicocorticóides; memória; envelhecimento; doença de Alzheimer

Texto completo disponível apenas em PDF.

Full text available only in PDF format.


  • Reul JM, de Kloet ER. Two receptor systems for corticosterone in rat brain: microdistribution and differential occupation. Endocrinology 1985;117:2505-2511.
  • de Kloet ER, Oitzl MS, Joels M. Stress and cognition: are corticosteroids good or bad guys? Trends Neurosci 1999;22: 422-426.
  • Diorio D, Viau V, Meaney MJ. The role of the medial prefrontal cortex (cingulate gyrus) in the regulation of hypothalamic-pituitary-adrenal responses to stress. J Neurosci 1993;13:3839-3847.
  • McGh JL. Memory: a century of consolidation. Science 2000 14;287(5451):248-251.
  • Beckner VE, Tucker DM, Delville Y, Mohr DC. Stress facilitates consolidation of verbal memory for a film but does not affect retrieval. Behav Neurosci 2006;120:518-527.
  • Schwabe L, Bohringer A, Chatterjee M, Schachinger H. Effects of pre-learning stress on memory for neutral, positive and negative words: different roles of cortisol and autonomic arousal. Neurobiol Learn Mem 2008;90:44-53.
  • Maheu FS, Joober R, Beaulieu S, Lupien SJ. Differential effects of adrenergic and corticosteroid hormonal systems on human short- and long-term larative memory for emotionally arousing material. Behav Neurosci 2004;118:420-428.
  • Buchanan TW, Tranel D. Stress and emotional memory retrieval: effects of sex and cortisol response. Neurobiol Learn Mem 2008;89:134-141.
  • Buchanan TW, Tranel D, Adolphs R. Impaired memory retrieval correlates with individual differences in cortisol response but not autonomic response. Learn Mem 2006;13:382-387.
  • Het S, Ramlow G, Wolf OT. A meta-analytic review of the effects of acute cortisol administration on human memory. Psychoneuroendocrinology 2005;30:771-784.
  • Lupien SJ, Wilkinson CW, Briere S, Menard C, Ng Ying Kin NM, Nair NP. The modulatory effects of corticosteroids on cognition: studies in young human populations. Psychoneuroendocrinology 2002;27:401-416.
  • Lupien SJ, McEwen BS. The acute effects of corticosteroids on cognition: integration of animal and human model studies. Brain Res Brain Res Rev 1997;24:1-27.
  • Baddeley A. The episodic buffer: a new component of working memory? Trends Cogn Sci 2000;4:417-423.
  • Lupien SJ, Gillin CJ, Her RL. Working memory is more sensitive than larative memory to the acute effects of corticosteroids: a dose-response study in humans. Behav Neurosci 1999;113:420-430.
  • Oei NY, Everaerd WT, Elzinga BM, van Well S, Bermond B. Psychosocial stress impairs working memory at high loads: an association with cortisol levels and memory retrieval. Stress 2006;9:133-141.
  • Van Cauter E, Leproult R, Kupfer DJ. Effects of gender and age on the levels and circadian rhythmicity of plasma cortisol. J Clin Endocr Metab 1996;81:2468-2473.
  • Touitou Y, Sulon J, Bogdan A, et al. Adrenal circadian system in young and elderly human subjects: a comparative study. J Endocrinol 1982;93:201-210.
  • Sharma M, Palacios-Bois J, Schwartz G, et al. Circadian rhythms of melatonin and cortisol in aging. Biol Psychiatry 1989;25:305-319.
  • Drafta D, Schindler AE, Stroe E, Neacsu E. Age-related changes of plasma steroids in normal adult males. J Steroid Biochem 1982;17:683-687.
  • Sherman B, Wysham C, Pfohl B. Age-related changes in the circadian rhythm of plasma cortisol in man. J Clin Endocrinol Metab 1985;61:439-443.
  • Waltman C, Blackman MR, Chrousos GP, Riemann C, Harman SM. Spontaneous and glucocorticoid-inhibited adrenocorticotropic hormone and cortisol secretion are similar in healthy young and old men. J Clin Endocr Metab 1991;73:495-502.
  • Lupien S, Lecours AR, Schwartz G, et al. Longitudinal study of basal cortisol levels in healthy elderly subjects: evidence for subgroups. Neurobiol Aging 1996;17:95-105.
  • Lee BK, Glass TA, McAtee MJ, et al. Associations of salivary cortisol with cognitive function in the Baltimore memory study. Arch Gen Psychiat 2007;64:810-818.
  • Wilkinson CW, Peskind ER, Raskind MA. Reased hypothalamic-pituitary-adrenal axis sensitivity to cortisol feedback inhibition in human aging. Neuroendocrinology 1997; 65:79-90.
  • Otte C, Yassouridis A, Jahn H, et al. Mineralocorticoid receptor-mediated inhibition of the hypothalamic-pituitary-adrenal axis in aged humans. J Gerontol Biol 2003;58:900-905.
  • Boscaro M, Paoletta A, Scarpa E, et al. Age-related changes in glucocorticoid fast feedback inhibition of adrenocorticotropin in man. J Clin Endocr Metab 1998;83:1380-1383.
  • O'Brien JT, Schweitzer I, Ames D, Tuckwell V, Mastwyk M. Cortisol suppression by dexamethasone in the healthy elderly: effects of age, dexamethasone levels, and cognitive function. Biol Psychiatry 1994;36:389-394.
  • Seeman TE, Berkman LF, Gulanski BI, et al. Self-esteem and neuroendocrine response to challenge: MacArthur studies of successful aging. J Psychosom Res 1995;39:69-84.
  • Gotthardt U, Schweiger U, Fahrenberg J, Lauer CJ, Holsboer F, Heuser I. Cortisol, ACTH, and cardiovascular response to a cognitive challenge paradigm in aging and depression. Am J Physiol 1995;268:R865-873.
  • Nicolson N, Storms C, Ponds R, Sulon J. Salivary cortisol levels and stress reactivity in human aging. J Gerontol A Biol Sci Med Sci 1997;52:M68-75.
  • Kudielka BM, Schmidt-Reinwald AK, Hellhammer DH, Schurmeyer T, Kirschbaum C. Psychosocial stress and HPA functioning: no evidence for a reduced resilience in healthy elderly men. Stress 2000;3:229-240.
  • Landfield PW, Baskin RK, Pitler TA. Brain aging correlates: retardation by hormonal-pharmacological treatments. Science 1981;214(4520):581-584.
  • Sandi C, Davies HA, Cordero MI, Rodriguez JJ, Popov VI, Stewart MG. Rapid reversal of stress induced loss of synapses in CA3 of rat hippocampus following water maze training. Eur J Neurosci 2003;17:2447-2456.
  • Sandi C. Stress, cognitive impairment and cell adhesion molecules. Nat Rev Neurosci 2004;5:917-930.
  • Borcel E, Perez-Alvarez L, Herrero AI, et al. Chronic stress in adulthood followed by intermittent stress impairs spatial memory and the survival of newborn hippocampal cells in aging animals: prevention by FGL, a peptide mimetic of neural cell adhesion molecule. Behav Pharmacol 2008; 19:41-49.
  • Issa AM, Rowe W, Gauthier S, Meaney MJ. Hypothalamic-pituitary-adrenal activity in aged, cognitively impaired and cognitively unimpaired rats. J Neurosci 1990;10:3247-3254.
  • Sapolsky RM, Krey LC, Mcewen BS. Prolonged glucocorticoid exposure reduces hippocampal neuron number - implications for aging. J Neurosci 1985;5:1222-1227.
  • Kerr DS, Campbell LW, Applegate MD, Brodish A, Landfield PW. Chronic stress-induced acceleration of electrophysiologic and morphometric biomarkers of hippocampal aging. J Neurosci 1991;11:1316-1324.
  • Woolley CS, Gould E, Mcewen BS. Exposure to excess glucocorticoids alters dendritic morphology of adult hippocampal pyramidal neurons. Brain Res 1990;531:225-231.
  • Gianaros PJ, Jennings JR, Sheu LK, Greer PJ, Kuller LH, Matthews KA. Prospective reports of chronic life stress predict reased grey matter volume in the hippocampus. Neuroimage 2007;35:795-803.
  • Gould E, Tanapat P. Stress and hippocampal neurogenesis. Biol Psychiatry 1999;46:1472-1479.
  • Montaron MF, Drapeau E, Dupret D, et al. Lifelong corticosterone level determines age-related line in neurogenesis and memory. Neurob Aging 2006;27:645-654.
  • Landfield PW, Waymire JC, Lynch G. Hippocampal aging and adrenocorticoids: quantitative correlations. Science 1978;202(4372):1098-1102.
  • Sapolsky RM, Krey LC, McEwen BS. The neuroendocrinology of stress and aging: the glucocorticoid cascade hypothesis. Endocr Rev 1986;7:284-301.
  • Christensen H. What cognitive changes can be expected with normal ageing? Aust Nz J Psychiat 2001;35:768-775.
  • Nyberg L, Persson J, Nilsson LG. Individual differences in memory enhancement by encoding enactment: relationships to adult age and biological factors. Neurosci Biobehav Rev 2002;26:835-839.
  • Lupien SJ, Evans A, Lord C, et al. Hippocampal volume is as variable in young as in older adults: Implications for the notion of hippocampal atrophy in humans. Neuroimage 2007;34:479-485.
  • Burgmans S, van Boxtel MPJ, Vuurman EFPM, et al. The prevalence of cortical gray matter atrophy may be overestimated in the healthy aging brain. Neuropsychol 2009; 23:541-550.
  • Lupien S, Lecours AR, Lussier I, Schwartz G, Nair NPV, Meaney MJ. Basal cortisol-levels and cognitive deficits in human aging. J Neurosci 1994;14:2893-2903.
  • Kalmijn S, Launer LJ, Stolk RP, et al. A prospective study on cortisol, dehydroepiandrosterone sulfate, and cognitive function in the elderly. J Clin Endocr Metab 1998;83:3487-3492.
  • Lupien SJ, Gaudreau S, Tchiteya BM, et al. Stress-induced larative memory impairment in healthy elderly subjects: relationship to cortisol reactivity. J Clin Endocrinol Metab 1997;82:2070-2075.
  • Lupien SJ, de Leon M, de Santi S, et al. Cortisol levels during human aging predict hippocampal atrophy and memory deficits. Nat Neurosci 1998;1:69-73.
  • Lupien SJ, Maheu F, Tu M, Fiocco A, Schramek TE. The effects of stress and stress hormones on human cognition: implications for the field of brain and cognition. Brain Cogn 2007;65:209-237.
  • Wolf OT, Convit A, McHugh PF, et al. Cortisol differentially affects memory in young and elderly men. Behav Neurosci 2001;115:1002-1011.
  • Hasher L, Zacks RT, Rahhal TA. Timing, instructions, and inhibitory control: some missing factors in the age and memory debate. Gerontology 1999;45:355-357.
  • Rahhal TA, Colcombe SJ, Hasher L. Instructional manipulations and age differences in memory: now you see them, now you don't. Psychol Aging 2001;16:697-706.
  • Lupien SJ, Wan N. Successful ageing: from cell to self. Philos Trans R Soc Lond B Biol Sci 2004;359(1449):1413-1426.
  • Pedersen W, Culmsee C, Ziegler D, Herman J, Mattson M. Aberrant stress response associated with severe hypoglycemia in a transgenic mouse model of Alzheimer's disease. J Mol Neurosci 1999;13:159-165.
  • Green K, Billings L, Roozendaal B, McGh J, LaFerla F. Glucocorticoids increase amyloid-beta and tau pathology in a mouse model of Alzheimer's disease. J Neurosci 2006;26: 9047-9056.
  • Dong H, Yuede C, Yoo H, et al. Corticosterone and related receptor expression are associated with increased beta-amyloid plaques in isolated Tg2576 mice. Neuroscience 2008; 155:154-163.
  • Elgh E, Lindqvist Astot A, Fagerlund M, Eriksson S, Olsson T, Näsman B. Cognitive dysfunction, hippocampal atrophy and glucocorticoid feedback in Alzheimer's disease. Biol Psychiatry 2006;59:155-161.
  • Davis K, Davis B, Greenwald B, et al. Cortisol and Alzheimer's disease, I: Basal studies. Am J Psychiatry 1986;143:300-305.
  • Dodt C, Dittmann J, Hruby J, et al. Different regulation of adrenocorticotropin and cortisol secretion in young, mentally healthy elderly and patients with senile dementia of Alzheimer's type. J Clin Endocrinol Metab 1991;72:272-276.
  • O'Brien J, Ames D, Schweitzer I, Colman P, Desmond P, Tress B. Clinical and magnetic resonance imaging correlates of hypothalamic-pituitary-adrenal axis function in depression and Alzheimer's disease. Br J Psychiatry 1996;168:679-687.
  • Hartmann A, Veldhuis J, Deuschle M, Standhardt H, Heuser I. Twenty-four hour cortisol release profiles in patients with Alzheimer's and Parkinson's disease compared to normal controls: ultradian secretory pulsatility and diurnal variation. Neurobiol Aging 1997;18:285-289.
  • Swanwick G, Kirby M, Bruce I, et al. Hypothalamic-pituitary-adrenal axis dysfunction in Alzheimer's disease: lack of association between longitudinal and cross-sectional findings. Am J Psychiatry 1998;155:286-289.
  • Umegaki H, Ikari H, Nakahata H, et al. Plasma cortisol levels in elderly female subjects with Alzheimer's disease: a cross-sectional and longitudinal study. Brain Res 2000; 881:241-243.
  • Wolf O, Convit A, Thorn E, de Leon M. Salivary cortisol day profiles in elderly with mild cognitive impairment. Psychoneuroendocrinology 2002;27:777-789.
  • Csernansky J, Dong H, Fagan A, et al. Plasma cortisol and progression of dementia in subjects with Alzheimer-type dementia. Am J Psychiatry 2006;163:2164-2169.
  • Arsenault-Lapierre G, Chertkow H, Lupien S. Seasonal effects on cortisol secretion in normal aging, mild cognitive impairment and Alzheimer's disease. Neurobiol Aging 2010; 31:1051-1054.
  • Petersen R, Stevens J, Ganguli M, Tangalos E, Cummings J, DeKosky S. Practice parameter: early detection of dementia: mild cognitive impairment (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2001;56:1133-1142.
  • Lind K, Edman A, Nordlund A, Olsson T, Wallin A. Increased saliva cortisol awakening response in patients with mild cognitive impairment. Dement Geriatr Cogn Disord 2007;24:389-395.
  • Popp J, Schaper K, Kölsch H, et al. CSF cortisol in Alzheimer's disease and mild cognitive impairment. Neurobiol Aging 2009;30:498-500.
  • Wilson R, Arnold S, Schneider J, Kelly J, Tang Y, Bennett D. Chronic psychological distress and risk of Alzheimer's disease in old age. Neuroepidemiology 2006;27:143-153.
  • Souza-Talarico JN. Chonic stress is associated with emotional coping style in subjects with mild cognitive impairment. Dement Geriatr Cogn Disord 2009:10.
  • Dong H, Goico B, Martin M, Csernansky C, Bertchume A, Csernansky J. Modulation of hippocampal cell proliferation, memory, and amyloid plaque deposition in APPsw (Tg2576) mutant mice by isolation stress. Neuroscience 2004;127:601-609.
  • Jeong Y, Park C, Yoo J, et al. Chronic stress accelerates learning and memory impairments and increases amyloid deposition in APPV717I-CT100 transgenic mice, an Alzheimer's disease model. FASEB J. 2006;20: 729-731.
  • Souza-Talarico J, Chaves E, Lupien S, Nitrini R, Caramelli P. Relationship between cortisol levels and memory performance may be modulated by the presence or absence of cognitive impairment: evidence from healthy elderly, mild cognitive impairment and Alzheimer's disease subjects. J Alzheimers Dis 2010;19:839-848.
  • Rothman S, Mattson M. Adverse stress, hippocampal networks, and Alzheimer's disease. Neuromolecular Med. 2010; 12:56-70.
  • Mattson M. Pathways towards and away from Alzheimer's disease. Nature 2004;430(7000):631-639.
  • Scheff S, Price D, Schmitt F, Mufson E. Hippocampal synaptic loss in early Alzheimer's disease and mild cognitive impairment. Neurobiol Aging 2006 Oct;27:1372-1384.
  • Scheff S, Price D, Schmitt F, DeKosky S, Mufson E. Synaptic alterations in CA1 in mild Alzheimer disease and mild cognitive impairment. Neurology 2007;68:1501-1508.
  • Pedersen W, McMillan P, Kulstad J, Leverenz J, Craft S, Haynatzki G. Rosiglitazone attenuates learning and memory deficits in Tg2576 Alzheimer mice. Exp Neurol 2006;199: 265-273.
  • Lee K, Kim J, Seo J, et al. Behavioral stress accelerates plaque pathogenesis in the brain of Tg2576 mice via generation of metabolic oxidative stress. J Neurochem 2009;108:165-175.
  • Li W, Li W, Yao Y, et al. Glucocorticoids increase impairments in learning and memory due to elevated amyloid precursor protein expression and neuronal apoptosis in 12-month old mice. Eur J Pharmacol 2010;628:108-115.
  • Pajović S, Pejić S, Stojiljković V, Gavrilović L, Dronjak S, Kanazir D. Alterations in hippocampal antioxidant enzyme activities and sympatho-adrenomedullary system of rats in response to different stress models. Physiol Res 2006;55: 453-460.
  • Singh A, Kumar A. Protective effect of alprazolam against sleep deprivation-induced behavior alterations and oxidative damage in mice. Neurosci Res 2008;60:372-379.
  • Zafir A, Banu N. Modulation of in vivo oxidative status by exogenous corticosterone and restraint stress in rats. Stress 2009;12:167-177.
  • Pérez-Nievas B, García-Bueno B, Caso J, Menchén L, Leza J. Corticosterone as a marker of susceptibility to oxidative/nitrosative cerebral damage after stress exposure in rats. Psychoneuroendocrinology 2007;32:703-711.
  • Goodman Y, Mattson M. Secreted forms of beta-amyloid precursor protein protect hippocampal neurons against amyloid beta-peptide-induced oxidative injury. Exp Neurol 1994;128:1-12.
  • Sultana R, Butterfield D. Oxidatively modified, mitochondria-relevant brain proteins in subjects with Alzheimer disease and mild cognitive impairment. J Bioenerg Biomembr 2009;41:441-446.
  • Nunomura A, Perry G, Aliev G, et al. Oxidative damage is the earliest event in Alzheimer disease. J Neuropathol Exp Neurol 2001;60:759-767.
  • Sultana R, Butterfield D. Role of oxidative stress in the progression of Alzheimer's disease. J Alzheimers Dis 2010;19: 341-353.
  • Marcourakis T, Bahia V, Kawamoto E, et al. Apolipoprotein E genotype is related to nitric oxide production in platelets. Cell Biochem Funct 2008;26:852-858.
  • Simon M, Czéh B, Fuchs E. Age-dependent susceptibility of adult hippocampal cell proliferation to chronic psychosocial stress. Brain Res 2005;1049:244-248.
  • Watanabe Y, Gould E, Cameron H, Daniels D, McEwen B. Phenytoin prevents stress- and corticosterone-induced atrophy of CA3 pyramidal neurons. Hippocampus 1992;2: 431-435.
  • Jacobsen J, Wu C, Redwine J, et al. Early-onset behavioral and synaptic deficits in a mouse model of Alzheimer's disease. Proc Natl Acad Sci USA. 2006;103:5161-5166.
  • Lupien S, de Leon M, de Santi S, et al. Cortisol levels during human aging predict hippocampal atrophy and memory deficits. Nat Neurosci 1998; 1:69-73.
  • Donohue H, Gabbott P, Davies H, et al. Chronic restraint stress induces changes in synapse morphology in stratum lacunosum-moleculare CA1 rat hippocampus: a stereological and three-dimensional ultrastructural study. Neuroscience 2006;140:597-606.
  • Fiocco AJ, Joober R, Lupien SJ. Education modulates cortisol reactivity to the Trier Social Stress Test in middle-aged adults. Psychoneuroendocrinology 2007; 32:1158-1163.
  • Valdois S, Joanette Y, Poissant A, Ska B, Dehaut F. Heterogeneity in the cognitive profile of normal elderly. J Clin Exp Neuropsychol 1990;12:587-596.
  • Ylikoski R, Ylikoski A, Keskivaara P, Tilvis R, Sulkava R, Erkintti T. Heterogeneity of cognitive profiles in aging: successful aging, normal aging, and individuals at risk for cognitive line. Eur J Neurology 1999;6:645-652.
  • Kumari M, Badrick E, Sacker A, Kirschbaum C, Marmot M, Chandola T. Identifying patterns in cortisol secretion in an older population. Findings from the Whitehall II study. Psychoneuroendocrinology 2010;35:1091-1099.
  • Rimmele U, Meier F, Lange T, Born J. Suppressing the morning rise in cortisol impairs free recall. Learn Mem 2010;17: 186-190.

Publication Dates

  • Publication in this collection
    Jan-Mar 2011


  • Received
    17 Nov 2010
  • Accepted
    14 Feb 2011
Academia Brasileira de Neurologia, Departamento de Neurologia Cognitiva e Envelhecimento R. Vergueiro, 1353 sl.1404 - Ed. Top Towers Offices, Torre Norte, São Paulo, SP, Brazil, CEP 04101-000, Tel.: +55 11 5084-9463 | +55 11 5083-3876 - São Paulo - SP - Brazil
E-mail: |