The role of estrogens in Alzheimer's disease (AD) is controversial. We investigated the association between well-recognized, and potentially functional, polymorphisms in the estrogen receptor (ER) α gene and the risk of AD in a prospective study of 6056 Caucasian older men and women aged 55 years and over. In a subset of 468 participants, we assessed volumes of the hippocampus and amygdala, which have a high density of ERα, with brain magnetic resonance imaging (MRI) (1.5 T MR unit). During a total of 35 405 person-years of follow-up (mean per persons 5.8 years), 312 new cases of dementia were detected, of whom 230 were diagnosed with AD. Neither the PvuII nor the XbaI polymorphism or haplotypes thereof were associated with the risk of all-cause dementia or AD. In contrast, we found that nondemented women who carried the PvuII p allele or haplotype ‘px’ had smaller amygdalar volumes on MRI in an allele–dose-dependent fashion. Total amygdalar volume was 4.50 (SE 0.10) in PP genotype, 4.45 (SE 0.06) in Pp genotype, and 4.18 ml (SE 0.08) in pp genotype (P trend=0.008). Further studies are required to investigate whether this smaller amygdalar volume has functional significance.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
The Rotterdam Study: 2012 objectives and design update
European Journal of Epidemiology Open Access 30 August 2011
The Rotterdam Study: 2010 objectives and design update
European Journal of Epidemiology Open Access 02 September 2009
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Rent or buy this article
Get just this article for as long as you need it
Prices may be subject to local taxes which are calculated during checkout
Behl C, Skutella T, Lezoualc'h F, Post A, Widmann M, Newton CJ et al. Neuroprotection against oxidative stress by estrogens: structure–activity relationship. Mol Pharmacol 1997; 51: 535–541.
Singh M, Meyer EM, Simpkins JW . The effect of ovariectomy and estradiol replacement on brain-derived neurotrophic factor messenger ribonucleic acid expression in cortical and hippocampal brain regions of female Sprague–Dawley rats. Endocrinology 1995; 136: 2320–2324.
Woolley CS, Gould E, Frankfurt M, McEwen BS . Naturally occurring fluctuation in dendritic spine density on adult hippocampal pyramidal neurons. J Neurosci 1990; 10: 4035–4039.
Maki PM, Resnick SM . Effects of estrogen on patterns of brain activity at rest and during cognitive activity: a review of neuroimaging studies. Neuroimage 2001; 14: 789–801.
Kawas C, Resnick S, Morrison A, Brookmeyer R, Corrada M, Zonderman A et al. A prospective study of estrogen replacement therapy and the risk of developing Alzheimer's disease: the Baltimore Longitudinal Study of Aging. Neurology 1997; 48: 1517–1521.
Tang MX, Jacobs D, Stern Y, Marder K, Schofield P, Gurland B et al. Effect of oestrogen during menopause on risk and age at onset of Alzheimer's disease. Lancet 1996; 348: 429–432.
Shumaker SA, Legault C, Thal L, Wallace RB, Ockene JK, Hendrix SL et al. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women's Health Initiative Memory Study: a randomized controlled trial. JAMA 2003; 289: 2651–2662.
Geerlings MI, Launer LJ, de Jong FH, Ruitenberg A, Stijnen T, van Swieten JC et al. Endogenous estradiol and risk of dementia in women and men: the Rotterdam Study. Ann Neurol 2003; 53: 607–615.
Dhandapani KM, Brann DW . Protective effects of estrogen and selective estrogen receptor modulators in the brain. Biol Reprod 2002; 67: 1379–1385.
Österlund MK, Keller E, Hurd YL . The human forebrain has discrete estrogen receptor α messenger RNA expression: high levels in the amygdaloid complex. Neuroscience 2000; 95: 333–342.
Yaffe K, Lui LY, Grady D, Stone K, Morin P . Estrogen receptor 1 polymorphisms and risk of cognitive impairment in older women. Biol Psychiatry 2002; 51: 677–682.
Isoe K, Ji Y, Urakami K, Adachi Y, Nakashima K . Genetic association of estrogen receptor gene polymorphisms with Alzheimer's disease. Alzheimer's Res 1997; 3: 195–197.
Ji Y, Urakami K, Wada-Isoe K, Adachi Y, Nakashima K . Estrogen receptor gene polymorphisms in patients with Alzheimer's disease, vascular dementia and alcohol-associated dementia. Dement Geriatr Cogn Disord 2000; 11: 119–122.
Maruyama H, Toji H, Harrington CR, Sasaki K, Izumi Y, Ohnuma T et al. Lack of an association of estrogen receptor α gene polymorphisms and transcriptional activity with Alzheimer disease. Arch Neurol 2000; 57: 236–240.
Mattila KM, Axelman K, Rinne JO, Blomberg M, Lehtimäki T, Laippala P et al. Interaction between estrogen receptor 1 and the ɛ4 allele of apolipoprotein E increases the risk of familial Alzheimer's disease in women. Neurosci Lett 2000; 282: 45–48.
Lambert JC, Harris JM, Mann D, Lemmon H, Coates J, Cumming A et al. Are the estrogen receptors involved in Alzheimer's disease? Neurosci Lett 2001; 306: 193–197.
Brandi ML, Becherini L, Gennari L, Racchi M, Bianchetti A, Nacmias B et al. Association of the estrogen receptor α gene polymorphisms with sporadic Alzheimer's disease. Biochem Biophys Res Commun 1999; 265: 335–338.
Convit A, De Leon MJ, Tarshish C, De Santi S, Tsui W, Rusinek H et al. Specific hippocampal volume reductions in individuals at risk for Alzheimer's disease. Neurobiol Aging 1997; 18: 131–138.
Callen DJ, Black SE, Gao F, Caldwell CB, Szalai JP . Beyond the hippocampus: MRI volumetry confirms widespread limbic atrophy in AD. Neurology 2001; 57: 1669–1674.
Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux R et al. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA 1997; 278: 1349–1356.
Struble RG, Rosario ER, Kircher ML, Ludwig SM, MacAdamis PJ, Watabe K et al. Regionally specific modulation of brain apolipoprotein E in the mouse during the estrous cycle and by exogenous 17beta estradiol. Exp Neurol 2003; 183: 638–644.
Hofman A, Grobbee DE, de Jong PTVM, van den Ouweland FA . Determinants of disease and disability in the elderly: the Rotterdam Elderly Study. Eur J Epidemiol 1991; 7: 403–422.
Ott A, Breteler MMB, van Harskamp F, Claus JJ, van der Cammen TJ, Grobbee DE et al. Prevalence of Alzheimer's disease and vascular dementia: association with education. The Rotterdam study. BMJ 1995; 310: 970–973.
Ott A, Breteler MMB, van Harskamp F, Stijnen T, Hofman A . Incidence and risk of dementia. The Rotterdam Study. Am J Epidemiol 1998; 147: 574–580.
Ruitenberg A, Ott A, van Swieten JC, Hofman A, Breteler MMB . Incidence of dementia: does gender make a difference? Neurobiol Aging 2001; 22: 575–580.
McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM . Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology 1984; 34: 939–944.
Román GC, Tatemichi TK, Erkinjuntti T, Cummings JL, Masdeu JC, Garcia JH et al. Vascular dementia: diagnostic criteria for research studies. Report of the NINDS-AIREN International Workshop. Neurology 1993; 43: 250–260.
Breteler MMB . Vascular involvement in cognitive decline and dementia. Epidemiologic evidence from the Rotterdam Study and the Rotterdam Scan Study. Ann NY Acad Sci 2000; 903: 457–465.
den Heijer T, Vermeer SE, Clarke R, Oudkerk M, Koudstaal PJ, Hofman A et al. Homocysteine and brain atrophy on MRI of non-demented elderly. Brain 2003; 126: 170–175.
Cuenod CA, Denys A, Michot JL, Jehenson P, Forette F, Kaplan D et al. Amygdala atrophy in Alzheimer's disease. An in vivo magnetic resonance imaging study. Arch Neurol 1993; 50: 941–945.
van Meurs JBJ, Schuit SCE, Weel AE, van der Klift M, Bergink AP, Arp PP et al. Association of 5′ estrogen receptor alpha gene polymorphisms with bone mineral density, vertebral bone area and fracture risk. Hum Mol Genet 2003; 12: 1745–1754.
Weel AE, Uitterlinden AG, Westendorp IC, Burger H, Schuit SC, Hofman A et al. Estrogen receptor polymorphism predicts the onset of natural and surgical menopause. J Clin Endocrinol Metab 1999; 84: 3146–3150.
Slooter AJC, Cruts M, Kalmijn S, Hofman A, Breteler MMB, Van Broeckhoven C et al. Risk estimates of dementia by apolipoprotein E genotypes from a population-based incidence study: the Rotterdam Study. Arch Neurol 1998; 55: 964–968.
Andersen PK, Borgan Ø, Gill RD, Keiding N . Statistical Models Based on Counting Processes. Springer-Verlag: Berlin, 1993.
Gustafson D, Rothenberg E, Blennow K, Steen B, Skoog I . An 18-year follow-up of overweight and risk of Alzheimer disease. Arch Intern Med 2003; 163: 1524–1528.
Ott A, Slooter AJC, Hofman A, van Harskamp F, Witteman JC, Van Broeckhoven C et al. Smoking and risk of dementia and Alzheimer's disease in a population-based cohort study: the Rotterdam Study. Lancet 1998; 351: 1840–1843.
Geerlings MI, Ruitenberg A, Witteman JC, van Swieten JC, Hofman A, van Duijn CM et al. Reproductive period and risk of dementia in postmenopausal women. JAMA 2001; 285: 1475–1481.
Yaffe K, Sawaya G, Lieberburg I, Grady D . Estrogen therapy in postmenopausal women: effects on cognitive function and dementia. JAMA 1998; 279: 688–695.
Lorentzon M, Lorentzon R, Nordstrom P . Vitamin D receptor gene polymorphism is associated with birth height, growth to adolescence, and adult stature in healthy Caucasian men: a cross-sectional and longitudinal study. J Clin Endocrinol Metab 2000; 85: 1666–1670.
Albagha OM, McGuigan FE, Reid DM, Ralston SH . Estrogen receptor alpha gene polymorphisms and bone mineral density: haplotype analysis in women from the United Kingdom. J Bone Miner Res 2001; 16: 128–134.
Fugger HN, Foster TC, Gustafsson J, Rissman EF . Novel effects of estradiol and estrogen receptor α and β on cognitive function. Brain Res 2000; 883: 258–264.
Vegeto E, Belcredito S, Etteri S, Ghisletti S, Brusadelli A, Meda C et al. Estrogen receptor-α mediates the brain antiinflammatory activity of estradiol. Proc Natl Acad Sci USA 2003; 100: 9614–9619.
Dubal DB, Zhu H, Yu J, Rau SW, Shughrue PJ, Merchenthaler I et al. Estrogen receptor α, not β, is a critical link in estradiol-mediated protection against brain injury. Proc Natl Acad Sci USA 2001; 98: 1952–1957.
Hu XY, Qin S, Lu YP, Ravid R, Swaab DF, Zhou JN . Decreased estrogen receptor-α expression in hippocampal neurons in relation to hyperphosphorylated tau in Alzheimer patients. Acta Neuropathol (Berl) 2003; 106: 213–220.
Shearman AM, Cupples LA, Demissie S, Peter I, Schmid CH, Karas RH et al. Association between estrogen receptor α gene variation and cardiovascular disease. JAMA 2003; 290: 2263–2270.
Shin A, Kang D, Nishio H, Lee MJ, Park SK, Kim SU et al. Estrogen receptor alpha gene polymorphisms and breast cancer risk. Breast Cancer Res Treat 2003; 80: 127–131.
Schuit SCE, van Meurs JBJ, Bergink AP, van der Klift M, Fang Y, Leusink G et al. Height in pre- and postmenopausal women is influenced by estrogen receptor alpha gene polymorphisms. J Clin Endocrinol Metab 2004; 89: 303–309.
Herrington DM, Howard TD, Brosnihan KB, McDonnell DP, Li X, Hawkins GA et al. Common estrogen receptor polymorphism augments effects of hormone replacement therapy on E-selectin but not C-reactive protein. Circulation 2002; 105: 1879–1882.
McEwen BS . Invited review: estrogens effects on the brain: multiple sites and molecular mechanisms. J Appl Physiol 2001; 91: 2785–2801.
Österlund MK, Gustafsson JA, Keller E, Hurd YL . Estrogen receptor β (ERβ) messenger ribonucleic acid (mRNA) expression within the human forebrain: distinct distribution pattern to ERα mRNA. J Clin Endocrinol Metab 2000; 85: 3840–3846.
Prichard Z, Jorm AF, Prior M, Sanson A, Smart D, Zhang Y et al. Association of polymorphisms of the estrogen receptor gene with anxiety-related traits in children and adolescents: a longitudinal study. Am J Med Genet 2002; 114: 169–176.
Westberg L, Melke J, Landen M, Nilsson S, Baghaei F, Rosmond R et al. Association between a dinucleotide repeat polymorphism of the estrogen receptor alpha gene and personality traits in women. Mol Psychiatry 2003; 8: 118–122.
Rauch SL, Shin LM, Wright CI . Neuroimaging studies of amygdala function in anxiety disorders. Ann N Y Acad Sci 2003; 985: 389–410.
Massana G, Serra-Grabulosa JM, Salgado-Pineda P, Gastó C, Junqué C, Massana J et al. Amygdalar atrophy in panic disorder patients detected by volumetric magnetic resonance imaging. Neuroimage 2003; 19: 80–90.
Comings DE, Muhleman D, Johnson P, MacMurray JP . Potential role of the estrogen receptor gene (ESR1) in anxiety. Mol Psychiatry 1999; 4: 374–377.
The Rotterdam Study has been supported by the Research Institute for Diseases in the Elderly, funded by the Ministry of Education & Science and the Ministry of Health, Welfare and Sports, through the Netherlands Organization for Scientific Research (NWO grant 014-90-001). We thank Freek Hoebeek and Eric Achten for their help in measuring the hippocampus and the amygdala and Wendy Hugens for technical assistance in the DNA analysis.
Rights and permissions
About this article
Cite this article
den Heijer, T., Schuit, S., Pols, H. et al. Variations in estrogen receptor α gene and risk of dementia, and brain volumes on MRI. Mol Psychiatry 9, 1129–1135 (2004). https://doi.org/10.1038/sj.mp.4001553
- Alzheimer's disease
- steroid hormone receptor
This article is cited by
Effects of Sex Steroids in the Human Brain
Molecular Neurobiology (2017)
The Rotterdam Study: 2012 objectives and design update
European Journal of Epidemiology (2011)
The Rotterdam Study: 2010 objectives and design update
European Journal of Epidemiology (2009)
Interaction between estrogen receptor-α and butyrylcholinesterase genes modulates Alzheimer’s disease risk
Journal of Neurology (2007)
Estrogen Receptor 1 gene (ESR1) variants in Alzheimer’s disease. Results of a meta-analysis
Aging Clinical and Experimental Research (2007)