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Can estrogen play a significant role in the prevention of Alzheimer’s disease?

  • J. P. Kesslak
Part of the Journal of Neural Transmission. Supplementa book series (NEURAL SUPPL, volume 62)

Abstract

In women the abrupt decline estrogen levels at menopause may be associated with cognitive deficits and increased risk for Alzheimer’s disease (AD); estrogen replacement therapy may reduce this risk. Animal studies indicate that estrogen modulates neurotransmitter systems, regulates synaptogenesis, and is neuroprotective. These beneficial effects occur in brain areas critical to cognitive function and involved in AD. Reduced estrogen levels can compromise neuronal function and survival. Estrogen replacement therapy can reverse cognitive deficits associated with low estrogen levels and may reduce the risk of AD. However, clinical trials for estrogen replacement in the treatment of AD have produced ambiguous results. Initial, small, open-label and double blind clinical trials indicated improved cognitive function in women with AD. Recent large trials failed to show a beneficial effect for long-term estrogen replacement for women with AD. There are several variables that could affect these results, such as genetic factors, time between estrogen loss and replacement, extent and types of AD pathology, and other environmental and health factors. Presently large prospective studies are being conducted as the National Institutes of Health in the Women’s Health Initiative and the Preventing Postmenopausal Memory Loss and Alzheimer’s with Replacement Estrogens studies to provide a better assessment of the role of estrogen for age related health issues, including dementia.

Keywords

Estrogen Replacement Therapy Conjugate Equine Estrogen Estrone Sulfate Brain Derive Neurotrophic Factor mRNA Estrogen Loss 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. APA (1994) Diagnostic and statistical manual of mental disorders, DSM-IV, 4th ed. American Psychiatric Association, Washington, DCGoogle Scholar
  2. Arking R (1998) Biology of aging: observations and principles, 2nd ed. Sinauer Associates, Sunderland, 570 pGoogle Scholar
  3. Asthana S, Baker LD, Craft S, Stanczyk FZ, Veith RC, Raskind MA, Plymate SR (2001) High-dose estradiol improves cognition for women with AD: results of a randomized study. Neurology 57: 605–612PubMedCrossRefGoogle Scholar
  4. Barrett-Connor E, Kritz-Silverstein D (1999) Gender differences in cognitive function with age: the Rancho Bernardo study. J Am Geriatr Soc 47: 159–164PubMedGoogle Scholar
  5. Baysal K, Losordo DW (1996) Oestrogen receptors and cardiovascular disease. Clin Exp Pharmacol Physiol 23: 537–548PubMedCrossRefGoogle Scholar
  6. Berchtold NC, Kesslak JP, Pike C, Adlard PA, Cotman CW (2001) Estrogen and exercise interact to regulate brain-derived neurotrophic factor mRNA and protein expression in the hippocampus. Eur J Neurosci 14: 1–13CrossRefGoogle Scholar
  7. Birge, SJ (1996) Is there a role for estrogen replacement therapy in the prevention and treatment of dementia? J Am Geriatr Soc 44: 865–870PubMedGoogle Scholar
  8. Birge SJ, Mortel KF (1997) Estrogen and the treatment of Alzheimer’s disease. Am J Med 103: 36S–45SPubMedCrossRefGoogle Scholar
  9. Braak H, Del Tredici K, Schultz C, Braak E (2000) Vulnerability of select neuronal types to Alzheimer’s disease. Ann NY Acad Sci 924: 53–61PubMedCrossRefGoogle Scholar
  10. Brinton RD (2001) Cellular and molecular mechanisms of estrogen regulation of memory function and neuroprotection against Alzheimer’s disease: recent insights and remaining challenges. Learning Memory 8:121–133PubMedCrossRefGoogle Scholar
  11. Brinton RD, Chen C, Montoya M, Hsieh D, Minaya J, Kim J, Chu H-P (2000) The women’s health initiative estrogen replacement therapy is neuortrophic and neuroptotective. Neurobiol Aging 21: 475–496CrossRefGoogle Scholar
  12. Brookmeyer R, Gray S, Kawas C (1998) Projections of Alzheimer’s disease in the United States and the public health impact of delaying disease onset. Am J Public Health 88: 1337–1343PubMedCrossRefGoogle Scholar
  13. Daniel JM, Fader AJ, Spencer AL, Dohanich GP (1997) Estrogen enhances performance of female rats during acquisition of a radial arm maze. Horm Behav 32: 217–225PubMedCrossRefGoogle Scholar
  14. Dubai DB, Shughrue PJ, Wilson ME, Merchenthaler I, Wise PM (1999) Estradiol modulates bcl-2 in cerebral ischemia: a potential role for estrogen receptors. J Neurosci 19: 6385–6393Google Scholar
  15. Duka T, Tasker R, McGowan JF (2000) The effects of 3-week estrogen hormone replacement on cognition in elderly healthy females. Psychopharm 149: 129–139CrossRefGoogle Scholar
  16. Eriksen EF, Kassem M, Langdahl B (1996) European and North American experience with HRT for the prevention of osteoporosis. Bone 19: 179S–183SPubMedCrossRefGoogle Scholar
  17. Evans DA, Funkenstein HH, Albert MS, Scherr PA, Cook NR, Chown MJ, Hebert LE, Hennekens CH, Taylor JO (1998) Prevalence of Alzheimer’s disease in a community population of older persons. Higher than previously. Jama 262: 2551–2556CrossRefGoogle Scholar
  18. Fader AJ, Johnson PE, Dohanich GP (1999) Estrogen improves working but not reference memory and prevents amnestic effects of scopolamine of a radial-arm maze. Pharmacol Biochem Behav 62: 711–717PubMedCrossRefGoogle Scholar
  19. Fahrbach SE, Meisel RL, Pfaff DW (1985) Preoptic implants of estradiol increase wheel running but not the open field activity of female rats. Physiol Behav 35: 985–992PubMedCrossRefGoogle Scholar
  20. Farhat MY, Lavigne MC, Ramwell PW (1996) The vascular protective effects of estrogen. Faseb J 10: 615–624PubMedGoogle Scholar
  21. Filht H, Weinreb H, Cholst I, Luine V, McEwen B, Amador R, Zabriskie J (1986) Observations in a preliminary open trial of estradiol therapy for senile dementia-Alzheimer’s type. Psychoneuroendocrinology 11: 337–345CrossRefGoogle Scholar
  22. Frankfurt M, McKittrick CR, Mendelson SD, McEwen BS (1994) Effect of 5,7-dihydroxytryptamine, ovariectomy and gonadal steroids on serotonin receptor binding in rat brain. Neuroendocrinology 59: 245–250PubMedCrossRefGoogle Scholar
  23. Gandy S, Duff K (2000) Post-menopausal estrogen deprivation and Alzheimer’s disease. Exp Gerontol 35: 503–511PubMedCrossRefGoogle Scholar
  24. Gibbs RB (1998) Impairment of basal forebrain cholinergic neurons associated with aging and long-term loss of ovarian function. Exp Neurol 151: 289–302PubMedCrossRefGoogle Scholar
  25. Gorski RA (1985) Sexual dimorphisms of the brain. J Anml Sci 61 [Suppl 3]: 38–61Google Scholar
  26. Green PS, Simpkins JW (2001) Neuroprotective effects of estrogens: potential mechanisms of action. Int J Dev Neurosci 18: 347–358CrossRefGoogle Scholar
  27. Grodstein F, Chen J, Pollen DA, Albert MS, Wilson RS, Folstein MF, Evans DA, Stampfer MJ (2000) Postmenopausal hormone therapy and cognitive function in healthy older women. J Am Geriatr Soc 48: 746–752PubMedGoogle Scholar
  28. Halbreich U (1997) Role of estrogen in postmenopausal depression. Neurology 48: S16–S19PubMedCrossRefGoogle Scholar
  29. Henderson VW, Paganini-Hill A, Emanuel CK, Dunn ME, Buckwalter JG (1994) Estrogen replacement therapy in older women. Comparisons between Alzheimer’s disease cases and nondemented control subjects. Arch Neurol 51: 896–900PubMedCrossRefGoogle Scholar
  30. Henderson VW, Paganini-Hill A, Miller BL, Elble RJ, Reyes PF, Shoupe D, McCleary CA, Klein RA, Hake AM, Farlow MR (2000) Estrogen for Alzheimer’s disease in women: randomized, double-blind, placebo-controlled trial. Neurology 54: 295–301PubMedCrossRefGoogle Scholar
  31. Hidalgo A, Bar ami K, Iversen K, Goldman SA (1995) Estrogens and non-estrogenic ovarian influences combine to promote the recruitment and decrease the turnover of new neurons in the adult female canary brain. J Neurobiol 27: 470–487PubMedCrossRefGoogle Scholar
  32. Hogervorst E, Barnetson L, Jobst KA, Nagy Z, Combrinck M, Smith AD (2000) Diagnosing dementia: interrater reliability assessment and accuracy of the NINCDS/ ADRDA criteria versus CERAD histopathological criteria for Alzheimer’s disease. Dementia Geriat Cogn Disord 11: 107–113CrossRefGoogle Scholar
  33. Hogervorst E, Williams J, Budge M, Riedel W, Jolles J (2000) The nature of the effect of female gonadal hormone replacement therapy on cognitive function in postmenopausal women: a meta-analysis. Neuroscience 101: 485–512PubMedCrossRefGoogle Scholar
  34. Honjo H, Ogino Y, Naitoh K, Urabe M, Kitawaki J, Yasuda J, Yamamoto T, Ishihara S, Okada H, Yonezawa T, et al (1989) In vivo effects by estrone sulfate on the central nervous system-senile dementia (Alzheimer’s type). J Steroid Biochem 34: 521–525PubMedCrossRefGoogle Scholar
  35. Inestrosa NC, Marzolo MP, Bonnefont AB (1998) Cellular and molecular basis of estrogen’s neuroprotection. Potential relevance for Alzheimer’s disease. Mol Neurobiol 17: 73–86PubMedCrossRefGoogle Scholar
  36. Janowsky JS, Oviatt SK, Orwoll ES (1994) Testosterone influences spatial cognition in older men. Behav Neurosci 108: 325–332PubMedCrossRefGoogle Scholar
  37. Jorm AF, Korten AE, Henderson AS (1987) The prevalence of dementia: a quantitative integration of the literature. Acta Psychiatr Scand 76: 465–479PubMedCrossRefGoogle Scholar
  38. Kampen DL, Sherwin BB (1994) Estrogen use and verbal memory in healthy postmenopausal women. Obstet Gynecol 83: 979–983PubMedCrossRefGoogle Scholar
  39. Kawas C, Resnick S, Morrison A, Brookmeyer R, Corrada M, Zonderman A, Bacal C, Lingle DD, Metter E (1997) A prospective study of estrogen replacement therapy and the risk of developing Alzheimer’s disease: the Baltimore Longitudinal Study of Aging. Neurology 48: 1517–1521PubMedCrossRefGoogle Scholar
  40. Kesslak JP, So V, Choi J, Cotman CW, Gomez-Pinilla F (1998) Learning upregulates BDNF mRNA: a mechanism to facilitate encoding and circuit maintenance? Behav Neurosci 112: 1012–1019PubMedCrossRefGoogle Scholar
  41. King JM (1979) Effects of lesions of the amygdala, preoptic area, and hypothalamus in estradiol-induced activity in the female rat. J Comp Physiol Psychol 93: 360–367PubMedCrossRefGoogle Scholar
  42. Klein R, Berlin L (1996) Benefits and risks of hormone replacement therapy. In: Pavlik EJ (ed) Estrogens, progestins and their antagonists. Birkhauser, Boston pp 3–50Google Scholar
  43. Kondo Y, Suzuki K, Sakuma Y (1997): Estrogen alleviates cognitive dysfunction following transient brain ischemia in ovariectomized gerbils. Neurosci Lett 238: 45–48PubMedCrossRefGoogle Scholar
  44. Kritzer MF, Kohama SG (1998) Ovarian hormones influence the morphology, distribution, and density of tyrosine hydroxylase immunoreactive axons in the dorsolateral prefrontal cortex of adult rhesus monkeys. J Comp Neurol 395: 1–17PubMedCrossRefGoogle Scholar
  45. Kritzer MF, Kohama SG (1999) Ovarian hormones differentially influence immunoreac-tivity for dopamine beta-hydroxylase, choline acetyltransferase, and serotonin in the dorsolateral prefrontal cortex of adult rhesus monkeys. J Comp Neurol 409: 438–451PubMedCrossRefGoogle Scholar
  46. McEwen BS, Alves SE (1999) Estrogen actions in the central nervous system. Endocr Rev 20: 279–307PubMedGoogle Scholar
  47. McEwen BS, Woolley CS (1994) Estradiol and progesterone regulate neuronal structure and synaptic connectivity in adult as well as developing brain. Exp Gerontol 29: 431–436PubMedCrossRefGoogle Scholar
  48. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM (1984) Clinical diagnosis of Alzheimer’s disease: a report of the NINCDS-ADRDA work group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 34: 939–944PubMedCrossRefGoogle Scholar
  49. Morris, JC (2000) The nosology of dementia. Neurol Clin 18: 773–788PubMedCrossRefGoogle Scholar
  50. Muck AO, Seeger H, Korte K, Lippert TH (1994) Cardiovascular protection by postmenopausal estrogen replacement therapy: possible mechanisms of the estrogen action. Clin Exp Obstet Gynecol 21: 143–149PubMedGoogle Scholar
  51. Mulnard RA, Cotman CW, Kawas C, van Dyck CH, Sano M, Doody R, Koss E, Pfeiffer E, Jin S, Gamst A, Grundman M, Thomas R, Thai LJ (2000) Estrogen replacement therapy for treatment of mild to moderate Alzheimer disease: a randomized controlled trial. Alzheimer’s Disease Cooperative Study. JAMA 283: 1007–1015PubMedCrossRefGoogle Scholar
  52. Packard MG (1998) Posttraining estrogen and memory modulation. Horm Behav 34: 126–139PubMedCrossRefGoogle Scholar
  53. Paganini-Hill A, Henderson VW (1996) Estrogen replacement therapy and risk of Alzheimer disease. Arch Intern Med 156: 2213–2217PubMedCrossRefGoogle Scholar
  54. Panay N, Studd JW (1998) The psychotherapeutic effects of estrogens. Gynecol Endocrinol 12: 353–365PubMedCrossRefGoogle Scholar
  55. Perl DP (200) Neuropathology of Alzheimer’s disease and related disorders. Neurol Clin 18: 847–864CrossRefGoogle Scholar
  56. Pike CJ (1999) Estrogen modulates neuronal Bcl-xL expression and beta-amyloid-induced apoptosis: relevance to Alzheimer’s disease. J Neurochem 72: 1552–1563PubMedCrossRefGoogle Scholar
  57. Rachman IM, Unnerstall JR, Pfaff DW, Cohen RS (1998) Regulation of neuronal nitric oxide synthase mRNA in lordosis-relevant neurons of the ventromedial hypothalamus following short-term estrogen treatment. Brain Res Mol Brain Res 59: 105–108PubMedCrossRefGoogle Scholar
  58. Raisman G (1997) An urge to explain the incomprehensible: Geoffrey Harris and the discovery of the neural control of the pituitary gland. Ann Rev Neurosci 20: 533–566PubMedCrossRefGoogle Scholar
  59. Rice MM, Graves AB, McCurry SM, Gibbons LE, Bowen JD, McCormick WC, Larson EB (2000) Postmenopausal estrogen and estrogen-progestin use and 2-year rate of cognitive change in a cohort of older Japanese American women: The Kame Project. Arch Int Med 160: 1641–1649CrossRefGoogle Scholar
  60. Sherwin BB (1999) Can estrogen keep you smart? Evidence from clinical studies. J Psychiatr Neurosci 24: 315–321Google Scholar
  61. Sherwin BB, Tulandi T (1996) “Add-back” estrogen reverses cognitive deficits induced by a gonadotropin-releasing hormone agonist in women with leiomyomata uteri. J Clin Endocrinol Metab 81: 2545–2549PubMedGoogle Scholar
  62. Simpkins JW, Green PS, Gridley KE, Singh M, de Fiebre NC, Rajakumar G (1997) Role of estrogen replacement therapy in memory enhancement and the prevention of neuronal loss associated with Alzheimer’s disease. Am J Med 103: 19S–25SPubMedCrossRefGoogle Scholar
  63. Singer CA, Figueroa-Masot XA, Batchelor RH, Dorsa DM (1999) The mitogen-activated protein kinase pathway mediates estrogen neuroprotection after glutamate toxicity in primary cortical neurons. J Neurosci 19: 2455–2463PubMedGoogle Scholar
  64. Smith CA, McCleary CA, Murdock GA, Wilshire TW, Buckwalter DK, Bretsky P, Marmol L, Gorsuch RL, Buckwalter JG (1999) Lifelong estrogen exposure and cognitive performance in elderly women. Brain Cog 39: 203–218CrossRefGoogle Scholar
  65. Sohrabji F, Miranda RC, Toran-Allerand CD (1995) Identification of a putative estrogen response element in the gene encoding brain-derived neurotrophic factor. PNAS 92: 11110–11114PubMedCrossRefGoogle Scholar
  66. Steffens DC, Norton MC, Plassman BL, Tschanz JT, Wyse BW, Welsh-Bohmer KA, Anthony JC, Breitner JC (1999) Enhanced cognitive performance with estrogen use in nondemented community-dwelling older women. J Am Geriatr Soc 47:1171–1175PubMedGoogle Scholar
  67. Toran-Allerand CD (1996) The estrogen/neurotrophin connection during neural development: is co-localization of estrogen receptors with the neurotrophins and their receptors biologically relevant? Dev Neurosci 18: 36–48PubMedCrossRefGoogle Scholar
  68. van Amelsvoort T, Compton J, Murphy D (2001) In vivo assessment of the effects of estrogen on human brain. Trends Endocrinol Metab 12: 273–276PubMedCrossRefGoogle Scholar
  69. Wade GN, Zucker I (1970) Modulation of food intake and locomotor activity in female rats by diencephalic hormone implants. J Comp Physiol Psychol 72: 328–336PubMedCrossRefGoogle Scholar
  70. Wang GH (1923) The relation between spontaneous activity and oestrus cycle in the white rat. Comp Psychol Monogr ii: 1–27Google Scholar
  71. Wang Q, Santizo R, Baughman VL, Pelligrino DA, Iadecola C (1999) Estrogen provides neuroprotection in transient forebrain ischemia through perfusion-independent mechanisms in rats. Stroke 30: 630–637PubMedCrossRefGoogle Scholar
  72. Wang PN, Liao SQ, Liu RS, Liu CY, Chao HT, Lu SR, Yu HY, Wang SJ, Liu HC (2000) Effects of estrogen on cognitionl2, mood, and cerebral blood flow in AD: a controlled study. Neurology 54: 2061–2066PubMedCrossRefGoogle Scholar
  73. Wise PM, Dubai DB, Wilson ME, Rau SW, Bottner M (2001) Minireview: neuroprotective effects of estrogen-new insights into mechanisms of action. Endocrinology 142: 969–973PubMedGoogle Scholar
  74. Woods JA (1998) Exercise and resistance to neoplasia. Can J Physiol Pharmacol 76: 581¡ª 588PubMedCrossRefGoogle Scholar
  75. Young WC, Fish wR (1945) The ovarian hormones and spontaneous running activity in the female rat. Enodcrinology 36: 181–189CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Wien 2002

Authors and Affiliations

  • J. P. Kesslak
    • 1
  1. 1.Institute for Brain Aging and Dementia, Department of NeurologyUniversity of California — IrvineIrvineUSA

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