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Estrogen, Cognition, and a Woman’s Risk of Alzheimer’s Disease

  • Victor W Henderson MS, MD
    Correspondence
    Victor W. Henderson, MD, Department of Neurology (GNH-5641), Los Angeles County-University of Southern California Medical Center, 1200 North State Street, Los Angeles, California 90033.
    Affiliations
    Departments of Neurology (Division of Cognitive Neuroscience and Neurogerontology) and Psychology, School of Gerontology, and Program in Neural, Informational, and Behavioral Sciences, University of Southern California; and the Los Angeles County-University of Southern California Medical Center, Los Angeles, California, USA
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      Abstract

      Alzheimer’s disease affects women more often than men, and women with this form of dementia show greater naming (semantic memory) deficits during the course of their illness. Gonadal steroids exert organizational and activational effects on central nervous system neurons and influence brain function in other important ways. Several estrogenic actions are potentially relevant to Alzheimer’s disease, and it is hypothesized that one consequence of estrogen deprivation after the menopause is a higher risk of this dementing disorder. In healthy women without dementia, estrogen may enhance cognitive performance, especially in the domain of verbal memory, although the magnitude of such effects is small. Several small treatment trials of estrogen replacement in women with Alzheimer’s disease, however, suggest that estrogen’s effects on cognition could be larger in this population and may be most apparent on tasks of semantic memory. Analyses in voluntary cohorts associate postmenopausal estrogen replacement therapy with a lower risk of subsequent Alzheimer’s disease. In 3 recent epidemiologic studies, information on postmenopausal estrogen use was collected prospectively; while inconclusive, findings raise the possibility that postmenopausal estrogen replacement reduces a woman’s risk of subsequent dementia. New information from basic research and from large randomized treatment studies, cohort studies, and case-control studies is needed to resolve important unanswered clinical issues.
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      References

        • Jorm AF
        • Korten AE
        • Henderson AS
        The prevalence of dementia: a quantitative integration of the literature.
        Acta Psychiatr Scand. 1987; 76: 465-479
        • Mölsä PK
        • Marttila RJ
        • Rinne UK
        Epidemiology of dementia in a Finnish population.
        Acta Neurol Scand. 1982; 65: 541-552
        • Rorsman B
        • Hagnell O
        • Lanke J
        Prevalence and incidence of senile and multi-infarct dementia in the Lundby study: a comparison between the time periods 1947–1957 and 1957–1972.
        Neuropsychobiology. 1986; 15: 122-129
        • Katzman R
        • Aronson M
        • Fuld P
        • et al.
        Development of dementing illnesses in an 80-year-old volunteer cohort.
        Ann Neurol. 1989; 25: 317-324
        • Bachman DL
        • Wolf PA
        • Linn RT
        • et al.
        Incidence of dementia and probable Alzheimer’s disease in a general population: the Framingham study.
        Neurology. 1993; 43: 515-519
        • Jarvik LF
        Human intelligence: sex differences.
        Acta Genet Med Gemellol. 1975; 24: 189-211
        • Halpern DF
        Sex Differences in Cognitive Abilities. Lawrence Erlbaum, Hillsdale, NJ1992
        • McGlone J
        Sex differences in human brain asymmetry: a critical survey.
        Behav Brain Sci. 1980; 3: 215-263
        • Shaywitz BA
        • Shaywitz SE
        • Pugh KR
        • et al.
        Sex differences in the functional organization of the brain for language.
        Nature. 1995; 373: 607-609
        • Henderson VW
        • Buckwalter JG
        Cognitive deficits of men and women with Alzheimer’s disease.
        Neurology. 1994; 44: 90-96
        • Buckwalter JG
        • Sobel E
        • Dunn ME
        • Diz MM
        • Henderson VW
        Gender differences on a brief measure of cognitive functioning in Alzheimer’s disease.
        Arch Neurol. 1993; 50: 757-760
        • Ripich DN
        • Petrill SA
        • Whitehouse PJ
        • Ziol EW
        Gender differences in language of AD patients: a longitudinal study.
        Neurology. 1995; 45: 299-302
        • Cohen D
        • Wilkie F
        Sex-related differences in cognition among the elderly.
        in: Wittig MA Petersen AC Sex-Related Differences in Cognitive Functioning. Academic Press, New York1979: 145-157
        • Ganguli M
        • Ratcliff G
        • Huff FJ
        • et al.
        Effects of age, gender, and education on cognitive tests in a rural elderly community sample: norms from the Monongahela Valley Independent Elders Survey.
        Neuroepidemiology. 1991; 10: 42-52
        • Jaffe RB
        The menopause and perimenopausal period.
        in: Yen SSC Jaffe RB Reproductive Endocrinology. 3rd ed. WB Saunders, Philadelphia1991: 389-408
        • Kawata M
        Roles of steroid hormones and their receptors in structural organization in the nervous system.
        Neurosci Res. 1995; 24: 1-46
        • Matsumoto A
        Synaptogenic action of sex steroids in developing and adult neuroendocrine brain.
        Psychoneuroendocrinology. 1991; 16: 25-40
        • Bachevalier J
        • Hagger C
        Sex differences in the development of learning abilities in primates.
        Psychoneuroendocrinology. 1991; 16: 177-188
        • Williams CL
        • Meck WH
        The organizational effects of gonadal steroids on sexually dimorphic spatial ability.
        Psychoneuroendocrinology. 1991; 16: 155-176
        • Chung SK
        • Pfaff DW
        • Cohen RS
        Estrogen-induced alterations in synaptic morphology in the midbrain central gray.
        Exp Brain Res. 1988; 69: 522-530
        • Toran-Allerand CD
        Organotypic culture of the developing cerebral cortex and hypothalamus: relevance to sexual differentiation.
        Psychoneuroendocrinology. 1991; 16: 7-24
        • Woolley CS
        • McEwen BS
        Roles of estradiol and progesterone in regulation of hippocampal dendritic spine density during the estrous cycle in the rat.
        J Comp Neurol. 1993; 336: 293-306
        • Lustig RH
        Sex hormone modulation of neural development in vitro.
        Hormon Behav. 1994; 28: 383-395
        • Miranda RC
        • Sohrabji F
        • Toran-Allerand CD
        Presumptive estrogen target neurons express mRNAs for both the neurotrophins and neurotrophin receptors: a basis for potential developmental interactions of estrogen with neurotrophins.
        Mol Cell Neurosci. 1993; 4: 510-525
        • Sohrabji F
        • Miranda RC
        • Toran-Allerand CD
        Estrogen differentially regulates estrogen and nerve growth factor receptor mRNAs in adult sensory neurons.
        J Neurosci. 1994; 14: 459-471
        • Shughrue PJ
        • Dorsa DM
        Estrogen modulates the growth-associated protein GAP-43 (neuromodulin) mRNA in the rat preoptic area and basal hypothalamus.
        Neuroendocrinology. 1993; 57: 439-447
        • Sar M
        • Stumpf WE
        Central noradrenergic neurones concentrate 3H-oestradiol.
        Nature. 1981; 289: 500-502
        • Loy R
        • Gerlach JL
        • McEwen BS
        Autoradiographic localization of estradiol-binding neurons in the rat hippocampal formation and entorhinal cortex.
        Dev Brain Res. 1988; 39: 245-251
        • Toran-Allerand CD
        • Miranda RC
        • Bentham WDL
        • et al.
        Estrogen receptors colocalize with low-affinity nerve growth factor receptors in cholinergic neurons of the basal forebrain.
        Proc Natl Acad Sci USA. 1992; 89: 4668-4672
        • Weiland NG
        Estradiol selectively regulates agonist binding sites on the N-methyl-D-aspartate receptor complex in the CA1 region of the hippocampus.
        Endocrinol. 1992; 131: 662-668
        • Woolley CS
        • McEwen BS
        Estradiol regulates hippocampal dendritic spine density via an N-methyl-D-aspartate receptor-dependent mechanism.
        J Neurosci. 1994; 14: 7680-7687
        • Singh M
        • Meyer EM
        • Millard WJ
        • Simpkins JW
        Ovarian steroid deprivation results in a reversible learning impairment and compromised cholinergic function in female Sprague-Dawley rats.
        Brain Res. 1994; 644: 305-312
        • Desjardins GC
        • Beaudet A
        • Meaney MJ
        • Brawer JR
        Estrogen-induced hypothalamic beta-endorphin neuron loss: a possible model of hypothalamic aging.
        Exp Gerontol. 1995; 30: 253-267
        • Jaffe AB
        • Toran-Allerand CD
        • Greengard P
        • Gandy SE
        Estrogen regulates metabolism of Alzheimer amyloid β precursor protein.
        J Biol Chem. 1994; 269: 13065-13068
        • Applebaum-Bowden D
        • McLean P
        • Steinmetz A
        • et al.
        Lipoprotein, apolipoprotein, and lipolytic enzyme changes following estrogen administration in postmenopausal women.
        J Lipid Res. 1989; 30: 1895-1906
        • Kushwaha RS
        • Foster DM
        • Barrett PHR
        • Carey KD
        • Bernard MG
        Metabolic regulation of plasma apolipoprotein E by estrogen and progesterone in the baboon (Papio sp).
        Metabolism. 1991; 40: 93-100
        • Muesing RA
        • Miller VT
        • LaRosa JC
        • Stoy DB
        • Phillips EA
        Effects of unopposed conjugated equine estrogen on lipoprotein composition and apolipoprotein-E distribution.
        J Clin Endocrinol Metab. 1992; 75: 1250-1254
        • Strittmatter WJ
        • Saunders AM
        • Schmechel D
        • et al.
        Apolipoprotein E: high-avidity binding to β-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease.
        Proc Natl Acad Sci USA. 1993; 90: 1977-1981
        • Vandenabeele P
        • Fiers W
        Is amyloidogenesis during Alzheimer’s disease due to an IL-1/IL-6-mediated “acute phase response” in the brain?.
        Immunol Today. 1991; 12: 217-219
        • Bauer J
        • Ganter U
        • Strauss S
        • et al.
        The participation of interleukin-6 in the pathogenesis of Alzheimer’s disease.
        Res Immunol. 1992; 143: 650-657
        • Ershler WB
        Interleukin-6: a cytokine for gerontologists.
        J Am Geriatr Soc. 1993; 41: 176-181
        • Belfort MA
        • Saade GR
        • Snabes M
        • et al.
        Hormonal status affects the reactivity of the cerebral vasculature.
        Am J Obstet Gynecol. 1995; 172: 1273-1278
        • Ohkura T
        • Teshima Y
        • Isse K
        • et al.
        Estrogen increases cerebral and cerebellar blood flows in postmenopausal women.
        Menopause. 1995; 2: 13-18
        • Bishop J
        • Simpkins JW
        Role of estrogens in peripheral and cerebral glucose utilization.
        Rev Neurosci. 1992; 3: 121-137
        • Niki E
        • Nakano M
        Estrogens as antioxidants.
        Method Enzymol. 1990; 186: 330-333
        • Mooradian AD
        Antioxidant properties of steroids.
        J Steroid Biochem Mol Biol. 1993; 45: 509-511
        • Sagara Y
        • Dargusch R
        • Klier FG
        • Schubert D
        • Behl C
        Increased antioxidant enzyme activity in amyloid β protein-resistant cells.
        J Neurosci. 1996; 16: 497-505
        • Lindheim SR
        • Legro RS
        • Bernstein L
        • et al.
        Behavioral stress responses in premenopausal and postmenopausal women and the effects of estrogen.
        Am J Obstet Gynecol. 1992; 167: 1831-1836
        • Davis KL
        • Davis BM
        • Greenwald BS
        • et al.
        Cortisol and Alzheimer’s disease.
        Am J Psychiatry. 1986; 143: 442-446
        • Heuser IJ
        • Litvan I
        • Juncos JL
        • et al.
        Cortisol baseline secretion and memory performance in patients with dementia of the Alzheimer type.
        in: Agnoli A Cahn J Lassen N Mayeux R Senile Dementias: II International Symposium. John Libbey Eurotext, Paris1988: 351-353
        • De Leon MJ
        • McRae T
        • Iasi JR
        • et al.
        Abnormal hypercortisolemic response in Alzheimer’s disease linked to hippocampal atrophy.
        Lancet. 1988; ii: 391-392
        • 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
        • McEwen BS
        • Sapolsky RM
        Stress and cognitive function.
        Curr Opin Neurobiol. 1995; 5: 205-216
        • Coyle JT
        • Price DL
        • DeLong MR
        Alzheimer’s disease: a disorder of cortical cholinergic innervation.
        Science. 1983; 219: 1184-1190
        • Knapp MJ
        • Knopman DS
        • Solomon PR
        • Pendlebury WW
        • Davis CS
        • Garcon SI
        A 30-week randomized controlled trial of high-dose tacrine in patients with Alzheimer’s disease.
        JAMA. 1994; 271: 985-991
        • Schneider LS
        • Farlow MR
        • Henderson VW
        • Pogoda JM
        Effects of estrogen replacement therapy on response to tacrine in patients with Alzheimer’s disease.
        Neurology. 1996; 46: 1580-1584
        • Kimura D
        • Hampson E
        Cognitive pattern in men and women is influenced by fluctuations in sex hormones.
        Curr Dir Psychol Sci. 1994; 3: 57-61
        • Van Goozen SHM
        • Cohen-Kettenis PT
        • Gooren LJG
        • Frijda NH
        • Van de Poll NE
        Gender differences in behaviour: activating effects of cross-sex hormones.
        Psychoneuroendocrinology. 1995; 20: 343-363
        • Sherwin BB
        Estrogen and/or androgen replacement therapy and cognitive functioning in surgically menopausal women.
        Psychoneuroendocrinology. 1988; 13: 345-357
        • Phillips SM
        • Sherwin BB
        Effects of estrogen on memory function in surgically menopausal women.
        Psychoneuroendocrinology. 1992; 17: 485-495
        • Kampen DL
        • Sherwin BB
        Estrogen use and verbal memory in healthy postmenopausal women.
        Obstet Gynecol. 1994; 83: 979-983
        • Robinson D
        • Friedman L
        • Marcus R
        • Tinklenberg J
        • Yesavage J
        Estrogen replacement therapy and memory in older women.
        J Am Geriatr Soc. 1994; 42: 919-922
        • Henderson VW
        • Watt L
        • Buckwalter JG
        Cognitive skills associated with estrogen replacement in women with Alzheimer’s disease.
        Psychoneuroendocrinology. 1996; 21: 421-430
        • Barrett-Connor E
        • Kritz-Silverstein D
        Estrogen replacement therapy and cognitive function in older women.
        JAMA. 1993; 269: 2637-2641
        • Doody RS
        • Young R
        • Lynn P
        • Cooke N
        • Rosenfeld JE
        Estrogen and psychomotor performance. (Abstr.).
        J Neuropsych Clin Neurosci. 1995; 7: 410
        • Schneider MA
        • Brotherton PL
        • Hailes J
        The effect of exogenous oestrogens on depression in menopausal women.
        Med J Austral. 1977; 2: 162-163
        • Sherwin BB
        Affective changes with estrogen and androgen replacement therapy in surgically menopausal women.
        J Affect Disord. 1988; 14: 177-187
        • Ditkoff EC
        • Crary WG
        • Cristo M
        • Lobo RA
        Estrogen improves psychological function in asymptomatic postmenopausal women.
        Obstet Gynecol. 1991; 78: 991-995
        • Best NR
        • Rees MP
        • Barlow DH
        • Cowen PJ
        Effect of estradiol implant on noradrenergic function and mood in menopausal subjects.
        Psychoneuroendocrinology. 1992; 17: 87-93
        • Palinkas LA
        • Barrett-Connor E
        Estrogen use and depressive symptoms in postmenopausal women.
        Obstet Gynecol. 1992; 80: 30-36
        • Vermeulen A
        • Verdonck L
        Sex hormone concentrations in post-menopausal women: relation to obesity, fat mass, age and years post-menopause.
        Clin Endocrinol. 1978; 9: 59-66
        • Meldrum DR
        • Davidson BJ
        • Tataryn IV
        • Judd HL
        Changes in circulating steroids with aging in postmenopausal women.
        Obstet Gynecol. 1981; 57: 624-628
        • Berlinger WG
        • Potter JF
        Low body mass index in demented outpatients.
        J Am Geriatr Soc. 1991; 1991: 973-978
        • Wolf-Klein GP
        • Silverstone FA
        • Levy AP
        Nutritional patterns and weight change in Alzheimer patients.
        Intern Psychogeriatr. 1992; 4: 103-118
        • Buckwalter JG
        • Schneider LS
        • Wilshire TW
        • Dunn ME
        • Henderson VW
        Body weight, estrogen and cognitive functioning in Alzheimer’s disease: an analysis of the tacrine study group.
        Arch Gerontol Geriatr. 1997; 24: 261-267
        • Fillit H
        • Weinreb H
        • Cholst I
        • et al.
        Observations in a preliminary open trial of estradiol therapy for senile dementia—Alzheimer’s type.
        Psychoneuroendocrinology. 1986; 11: 337-345
        • Honjo H
        • Ogino Y
        • Naitoh K
        • et al.
        In vivo effects by estrone sulfate on the central nervous system—senile dementia (Alzheimer’s type).
        J Steroid Biochem. 1989; 34: 521-525
        • Honjo H
        • Ogino Y
        • Tanaka K
        • et al.
        An effect of conjugated estrogen to cognitive impairment in women with senile dementia—Alzheimer’s type: a placebo-controlled double blind study.
        J Japan Menopause Soc. 1993; 1: 167-171
        • Ohkura T
        • Isse K
        • Akazawa K
        • Hamamoto M
        • Yaoi Y
        • Hagino N
        Evaluation of estrogen treatment in female patients with dementia of the Alzheimer type.
        Endocrine J. 1994; 41: 361-371
        • Ohkura T
        • Isse K
        • Akazawa K
        • Hamamoto M
        • Yaoi Y
        • Hagino N
        Low-dose estrogen replacement therapy for Alzheimer disease in women.
        Menopause. 1994; 1: 125-130
        • Henderson VW
        • Paganini-Hill A
        • Emanuel CK
        • Dunn ME
        • Buckwalter JG
        Estrogen replacement therapy in older women: comparisons between Alzheimer’s disease cases and nondemented control subjects.
        Arch Neurol. 1994; 51: 896-900
        • Birge SJ
        The role of estrogen deficiency in the aging central nervous system.
        in: Lobo RA Treatment of the Postmenopausal Woman: Basic and Clinical Aspects. Raven Press, New York1994: 153-157
        • Mortel KF
        • Meyer JS
        Lack of postmenopausal estrogen replacement therapy and the risk of dementia.
        J Neuropsychiatr Clin Neurosci. 1995; 7: 334-337
        • Lerner A
        • Cole R
        • Debanne S
        • et al.
        Immunological and endocrine conditions in an Alzheimer’s disease case-control study. (Abstr.).
        Neuroepidemiology. 1995; 14: 307
        • Heyman A
        • Wilkinson WE
        • Stafford JA
        • Helms JJ
        • Sigmon AH
        • Weinberg T
        Alzheimer’s disease: a study of epidemiological aspects.
        Ann Neurol. 1984; 15: 335-341
        • Amaducci LA
        • Fratiglioni L
        • Rocca WA
        • et al.
        Risk factors for clinically diagnosed Alzheimer’s disease: a case-control study of an Italian population.
        Neurology. 1986; 36: 922-931
        • Broe GA
        • Henderson AS
        • Creasey H
        • et al.
        A case-control study of Alzheimer’s disease in Australia.
        Neurology. 1990; 40: 1698-1707
        • Graves AB
        • White E
        • Koepsell TD
        • et al.
        A case-control study of Alzheimer’s disease.
        Ann Neurol. 1990; 28: 766-774
        • Paganini-Hill A
        • Henderson V
        Estrogen deficiency and risk of Alzheimer’s disease in women.
        Am J Epidemiol. 1994; 140: 256-261
        • Brenner DE
        • Kukull WA
        • Stergachis A
        • et al.
        Postmenopausal estrogen replacement therapy and the risk of Alzheimer’s disease: a population-based case-control study.
        Am J Epidemiol. 1994; 140: 262-267
        • Tang M-X
        • Jacobs D
        • Stern Y
        • et al.
        Effect of oestrogen during menopause on risk and age at onset of Alzheimer’s disease.
        Lancet. 1996; 348: 429-432
        • Sands R
        • Studd J
        Exogenous androgens in postmenopausal women.
        Am J Med. 1995; 98: 76S-79S
        • Vermeulen A
        Androgens in the aging male.
        J Clin Endocrinol Metab. 1991; 73: 221-224
        • Janowsky JS
        • Oviatt SK
        • Orwoll ES
        Testosterone influences spatial cognition in older men.
        Behav Neurosci. 1994; 108: 325-332
        • Hemminki E
        • Malin M
        • Topo P
        Selection to postmenopausal therapy by women’s characteristics.
        J Clin Epidemiol. 1993; 46: 211-219
        • Sturgeon SR
        • Schairer C
        • Brinton LA
        • Pearson T
        • Hoover RN
        Evidence of a healthy estrogen user survivor effect.
        Epidemiology. 1995; 6: 227-231
        • Wysowski DK
        • Golden L
        • Burke L
        Use of menopausal estrogens and medroxyprogesterone in the United States, 1982–1992.
        Obstet Gynecol. 1995; 85: 6-10
        • Stampfer MJ
        • Colditz GA
        Estrogen replacement and coronary heart disease: a quantitative assessment of the epidemiologic evidence.
        Prevent Med. 1991; 20: 47-63
        • Folsom AR
        • Mink PJ
        • Sellers TA
        • Hong C-P
        • Zheng W
        • Potter JD
        Hormonal replacement therapy and morbidity and mortality in a prospective study of postmenopausal women.
        Am J Public Health. 1995; 85: 1128-1132
        • Ettinger B
        • Friedman GD
        • Bush T
        • Quesenberry Jr., CP
        Reduced mortality associated with long-term postmenopausal estrogen therapy.
        Obstet Gynecol. 1996; 87: 6-12