Hormone Replacement Therapy and Incidence of Alzheimer Disease in Older Women: The Cache County Study | Dementia and Cognitive Impairment | JAMA | JAMA Network
[Skip to Navigation]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address Please contact the publisher to request reinstatement.
Andersen K, Launer LJ, Dewey ME.  et al. for the EURODEM Incidence Research Group.  Gender differences in the incidence of AD and vascular dementia: the EURODEM Studies.  Neurology.1999;53:1992-1997.Google Scholar
Fratiglioni L, Viitanen M, von Strauss E.  et al.  Very old women at highest risk of dementia and Alzheimer's disease: incidence data from the Kungsholmen Project, Stockholm.  Neurology.1997;48:132-138.Google Scholar
Miech RA, Breitner JC, Zandi PP, Khachaturian AS, Anthony JC, Mayer L. Incidence of AD may decline in the early 90s for men, later for women: the Cache County Study.  Neurology.2002;58:209-218.Google Scholar
Skoog I, Gustafson D. HRT and dementia.  J Epidemiol Biostat.1999;4:227-251.Google Scholar
Heyman A, Wilkinson WE, Stafford JA.  et al.  Alzheimer's disease: a study of epidemiological aspects.  Ann Neurol.1984;15:335-341.Google Scholar
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.Google Scholar
Broe GA, Henderson AS, Creasey H.  et al.  A case-control study of Alzheimer's disease in Australia.  Neurology.1990;40:1698-1707.Google Scholar
Graves AB, White E, Koepsell TD.  et al.  A case-control study of Alzheimer's disease.  Ann Neurol.1990;28:766-774.Google Scholar
Henderson VW, Paganini-Hill A, Emanuel CK.  et al.  Estrogen replacement therapy in older women.  Arch Neurol.1994;51:896-900.Google Scholar
Paganini-Hill A, Henderson VW. Estrogen deficiency and risk of Alzheimer's disease in women.  Am J Epidemiol.1994;140:256-261.Google Scholar
Mortel KF, Meyer JS. Lack of postmenopausal estrogen replacement therapy and the risk of dementia.  J Neuropsychiatry Clin Neurosci.1995;7:334-337.Google Scholar
Lerner A, Koss E, Debanne S.  et al.  Smoking and oestrogen-replacement therapy as protective factors for Alzheimer's disease.  Lancet.1997;349:403-404.Google Scholar
Baldereschi M, Di Carlo A, Lepore V.  et al.  Estrogen-replacement therapy and Alzheimer's disease in the Italian Longitudinal Study on Aging.  Neurology.1998;50:996-1002.Google Scholar
Brenner DE, Kukull WA, Stergachis A.  et al.  Postmenopausal estrogen replacement therapy and the risk of Alzheimer's disease.  Am J Epidemiol.1994;140:262-267.Google Scholar
Waring SC, Rocca WA, Petersen RC.  et al.  Postmenopausal estrogen replacement therapy and risk of AD: a population-based study.  Neurology.1999;52:965-970.Google Scholar
Tang MX, 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.Google Scholar
Kawas C, Resnick S, Morrison 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.Google Scholar
Seshadri S, Zornberg GL, Derby LE.  et al.  Postmenopausal estrogen replacement therapy and the risk of Alzheimer disease.  Arch Neurol.2001;58:435-440.Google Scholar
Breitner JC, Wyse BW, Anthony JC.  et al.  APOE-∊-4 count predicts age when prevalence of AD increases, then declines: the Cache County Study.  Neurology.1999;53:321-331.Google Scholar
Teng EL, Chui HC. The Modified Mini-Mental State (3MS) examination.  J Clin Psychiatry.1987;48:314-318.Google Scholar
Jorm AF. A short form of the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE).  Psychol Med.1994;24:145-153.Google Scholar
Silverman JM, Breitner JC, Mohs RC, Davis KL. Reliability of the family history method in genetic studies of Alzheimer's disease and related dementias.  Am J Psychiatry.1986;143:1279-1282.Google Scholar
McKhann G, Drachman D, Folstein M.  et al.  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.Google Scholar
Allison P. Event History Analysis: Regression for Longitudinal Event Data. Beverly Hills, Calif; Sage Publications; 1984.
Anthony JC, Breitner JC, Zandi PP.  et al.  Reduced prevalence of AD in users of NSAIDs and H2 receptor antagonists: the Cache County Study.  Neurology.2000;54:2066-2071.Google Scholar
Finch CE, Kirkwood TBL. Chance, Development and Aging. New York, NY: Oxford University Press; 2000.
Matthews K, Cauley J, Yaffe K, Zmuda JM. Estrogen replacement therapy and cognitive decline in older community women.  J Am Geriatr Soc.1999;47:518-523.Google Scholar
in t' Veld BA, Ruitenberg A, Hofman A.  et al.  Nonsteroidal anti-inflammatory drugs and the risk of Alzheimer's disease.  N Engl J Med.2001;345:1515-1521.Google Scholar
Henderson VW, Paganini-Hill A, Miller BL.  et al.  Estrogen for Alzheimer's disease in women.  Neurology.2000;54:295-301.Google Scholar
Marder K, Sano M. Estrogen to treat Alzheimer's disease: too little, too late? so what's a woman to do?  Neurology.2000;54:2035-2037.Google Scholar
Mulnard RA, Cotman CW, Kawas C.  et al. for the Alzheimer's Disease Cooperative Study.  Estrogen replacement therapy for treatment of mild to moderate Alzheimer disease.  JAMA.2000;283:1007-1015.Google Scholar
Shumaker SA, Melton BA, Espeland MA.  et al.  The Women's Health Initiative Memory Study (WHIMS): a trial of the effect of estrogen therapy in preventing and slowing the progression of dementia.  Control Clin Trials.1998;19:604-621.Google Scholar
Original Contribution
November 6, 2002

Hormone Replacement Therapy and Incidence of Alzheimer Disease in Older Women: The Cache County Study

Author Affiliations

Author Affiliations: Department of Mental Hygiene, School of Hygiene and Public Health, the Johns Hopkins University, Baltimore, Md (Drs Zandi, Carlson, Mayer, and Breitner); Department of Psychiatry and Behavioral Sciences (Drs Plassman, Welsh-Bohmer, and Steffens), and The Joseph and Kathleen Bryan Alzheimer's Disease Research Center, Duke University Medical Center, Durham, NC (Dr Welsh-Bohmer); Banner Health System, Phoenix, Ariz (Dr Mayer); and VA Puget Sound Health Care System and Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle (Dr Breitner).

JAMA. 2002;288(17):2123-2129. doi:10.1001/jama.288.17.2123

Context Previous studies have shown a sex-specific increased risk of Alzheimer disease (AD) in women older than 80 years. Basic neuroscience findings suggest that hormone replacement therapy (HRT) could reduce a woman's risk of AD. Epidemiologic findings on AD and HRT are mixed.

Objective To examine the relationship between use of HRT and risk of AD among elderly women.

Design, Setting, and Participants Prospective study of incident dementia among 1357 men (mean age, 73.2 years) and 1889 women (mean age, 74.5 years) residing in a single county in Utah. Participants were first assessed in 1995-1997, with follow-up conducted in 1998-2000. History of women's current and former use of HRT, as well as of calcium and multivitamin supplements, was ascertained at the initial contact.

Main Outcome Measure Diagnosis of incident AD.

Results Thirty-five men (2.6%) and 88 women (4.7%) developed AD between the initial interview and time of the follow-up (3 years). Incidence among women increased after age 80 years and exceeded the risk among men of similar age (adjusted hazard ratio [HR], 2.11; 95% confidence interval [CI], 1.22-3.86). Women who used HRT had a reduced risk of AD (26 cases among 1066 women) compared with non-HRT users (58 cases among 800 women) (adjusted HR, 0.59; 95% CI, 0.36-0.96). Risk varied with duration of HRT use, so that a woman's sex-specific increase in risk disappeared entirely with more than 10 years of treatment (7 cases among 427 women). Adjusted HRs were 0.41 (95% CI, 0.17-0.86) for HRT users compared with nonusers and 0.77 (95% CI, 0.31-1.67) compared with men. No similar effect was seen with calcium or multivitamin use. Almost all of the HRT-related reduction in incidence reflected former use of HRT (9 cases among 490 women; adjusted HR, 0.33 [95% CI, 0.15-0.65]). There was no effect with current HRT use (17 cases among 576 women; adjusted HR, 1.08 [95% CI, 0.59-1.91]) unless duration of treatment exceeded 10 years (6 cases among 344 women; adjusted HR, 0.55 [95% CI, 0.21-1.23]).

Conclusions Prior HRT use is associated with reduced risk of AD, but there is no apparent benefit with current HRT use unless such use has exceeded 10 years.