The Role of Estrogen in the Development of Age-Related Cognitive Impairment and Dementia

By Julie Dumas, PhD, Jessica Salerno, and Paul Newhouse, MD | April 1, 2006

These results support the findings from the primate literature showing that estrogen and the cholinergic system interact to affect attentional performance.⁴² These findings further support the proposal that estrogen may preserve cognitive functions by acting through the cholinergic system as well as adding to the evidence showing that estrogen treatment after menopause may be beneficial for cognition. The estrogencholinergic system link has implications for the ability of estrogen to be useful in the prevention or treatment of AD. Many epidemiologic and some experimental studies support the use of estrogen for the maintenance of premenopausal levels of cognitive functioning in healthy older women and the possibility of prevention of AD.

Summary

While evidence is conflicting, estrogen cannot be recommended for the treatment of dementia but may have a role in preserving cognitive functioning in older women. Estrogen may have a dementia-prevention effect after menopause based on epidemiologic studies (not primary prevention studies), but this is not an approved indication. At this point, the off-label prescribing of estrogen for cognitive decline in the absence of dementia is not a routine clinical practice and should be regarded as appropriate only within the context of a research study. Estrogen may be used in late-stage dementia to treat aggressive or sexually disinhibited behavior,⁴⁵ but this would not be considered a routine use in dementia patients.

Estrogen use after menopause has been linked to increased risk of venous thrombosis, and this risk increases with age and years of estrogen treatment.⁴⁶ Therefore, if estrogen were to be used for the prevention of cognitive impairment, it may have to be started early (during or soon after menopause) and continued only until the risk of vascular and thrombolytic complications related to estrogen use begins to rise, possibly in the seventh decade.

Variables such as the type of estrogen, the method of administration, and the timing of ET relative to the menopause transition may affect the success of estrogen in preserving cognition and will require further research to resolve. Also, the role of progesterone(Drug information on progesterone) remains to be investigated. Evidence from our laboratory strongly suggests that beneficial effects of estrogen on cognition may be acting through salutary interactions with the brain cholinergic system, the same system that is responsible for the cognitive loss in AD.

Dr Dumas is a postdoctoral fellow at the Clinical Neuroscience Research Unit in the department of psychiatry at the University of Vermont in Burlington. She acknowledges project support from the National Institute on Aging.

Ms Salerno is a research associate at the Clinical Neuroscience Research Unit in the department of psychiatry at the University of Vermont in Burlington. She has no conflicts to report regarding the subject matter of this article.

Dr Newhouse is the director of the Clinical Neuroscience Research Unit and Functional Brain Imaging Program in the department of psychiatry at the University of Vermont in Burlington. He acknowledges project support from the National Institute on Aging and the National Center for Research Resources.

Pages: 1 2 3

References

1. Duka T, Tasker R, McGowan JF. The effects of 3- week estrogen hormone replacement on cognition in elderly healthy females. Psychopharmacology (Berl). 2000;149:129-139.
2. Jacobs DM, Tang MX, Stern Y, et al. Cognitive function in nondemented older women who took estrogen after menopause. Neurology. 1998;50:368-373.
3. Resnick SM, Metter EJ, Zonderman AB. Estrogen replacement therapy and longitudinal decline in visual memory. A possible protective effect? Neurology. 1997;49:1491-1497.
4. Smith YR, Giordani B, Lajiness-O&39;Neill R, Zubieta JK. Long-term estrogen replacement is associated with improved nonverbal memory and attentional measures in postmenopausal women. Fertil Steril. 2001;76:1101-1107.
5. Paganini-Hill A, Henderson VW. Estrogen deficiency and risk of Alzheimer&39;s disease in women. Am J Epidemiol. 1994;140:256-261.
6. Panidis DK, Matalliotakis IM, Rousso DH, et al. The role of estrogen replacement therapy in Alzheimer&39;s disease. Eur J Obstet Reprod Biol. 2001;95:86-91.
7. Tang MX, Jacobs D, Stern Y, et al. Effect of oestrogen during menopause on risk and age at onset of Alzheimer&39;s disease. Lancet. 1996;348:429-432.
8. Zandi PP, Carlson MC, Plassman BL, et al. Hormone replacement therapy and incidence of Alzheimer disease in older women: the Cache County Study. JAMA. 2002;288:2123-2129.
9. Manly JJ, Merchant CA, Jacobs DM, et al. Endogenous estrogen levels and Alzheimer&39;s disease among postmenopausal women. Neurology. 2000;54:833-837.
10. Cunningham CJ, Sinnott M, Denihan A, et al. Endogenous sex hormone levels in postmenopausal women with Alzheimer&39;s disease. J Clin Endocrinol Metab. 2001;86:1099-1103.
11. Bretsky PM, Buckwalter JG, Seeman TE, et al. Evidence for an interaction between apolipoprotein E genotype, gender, and Alzheimer disease. Alzheimer Dis Assoc Disord. 1999;13:216-221.
12. Yaffe K, Lui LY, Grady D, et al. Estrogen receptor 1 polymorphisms and risk of cognitive impairment in older women. Biol Psychiatr y. 2002;51:677-682.
13. Xu H, Gouras GK, Greenfield JP, et al. Estrogen reduces neuronal generation of Alzheimer betaamyloid peptides. Nat Med. 1998;4:447-451.
14. Kawas C, Resnick S, Morrison A, et al. A prospective study of estrogen replacement therapy and the risk of developing Alzheimer&39;s disease; the Baltimore Longitudinal Study of Aging [published correction appears in Neurology. 1998;51:654]. Neurology. 1997;48:1517-1521.
15. 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.
16. LeBlanc ES, Janowsky J, Chan BK, Nelson HD. Hormone replacement therapy and cognition: systematic review and meta-analysis. JAMA. 2001;285:1489- 1499.
17. Seshadri S, Zornberg GL, Derby LE, et al. Postmenopausal estrogen replacement therapy and the risk of Alzheimer disease. Arch Neurol. 2001;58:435-440.
18. Asthana S, Baker LD, Craft S, et al. High-dose estradiol improves cognition for women with AD: results of a randomized study. Neurology. 2001;57:605-612.
19. Henderson VW, Paganini-Hill A, Miller BL, et al. Estrogen for Alzheimer&39;s disease in women: randomized, double-blind, placebo-controlled trial. Neurology. 2000;54:295-301.
20. Mulnard RA, Cotman CW, Kawas C, et al. Estrogen replacement therapy for treatment of mild to moderate Alzheimer disease: a randomized controlled trial. Alzheimer&39;s Disease Cooperative Study [published correction appears in JAMA. 2000;284:2597]. JAMA. 2000;283:1007-1015.
21. Wang PN, Liao SQ, Liu RS, et al. Effects of estrogen on cognition, mood, and cerebral blood flow in AD: a controlled study. Neurology. 2000;54:2061- 2066.
22. Sherwin BB. Estrogen and/or androgen replacement therapy and cognitive functioning in surgically menopausal women. Psychoneuroendocrinology. 1988;13:345-357.
23. Phillips SM, Sherwin BB. Effects of estrogen on memory function in surgically menopausal women. Psychoneuroendocrinology. 1992;17:485-495.
24. Verghese J, Kuslansky G, Katz MJ, et al. Cognitive performance in surgically menopausal women on estrogen. Neurology. 2000;55:872-874.
25. Saletu B, Anderer P, Saletu-Zyhlarz GM, et al. Identifying target regions for vigilance improvement under hormone replacement therapy in postmenopausal syndrome patients by means of electroencephalographic tomography (LORETA). Psychopharmacology (Berl). 2005;178:389-399.
26. Barrett-Connor E, Kritz-Silverstein D. Estrogen replacement therapy and cognitive function in older women. JAMA. 1993;269:2637-2641.
27. Binder EF, Schechtman KB, Birge SJ, et al. Effects of hormone replacement therapy on cognitive performance in elderly women. Maturitas. 2001;38:137-146.
28. Ditkoff EC, Crary WG, Cristo M, Lobo RA. Estrogen improves psychological function in asymptomatic postmenopausal women. Obstet Gynecol. 1991;78:991-995.
29. Polo-Kantola P, Portin R, Polo O, et al. The effect of short-term estrogen replacement therapy on cognition: a randomized, double-blind, cross-over trial in postmenopausal women. Obstet Gynecol. 1998; 91:459-466.
30. Wolf OT, Heinrich AB, Hanstein B, Kirschbaum C. Estradiol or estradiol/progesterone treatment in older women: no strong effects on cognition. Neurobiol Aging. 2005;26:1029-1033.
31. Shumaker SA, Legault C, Kuller L, et al. Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Women&39;s Health Initiative Memory Study. JAMA. 2004;291:2947-2958.
32. Shumaker SA, Legault C, Rapp SR, et al. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women&39;s Health Initiative Memory Study: a randomized controlled trial. JAMA. 2003;289:2651- 2662.
33. Rapp SR, Espeland MA, Shumaker SA, et al. Effect of estrogen plus progestin on global cognitive function in postmenopausal women: the Women&39;s Health Initiative Memory Study: a randomized controlled trial. JAMA. 2003;289:2663-2672.
34. Grady D, Yaffe K, Kristof M, et al. Effect of postmenopausal hormone therapy on cognitive function: the Heart and Estrogen/progestin Replacement Study. Am J Med. 2002;113:543-548.
35. Vermeer SE, Prins ND, den Heijer T, et al. Silent brain infarcts and the risk of dementia and cognitive decline. N Engl J Med. 2003;348:1215-1222.
36. Simpkins JW, Green PS, Gridley KE, et al. Role of estrogen replacement therapy in memory enhancement and the prevention of neuronal loss associated with Alzheimer&39;s disease. Am J Med. 1997; 103(3A):19S-25S.
37. Gibbs RB. Basal forebrain cholinergic neurons are necessary for estrogen to enhance acquisition of a delayed matching-to-position T-maze task. Horm Behav. 2002;42:245-257.
38. Gibbs RB, Gabor R. Estrogen and cognition: applying preclinical findings to clinical perspectives. J Neurosci Res. 2003;74:637-643.
39. Yaffe K. Hormone therapy and the brain: deja vu all over again? JAMA. 2003;289:2717-2719.
40. Schneider LS, Farlow MR, Henderson VW, Pogoda JM. Effects of estrogen replacement therapy on response to tacrine in patients with Alzheimer&39;s disease. Neurology. 1996;46:1580-1584.
41. Gibbs RB. Fluctuations in relative levels of choline acetyltransferase mRNA in different regions of the rat basal forebrain across the estrous cycle: effects of estrogen and progesterone. J Neurosci. 1996; 16:1049-1055.
42. Tinkler GP, Voytko ML. Estrogen modulates cognitive and cholinergic processes in surgically menopausal monkeys. Prog Neuropsychopharmacol Biol Psychiatry. 2005;29:423-431.
43. Voytko ML. Estrogen and the cholinergic system modulate visuospatial attention in monkeys (Macaca fascicularis). Behav Neurosci. 2002;116:187-197.
44. Dumas J, Hancur-Bucci C, Naylor M, et al. Estrogen treatment effects on anticholinergically-induced cognitive dysfunction in normal postmenopausal women. Neuropsychopharmacology. 2006; Epub ahead of print.
45. Kyomen HH, Satlin A, Hennen J, Wei JY. Estrogen therapy and aggressive behavior in elderly patients with moderate-to-severe dementia: results from a short-term, randomized, double-blind trial. Am J Geriatr Psychiatry. 1999;7:339-348.
46. Cushman M, Kuller LH, Prentice R, et al. Estrogen plus progesterone and risk of venous thrombosis. JAMA. 2004;292:1573-1580.

The Role of Estrogen in the Development of Age-Related Cognitive Impairment and Dementia

Join the Conversation