Journal of Mid-life Health Journal of Mid-life Health
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 Table of Contents 
Year : 2014  |  Volume : 5  |  Issue : 1  |  Page : 38-40  

Alzheimer disease in post-menopausal women: Intervene in the critical window period

1 Department of Emergency Medicine, All India Institute of Medical Sciences, New Delhi, India
2 Department of Forensic Medicine, Hamdard Institute of Medical Sciences and Research, New Delhi, India

Date of Web Publication24-Feb-2014

Correspondence Address:
Nayer Jamshed
Department of Emergency Medicine, All India Institute of Medical Sciences, Ansari Nagar, New Delhi - 110 029
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0976-7800.127791

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Alzheimer disease (AD) is a crippling neurodegenerative disorder. It is more common in females after menopause. Estrogen probably has a protective role in cognitive decline. Large amount of research has been carried out to see the benefits of hormone replacement therapy with regards to Alzheimer still its neuroprotective effect is not established. Recent studies suggest a reduced risk of AD and improved cognitive functioning of post-menopausal women who used 17 β-estradiol in the critical period. Use of 17 β-estradiol in young and healthy post-menopausal women yields the maximum benefit when the neurons are intact or neuronal stress has just started. Hence intervention in the critical period is key in the prevention or delay of AD in post-menopausal women.

Keywords: 17 β-estradiol, Alzheimer disease, critical period, post-menopausal

How to cite this article:
Jamshed N, Ozair FF, Aggarwal P, Ekka M. Alzheimer disease in post-menopausal women: Intervene in the critical window period. J Mid-life Health 2014;5:38-40

How to cite this URL:
Jamshed N, Ozair FF, Aggarwal P, Ekka M. Alzheimer disease in post-menopausal women: Intervene in the critical window period. J Mid-life Health [serial online] 2014 [cited 2022 Nov 27];5:38-40. Available from:

   Introduction Top

Alzheimer's disease (AD) is the most common neurodegenerative disease, accounting for more than 50% of all dementia types. [1] Its twice more common in females which could be due to increased longevity and sex difference in brain size. [2] Estrogen has neurotrophic action in areas involved in memory and cognition. Post-menopausal women are at increased risk than their male counterpart. Women with Alzheimer have lower endogenous estrogen level which lead to the hypothesis that estrogen could be neuroprotective. Hormone replacement therapy (HRT) has been extensively studied in the past, but results were inconclusive. Recent studies suggest that 17 β-estradiol based therapies may provide the most beneficial neuroprotective effect. Early introduction and prolonged therapy preferably for <5 years with 17 β-estradiol prevents AD.

   Role of Estrogen Therapy in AD Top

Observational studies have examined both HRT and estrogen replacement therapy (ERT), in relation to AD. ERT was associated with moderately reduced risk for development of AD. [3] An inverse relationship was seen for the duration of ERT and risk for Alzheimer. [4] Increased risk of Alzheimer is seen with younger age at oophorectomy (bilateral or unilateral). These findings suggest that earlier age of surgical menopause increases the risk of cognitive impairment. [5] In Women's Health Initiative Memory Study (WHIMS), investigators enrolled 7479 post-menopausal women. A total of 4532 women with natural menopause were randomized into a trial comparing conjugated equine estrogen (CEE) with medroxyprogesterone (MPA) versus placebo. However, the trial was discontinued before completion due to unexpected adverse health risks. Study revealed that women who received CEE with MPA demonstrated greater cognitive decline compared with the placebo group. Additional analysis revealed that risk for dementia was doubled for women who received CEE with MPA compared with the placebo group. Taken together, data from the WHIMS demonstrated a higher incidence of dementia and greater cognitive decline among hormone user. [6],[7] Hence combination therapies that include progestin may actually ameliorate the beneficial effects of estrogen. [8] Predominant estrogen in premenopausal women is estradiol and its decline is more than estrone in post-menopausal age. CEE contains predominantly estrone rather than estradiol; it also contains other hormones which are not desired. In contrast 17 β-estradiol, administration achieved a hormone state close to that observed prior to menopause.

   Role of 17 β-Estradiol in AD Top

Studies suggest that 17 β-estradiol significantly improved the verbal memory by enhancing verbal information processing and decreased forgetfulness. It reduced the errors in memory tasks. 17 β-estradiol increased the metabolism in receptive language and auditory association area. [9] For getting the desired result, a minimum of 3 months of therapy with no upper cut off is needed. [10] β-amyloid and tau proteins are involved in the structural changes that lead to AD pathology, particularly in the hippocampus, medial temporal, parietal and frontal cortical regions. [11] Evidence has shown that estrogen particularly 17 β-estradiol provides protection against β-amyloid induced damage and tau-related changes. [12] Neuroimaging outcomes have also been supportive of the benefits of 17 β-estradiol, particularly in the brain regions that show preclinical abnormalities in individuals who are at risk for AD. 17 β-estradiol, increases the blood flow to the hippocampus and superior temporal gyrus and it also activates left middle, superior frontal cortex and inferior parietal cortex during verbal memory encoding task on functional magnetic resonant imaging. [13],[14] 17 β-estradiol also reduces the level of amyloid precursor protein (APP) through enhanced alpha secretase processing resulting in marked reduction of APP-C terminal fragment, amyloid beta and plaque burden. It also enhances the level of transthyretin in the brain, which inhibits the aggregation of amyloid βeta into plaque. [15] 17 β-estradiol also promotes the growth and survival of cholinergic neurons, increases the density of hippocampal neurons and increases the synaptic plasticity in the hippocampus which enhance the short and long term memory. [16]

   Hypothesis of Healthy Cell Bias Top

17 β-estradiol benefits most to those post-menopausal women who are cognitively intact. It selectively benefits healthy neurons (healthy cell bias) or when neuronal stress has just started. [17] In degenerating neurons particularly in the presence of apolipoprotein E 4 , it is not helpful even at higher doses. [18]

   Hypothesis of Critical Period Top

There are studies which suggest that there may be a "critical period" for post-menopausal women during which 17 β-estradiol selectively provides a beneficial effect. Its benefit is more when cholinergic system is intact or transiently disrupted. Younger post-menopausal women have higher density of muscarinic receptor than an older one. 17 β-estradiol in early post-menopausal women significantly decreased the anticholinergic induced verbal memory task. [19],[20] In Cache County Study investigators enrolled 1768 women between 1995 and 2006 at the age of menopause who were given HRT particularly17 β-estradiol without progesterone. When started within a critical period of 5 years post-menopausal, it decreased the incidence of AD by 30%. [21]

   When and How to Give 17 β-Estradiol Top

Ideally 17 β-estradiol should be started within a critical period of 5 years post-menopause in a dose of 50 μg/day transdermally. Transdermal route byepasses the hepatic metabolism and hence results in steady state plasma concentration of estradiol. It also maintains 1:1 estrone to estradiol ratio which is normally observed in selected phases of the menstrual cycle. Duration of therapy with 17 β-estradiol can vary from 3 months to 10 years. Favorable results are noted from both short and long term therapy. [21],[22] Food and Drug Administration recommends HRT at lowest possible dose for the shortest duration but in 2013 British and International Menopause Society put no arbitrary limit on duration of HRT. If symptoms persist, the benefits of hormone therapy outweigh the risk. [23] The major concern with estrogen therapy is increased risk of venous thrombosis, coronary artery disease, breast and endometrial carcinoma, dysmenorrhea, abnormal vaginal bleeding and hypersensitivity. Screening of patients who are at risk to develop above complications and mammography should be done in every case. Regular annual follow-up for early detection of complication is advisable just like any other HRT.

   Conclusion Top

Neuroprotective role of estrogen containing hormone therapy is useful but controversial. Recent studies suggest that estrogen particularly 17 β-estradiol has a positive effect in increasing blood flow, stimulating dendrites, protecting against oxidative stress and modulating neurotransmitters. There appears to be a critical window (window of opportunity) between 50 and 60 years of age, ideally within first 5 years of menopause during which estrogens have this positive effect but thereafter the cells deteriorate and estrogen may accelerate cell damage, the so called "healthy cell bias". So it is advised to start 17 β-estradiol in early menopause for longer duration as an inverse relation exists between HRT and risk for AD. Additional research is needed to optimize hormone therapy to delay, prevent and treat AD and to prevent estrogen related complications such as carcinoma and venous thrombosis.

   References Top

1.Plassman BL, Langa KM, Fisher GG, Heeringa SG, Weir DR, Ofstedal MB, et al. Prevalence of dementia in the United States: The aging, demographics, and memory study. Neuroepidemiology 2007;29:125-32.  Back to cited text no. 1
2.Zandi PP, Carlson MC, Plassman BL, Welsh-Bohmer KA, Mayer LS, Steffens DC, et al. Hormone replacement therapy and incidence of Alzheimer disease in older women: The Cache County Study. JAMA 2002;288:2123-9.  Back to cited text no. 2
3.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;348:429-32.  Back to cited text no. 3
4.Paganini-Hill A, Henderson VW. Estrogen deficiency and risk of Alzheimer's disease in women. Am J Epidemiol 1994;140:256-61.  Back to cited text no. 4
5.Rocca WA, Grossardt BR, Maraganore DM. The long-term effects of oophorectomy on cognitive and motor aging are age dependent. Neurodegener Dis 2008;5:257-60.  Back to cited text no. 5
6.Shumaker SA, Legault C, Rapp SR, Thal L, Wallace RB, Ockene JK, 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;289:2651-62.  Back to cited text no. 6
7.Rapp SR, Espeland MA, Shumaker SA, Henderson VW, Brunner RL, Manson JE, et al. Effect of estrogen plus progestin on global cognitive function in postmenopausal women: The Women's Health Initiative Memory Study: A randomized controlled trial. JAMA 2003;289:2663-72.  Back to cited text no. 7
8.Silverman DH, Geist CL, Kenna HA, Williams K, Wroolie T, Powers B, et al. Differences in regional brain metabolism associated with specific formulations of hormone therapy in postmenopausal women at risk for AD. Psychoneuroendocrinology 2011;36:502-13.  Back to cited text no. 8
9.Joffe H, Hall JE, Gruber S, Sarmiento IA, Cohen LS, Yurgelun-Todd D, et al. Estrogen therapy selectively enhances prefrontal cognitive processes: A randomized, double-blind, placebo-controlled study with functional magnetic resonance imaging in perimenopausal and recently postmenopausal women. Menopause 2006;13:411-22.  Back to cited text no. 9
10.Dumas J, Hancur-Bucci C, Naylor M, Sites C, Newhouse P. Estradiol interacts with the cholinergic system to affect verbal memory in postmenopausal women: Evidence for the critical period hypothesis. Horm Behav 2008;53:159-69.  Back to cited text no. 10
11.Small GW, Kepe V, Ercoli LM, Siddarth P, Bookheimer SY, Miller KJ, et al. PET of brain amyloid and tau in mild cognitive impairment. N Engl J Med 2006;355:2652-63.  Back to cited text no. 11
12.Xu H, Wang R, Zhang YW, Zhang X. Estrogen, beta-amyloid metabolism/trafficking, and Alzheimer's disease. Ann N Y Acad Sci 2006;1089:324-42.  Back to cited text no. 12
13.Maki PM, Resnick SM. Longitudinal effects of estrogen replacement therapy on PET cerebral blood flow and cognition. Neurobiol Aging 2000;21:373-83.  Back to cited text no. 13
14.Persad CC, Zubieta JK, Love T, Wang H, Tkaczyk A, Smith YR. Enhanced neuroactivation during verbal memory processing in postmenopausal women receiving short-term hormone therapy. Fertil Steril 2009;92:197-204.  Back to cited text no. 14
15.Amtul Z, Wang L, Westaway D, Rozmahel RF. Neuroprotective mechanism conferred by 17 beta-estradiol on the biochemical basis of Alzheimer's disease. Neuroscience 2010;169:781-6.  Back to cited text no. 15
16.Luine VN. Estradiol increases choline acetyltransferase activity in specific basal forebrain nuclei and projection areas of female rats. Exp Neurol 1985;89:484-90.  Back to cited text no. 16
17.Chen S, Nilsen J, Brinton RD. Dose and temporal pattern of estrogen exposure determines neuroprotective outcome in hippocampal neurons: Therapeutic implications. Endocrinology 2006;147:5303-13.  Back to cited text no. 17
18.Brown CM, Choi E, Xu Q, Vitek MP, Colton CA. The APOE4 genotype alters the response of microglia and macrophages to 17beta-estradiol. Neurobiol Aging 2008;29:1783-94.  Back to cited text no. 18
19.Craig MC, Murphy DG. Alzheimer's disease in women. Best Pract Res Clin Obstet Gynaecol 2009;23:53-61.  Back to cited text no. 19
20.Norbury R, Travis MJ, Erlandsson K, Waddington W, Ell PJ, Murphy DG. Estrogen therapy and brain muscarinic receptor density in healthy females: A SPET study. Horm Behav 2007;51:249-57.  Back to cited text no. 20
21.Shao H, Breitner JC, Whitmer RA, Wang J, Hayden K, Wengreen H, et al. Hormone therapy and Alzheimer disease dementia: New findings from the Cache County Study. Neurology 2012;79:1846-52.  Back to cited text no. 21
22.Wharton W, Baker LD, Gleason CE, Dowling M, Barnet JH, Johnson S, et al. Short-term hormone therapy with transdermal estradiol improves cognition for postmenopausal women with Alzheimer's disease: Results of a randomized controlled trial. J Alzheimers Dis 2011;26:495-505.  Back to cited text no. 22
23.Pitkin J. Alternative and complementary therapies for the menopause. Menopause Int 2012;18:20-7.  Back to cited text no. 23

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