Biology 202
2000 Third Web Report
On Serendip

Who Can Fill the Holes in the Brain? Estrogen and Alzheimer's Disease

Maria Vasiliadis

William Shakespeare (1564-1616) called old age a second childhood-a period of both physical and mental weakness. In his description of the seven ages of man, he had this to say about old age:

Last scene of all,

What ends this strange eventful history,

Is second childishness and mere oblivion,

Sans teeth, sans eyes, sans taste, sans every thing.

-As you Like It II :vii-

As we grow older, we will begin to lose more of our motor functioning. While this is most apparent with physical memory 'losing our mind' is what terrifies most of us. Alzheimer's disease (AD) is a devastating, progressive, presently incurable brain disorder that, affects less than one out of every 20 people between 65 and 75, no more than one out of every 10 people between 75 and 85, and nearly one out of every three over the age of 85. It is the most common cause of dementia in older people, and is believed to affect about 4 million American adults (1). The disease usually begins after age 65, and the risk of acquiring it goes up with age. Alzheimer's is one of the most debilitating and dreaded diseases of aging, and until a few years ago used to be described more generally as senile dementia, now sometimes as senile dementia of the Alzheimer type. At present, the causes of Alzheimer's are unknown, and it is neither preventable nor curable. Although no cures have been found, prevention and improvements of patients suffering from Alzheimer's have been found. In particular estrogen, a female hormone, has been shown to help prevent Alzheimer's in female patients because of its benefits to improve on memory.

Memory, which links Alzheimer's disease and estrogen is complicated; the theories about it range far and wide; the literature covering it is copious enough to fill a good sized library; and, with all that, no one yet has all the answers. Even though estrogen does not offer a cure for Alzheimer's disease nor is estrogen offering a prevention since the cause of it is still unknown, but rather certain factors and research are showing some evidence of reducing the risk.

Estrogen, the primary female hormone, appears to have properties that protect against the memory loss and lower mental functioning associated with normal aging. Studies also report that there is a connection between estrogen replacement therapy (ERT) and protection against Alzheimer's. Studies suggest that 40 to 60 percent reductions in the risk of Alzheimer' s are seen in women who have taken supplemental hormone (2). New research is leading to a better understanding of how estrogen interacts with other chemicals to carry out many tasks, insight on how memories are made and how dementia is born and the effects estrogen treatments can have on Alzheimer's patients or patients prone to the disease. Clinical evidence suggests however that estrogen may be women's secret defense against Alzheimer's to delay their onset and lessen their symptoms.

Our potential to remember began, of course, when we were born, but our memory ability took a great spurt when we were about eight months old. It was then that we had enough experience and brain growth to begin to develop what child psychologists call active memory, that is the ability to retrieve the past, to hold it in the present, and to simultaneously compare and relate new or incoming information with that past knowledge. It's a skill we continue to develop and to bring into our adult life. It allows us to find connections between "pieces" of experience. That ability to continue to make memories and new connections during our lifetime has led cognitive researchers to believe that the brain actually has more plasticity-that certain neurons can change structurally or functionally-than they previously thought. Once we reach adulthood, and certainly by middle age, our memory starts to decline and in the case of Alzheimer's disease it is a decline in memory and the progressive decline of brain cells (3).

It should already be apparent that much of the knowledge of both the taxonomy and the biology of human memory is based on the subject of memory dysfunctions. Until just a few years ago, physicians did not need to know very much about the scientific underpinnings of Alzheimer's disease. The hallmarks of the disease were plaques and tangles; plaques are proteinaceous deposits outside cells and neurofibrillary tangles are the debris inside neurons, both described by Alois Alzheimer in the beginning of the twentieth century. Plaques and tangles could be counted more accurately and described more precisely today than in 1906, thanks to new technology (3).

First identified in 1906 by the German physician Alois Alzheimer, in its advanced stage it progresses well beyond the normal aging process, (the early stage of AD looks very much like aged associated memory impairment (AAMI)). Indeed, the difference between the two is not always easy to diagnose. In fact, it took a lot of work to even lay down the definitions needed to differentiate one from the other. Before Dr. Alzheimer's discovery, the disorder was frequently described simply as senile dementia. Even though the small group of pioneers who conducted research on the disease in the 1970s has expanded to thousands of scientist all over the world, the cause of AD is still unknown. The means by which the brain cells in AD die much more rapidly than ages associated memory impairments is a matter of intensive study. Much of the evidence points to a factor known as beta-amyloid protein, which is a major component in the nerve cells. Although beta-amyloid, a waxy substance consisting of some protein combined with certain carbohydrates, is present in normal brains and has a normal biological function the brains of AD patients seem to produce an overabundance (3).

This very high concentration is toxic to nerve cells and may cause the hipppocampal neurons to degenerate, so that short-term memory and the ability to perform routine tasks begin to falter. As the disease spreads through the cerebral cortex, it begins to take away language. In its final stages, the disease wipes out a person's ability to recognize even close family members or to communicate in any way, leaving them completely dependent on others for care. In AD, nerve cell death begins insidiously, many years before the onset of memory loss or any other symptoms. During that time, remaining nerve cells in particular area of the brain die and symptoms begin. After diagnosis, the average survival of people with AD ranges from four to eight years, although some may live for as long as 20 years. Typically they die from pneumonia or other disease. The drug tacrine may slightly alleviate some cognitive symptoms, while other medications may be of limited help in somewhat controlling such behavioral symptoms of AD such as sleeplessness, agitation, wandering, anxiety, and depression. Treating symptoms often helps Alzheimer's patients be more comfortable and makes their care a little easier for caregivers. However, sadly, nothing close to a cure is yet available (4)..

With research being done new studies are showing two interesting turns in the story of Alzheimer's disease. The first deal with the theory that more women are likely to get AD and the other is that estrogen is linked in the prevention and ability to enhance memory. New research shows that by next century, women will be twice as likely as men to have the disease (5).. This involvement of sex in the equation awakes us to the fact that men lose brain cells three times as fast as women do. Although the brains of males are larger in youth, by middle age they have come to be about the same size as that of females. Men generally have thicker, more developed right hemisphere and typically perform better than women on visual spatial tasks of memory. Women, who have more developed left hemisphere, outperform men on tests of verbal fluency and do better in remembering details. These differences are juts some of the variations between men and women. What scientists are discovering is that these differences may be, in part, due to hormones (6).

Several controlled clinical studies of the administration of estrogen to postmenopausal women have found that estrogen enhances verbal memory and helps maintain the ability to learn new material (6). Estrogen activates neural pathways in women that were already established under its influence during prenatal life. Estrogen also increases the production of the neurotransmitters acetylcholine and stimulates a significant increase in dopamine receptors in the brain (6). From this information scientists found that estrogen boosts the production of acetylcholine and impedes the deposit of beta-amyloid, the protein believed to be involved in the characteristic plaques of Alzheimer's disease. In one of the most remarkable findings to date, a16 year study by scientists at the National Institute of Aging at Johns Hopkins, showed that a history of estrogen-replacement therapy (ERT) in women after menopause was associated with close to a 50 percent reduction in the risk of developing Alzheimer's disease (7). Estrogen may also improve blood flow and helps maintain the integrity of the hippocampus. When some of the same researchers in the preceding study compared 116 postmenopausal women who were receiving ERT with 172 women who had never received ERT, those who were taking the hormone showed fewer errors on a measure of short term visual memory and on visual perception. Furthermore, EPT appeared to protect against age changes in a subgroup of 18 women for memory scores were available before and during ERT treatment (8).

Dr. Stanley J. Birge, MD, associate professor, Division of Geriatrics, Washington University School of Medicine, St. Louis, Missouri, has done further research on the effects of estrogen preventing and treating Alzheimer's disease. Dr. Birge believes that estrogen is a major player in AD and in other neurodegenerative processes. What they found was that women with a history of myocardial infraction are more likely to have Alzheimer's disease, which may be because of MI in women, is a detector for relative estrogen deficiency. Also women who have had a hysterectomy also are more likely to develop AD, this suggests that the loss of estrogen at menopause may contribute to the dementia that develops 15 to 25 years later after menopause (9).One study that illustrates the connection between AD and estrogen was a study of 8,00 older women from 1981 to 1992. During that time 2,00 deaths were seen in the group. Those that died of AD were matched with controls and compared for use of estrogen. The researchers found that a woman's risk of dying from AD was reduced by 50 percent when taking estrogen. It also showed that the risk varied with the dose of estrogen taken (9).

While research continues, there is still no clear understanding of how estrogen works to lower the risk of AD or delay the onset of symptoms. Some research suggests that it actually helps brain cells survive, thus slowing the onset of the disease. The results of other studies suggest that it has a role in preventing the formation of beta-amyloid fibers (a protein associated with neuron damage) in the brain. Another theory is that estrogen works as an antioxidant to protect nerve cells. Reports from these population based studies also suggest that estrogen may help to maintain or improve cognitive abilities in postmenopausal women. Similarly in community based samples, what was observed was preservation of verbal memory, abstract reasoning and language skills among women reporting estrogen use in the past. The results of several small trails of estrogen therapy in AD patients generally show improvement in emotional and cognitive measures. Others have demonstrated improvement in memory, orientation and calculation, although most studies have been small, improvement in global ratings, mental status examination and depression scales have been reported in patients with AD using estrogen.

The goal of finding a treatment to prevent or delay Alzheimer's disease has understandably received great attention in recent years. After age 65, the prevalence of dementia and Alzheimer's disease doubles every five years. Apart from the emotional, physical, and social costs, the economic cost of care for Alzheimer's patients is greater than that for heart disease and cancer combines (10).For now, estrogen is not prescribed solely for its protective effects against memory loss and AD. But it may offer that added benefit to women already taking it for other reasons. The changes in levels of neurotransmitters, the chemicals that bridge synapses between neurons, may play a role in AD. In 1976, researchers discovered that levels of the neurotransmitter acteylcholine dropped up to 90 percent in people with AD. And the number of synaptic connections between neurons was reduced by about 40 percent (11). But scientists now think the decrease on acetylcholine and other neurotansmitters may happen late in AD, and that the neurotransmitter decline may actually be a result of the disease process rather than a cause. To find the cause of neuron breakdown, researchers today are focusing on abnormal structures, the senile plaques and tangled nerve fiber, which are found throughout the brain of AD patients.

WWW Sources

1)Alzheimer's Disease Cooperative Study, Background information on AD and statistical results on patients suffering form AD.

2)Alzheimer's Disease, Information regarding prevention methods and basic background information.

3)Alzheimer's, Memory, and Acetylcholine, Information regarding memory and the chemical effects of acetylcholine in the brain.

4)Web Pages; Fighting Alzheimer's, Information about the drug tacrine used for AD patients.

5)Women More Likely to Get Alzheimer's, Information about the likely of women suffering greater form AD.

6)Estrogen Replacement May Help Slow Decline in Memory in Post-Menopausal Women, Information concerning the link between estrogen, menopause and AD.

7)Alzheimer's Disease; Unraveling the Mystery, Overview of research being down on Ad, history, background information, good source for information on causes and various treatments.

8)Estrogen Replacement May Help Slow Decline Memory, Information on estrogen replacement therapy.

9)Estrogen and Alzheimer's Disease , More treatment information and information on studies done on AD.

10)Brainwork-The Neuroscience Newsletter, Treatment information.

11)The Changes of Alzheimer's Disease, Information regarding the research about the causes of Alzheimer's disease.

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