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Written by Dr. Welsh, Article reviewed and edited by Dr. Fine M.D..
Published on 08 March 2013

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Estrogen Hormone Replacement Therapy May Diminish Alzheimer's Disease Risk

What is Alzheimer's?

Alzheimer's disease is the most diagnosed form of dementia in the world. As of yet there is no cure for the disease, but researchers worldwide are spending their entire careers attempting to discover ways to alleviate or even cure the syndrome. Our knowledge of the disease grows more quickly by the year and there is significant hope that within the coming generation our world's greatest minds will discover a means to defeat this dreaded degenerative condition. Alzheimer's develops in a different pattern and at a different speed for every patient, but the common symptoms are:

  • Increased aggression and irritability

  • High levels of confusion and disorientation

  • Rapid changes in mood

  • Atrophy of language ability

  • Long term, and eventually short term memory loss

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  • In later stages, a loss of physiological control, in which over time, the patient is eventually completely dependent upon a caregiver

There are three primary hypotheses regarding the cause of Alzheimer's:

Cholinergenic Hypothesis:

This was the original hypothesis regarding Alzheimer's disease, and treatment approaches using this theory as a starting point produce only minimal beneficial effects. This hypothesis predicts that Alzheimer's disease is largely the result of a reduced ability for the brain to synthesize acetylcholine.

Tau Hypothesis:

This hypothesis centers around the idea that abnormalities in a certain type of protein known as Tau Protein can cause the effects of Alzheimer's disease. It is hypothesized that hyperphosphorylated tau interacts with other forms of tau protein, creating clumps of protein known as neurofibrillary tangles inside of nerve cells. These tangles disrupt the function of nerve cells, clogging up the active transport system and preventing neuronal messages from reaching target destinations. At first, this leads to misdirected neuron firing but can eventually lead to the death of the neurons themselves.

The Amyloid hypothesis

The Amyloid Hypothesis is the most widely researched and studied hypothesis, and is the hypothesis for which the research discussed in this article is related to. According to this hypothesis, Alzheimer's is primarily caused by the formation of Beta-Amyloid deposits in the brain which clog up neuronal pathways, leading to the detrimental effects of the disease. One of the primary reasons why this hypothesis carries so much weight is because individuals who display an increased proclivity for the formation of these proteins display a greatly increased risk of the disease. Individuals with Down syndrome have three copies of this genetic abnormality, and as a result, these patients display symptoms of Alzheimer's at an age as early as 40.

New Study: APoE4 Precursor for Alzheimer's and Advanced Aging

Endocrinologists have made a number of discoveries regarding the effect of Estrogen Replacement Therapy on Alzheimer's, and New clinical research provides evidence that Estrogen Hormone Treatments may be able to slow down the process of aging in middle-aged females who are at increased risk of Alzheimer's disease. In this clinical study, otherwise healthy female patients who were going through menopause while also harboring a genetic increased risk of Alzheimer's did not succumb to the disease when treated with Hormone Replacement Therapy.

The genetic abnormality APoE4 has been linked to processes which speed up the natural aging process in women. Hormone Replacement Therapy featuring Estrogen may counteract the detrimental effects of this genetic condition and help older women avoid the ravages of Alzheimer's disease.

What is APoE4?

AP0e4 is the strongest causal genetic link for developing Alzheimer's disease. This gene is responsible for the production of an enzyme known as Apolipoprotein E Type 4. Apolipoprotein E is primarily released by macrophages and the liver in order to break down triglycerides. Ap0E4 performs this function, but is also correlated with creating devastating protein abnormalities in the brain which lead to Alzheimer's. Those who carry 2 copies of the Ap0E4 gene have a ten to thirty times increased likelihood of developing Alzheimer's disease.

Ap0E4 is so strongly correlated with Alzheimer's disease that James Watson, one member of the duo of scientists who first discovered the existence of DNA, refuses to be tested for the genetic abnormality. Individuals who have an active Ap0E4 gene have a 90% chance of developing Alzheimer's by the age of eighty without treatment. Although Alzheimer's research is incredibly active, there are still more questions than answers in regard to this devastating disease.

APoE4 Slowly Degrades the Body

According to Dr. Natalie Rasgon, ApoE4 affects women at the cellular level long before these changes affect the body to a noticeable extent, increasing the physiological age of the cells long before this aging process becomes apparent and symptomatic. Dr. Rasgon is a professor of behavioral science and psychiatry at the Stanford School of Medicine in California.

This new study provides further evidence that Estrogen Replacement Therapy may be able to shield many older women from the effects of Alzheimer's diseaseespecially those who harbor this critical gene.

One of a Number of Studies Linking APoE4 to Alzheimer's

There have been a number of previously conducted studies which have shown that ApoE4 likely plays a role in Alzheimer's disease and general cognitive decline as a result of the aging process.

In another similar study, not directly related to ApoE4, 472 female patients were followed for 16 years. Some of the participants utilized Hormone Replacement Therapy while others did not utilize the treatment. Researchers found that patients who used Estrogen in addition to other forms of Hormone Replacement Therapy had an incidence of Alzheimer's which was fifty percent lower than those patients which did not use the therapy.

This gene is incredibly common among Alzheimer's patients, and is active in around forty percent of patients that are afflicted with the disease.

Dr. Rasgon's laboratory group focused primarily on telomeres, which are caps which close off the ends of chromosomes and are responsible for genetic stability. These telomeres function like genetic fuses over time. Each time that a cell reproduces, the telomeres become slightly shorter in length.

What are Telomeres?

Telomeres are areas of DNA which are at the ends of chromosome strands which consist of repeating lines of genetic data which are inert. These lines form a sort of cap on the ends of the chromosomes in order to prevent them from breaking down. During the process of cell replication, the enzymes which encourage the reproduction of chromosomes are unable to perform their function all the way to the very ends of cells, leaving a very brief portion of the chromosome un-copied.

If chromosomes did not have telomeres which featured this inert genetic data, then every time the cells divided, our chromosomes would lose vital genetic code and our bodies would deteriorate. These telomeres are partially consumed by the enzymes which encourage cell replication, but there are other cellular enzymes which are responsible for rebuilding telomeres. These cells are known as Telomerase Reverse Transcriptase. Under normal circumstances, telomeres set a soft limit on the natural life spans of animals, including humans. Telomeres play a major role in the aging process.

Studies such as those performed by Dr. Ragson help us understand more about telomeres and how we can extend our lifespans by manipulating the rate at which telomeres break down. There is also ongoing research regarding ways that telomeres can be adequately preserved or even lengthened in order to extend the lifespan. In many ways Hormone Replacement Therapy and Telomere Maintenance appear to be related.

Alzheimer's Correlated to Quicker Aging

The current body of scientific knowledge suggests that Alzheimer's and the biological aging process are likely correlated in a large subset of female patients.

If the telomeres reach a certain abridged size, the cells can begin to die off, or in other cases, the cells may lose their ability to continue to divide.

When the cells start to function abnormally as a result of the aging process, the signs of aging begin to become physiologically apparent on a holistic level. Symptoms of aging such as loss of muscle tone and cognitive sharpness, as well as wrinkled skin start to manifest, in addition to other negative side-effects which affect every system of the human body.

The rate at which the telomeres shorten is highly variable among individuals, and this can be used in order to accurately measure biological age, which is systematically different from chronological age, affecting each individual at a unique rate not entirely dependent upon simply time.

The researchers studied telomeres sampled from white blood cells drawn from seventy completely healthy women, generally aged between forty five and sixty five. All seventy were taking Estrogen Hormone Replacement Therapy.

How Might Estrogen Prevent Alzheimer's?

When menopause begins, estrogen levels decline at a rapid pace. There are a number of symptoms that almost all women are aware of, including cold sweats, hot flashes, mood instability, and lapses in memory. What most women probably do not realize is that menopause can increase the risks of a number of other medical issues as well, including Alzheimer's disease. In the past, there have been a few small scale studies that suggested that Estrogen Replacement Therapy may be a treatment option for those who suffer from Alzheimer's disease.

Although the benefits in regard to reversing the effects of Alzheimer's with Estrogen Replacement Therapy seem to be slim, there is growing evidence that Estrogen may be able to prevent the disease or slow its progression, especially when utilized during the period of Menopause. These benefits may persist later in life as well, when Estrogen HRT is utilized in smaller doses.

New studies have also shown that Estrogen provides a number of benefits to the brain in addition to safeguarding it against the threat of Alzheimer's. There has been a significant amount of animal research performed in regard to the Effects of Estrogen on Brain Cells, and it is apparent that the hormone plays a major role in protecting and supporting the function of brain cells.

Estrogen Associated with Healthy Acetylcholine Levels

Healthy Estrogen levels are associated with optimal levels of acetylcholine in the brain, which is important to the maintenance of cognition and memory. Estrogen also apparently has the ability to shut down the formation of plaques known as Beta Amyloids, which cause the symptoms of Alzheimer's disease. Beta Amyloid plaques are the result of an enzyme abnormality which causes the enzymes to produce malfunctioning proteins which breakdown the function of the brain, eventually leading to total cognitive breakdown and death.

Although Estrogen alone may not be a proper treatment for active Alzheimer's, there is still promise that Estrogen HRT when utilized in combination with other forms of Alzheimer's medical treatment such as Aricept (donepezil) may be able to improve health outcomes for patients with Alzheimer's disease.

APoE4 Study Parameters

The seventy women on Estrogen HRT were split into two variable groups. The first group of women stayed on Hormone Replacement Treatments, while the second group stopped all hormone therapy.

After two years, the participants had their white blood cells drawn a second time, and the scientists measured the rate by which the length of the telomeres shortened.

Among the healthy patients who halted Hormone Replacement Therapy, those with the active Alzheimer's gene were found to be 6 times as likely to have telomeres which shortened at an abnormally rapid pace than participants who did not have an active Alzheimer's gene.

For these women who did have the active ApoE4 gene, the telomeres reduced in length at a rate which would normally be expected over the course of a decade, rather than simply two years. Physiologically, these women were aging at a rate which was five times as fast as those with the deactivated gene.

Estrogen Slows Down Biological Aging Associated with APoE4

Hormone Replacement Therapy featuring Estrogen was shown to alleviate this issue, however. In patients who were at enhanced risk of Alzheimer's yet remained on Estrogen HRT, telomere length shortened at a normal rate which correlated with their cohorts with the deactivated gene.

This is powerful evidence that Hormone Replacement Treatments with Estrogen may have the ability to delay or prevent Alzheimer's disease, although much more study is needed in order to prove the hypothesis.

Professor Rasgon says that this study increases our knowledge of the benefits of Estrogen Replacement Therapy and in the future will help us pinpoint exactly which patients are likely to receive the maximum benefit from the hormone treatment.

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