Does estrogen prevent Alzheimer’s disease?

I don’t think many people will disagree with me if I say that the brain is the most important organ in the body.  We can live without some body parts and manage pretty well if other parts aren’t working 100%.  But most of us would prefer that our brains continue to function perfectly throughout our lives.

Unfortunately, this isn’t the case, and this is because we lose brain cells over time simply due to the aging process.  To put things in perspective, we are born with approximately 100 billion brain cells, and by age 30 we lose about 10,000 of these precious neurons per day.  This leads to a loss of brain function, which affects our memory, our thinking, our senses, and our physical abilities.  This age-related brain cell loss causes a fair amount of impairment as we get older, but many people can remain independent well into their 90’s.

Unfortunately, in some people, there is such a substantial amount of brain cell loss that the end result is an inability to function.  In this case, we describe the person as having dementia.

What is dementia and what causes it?

Dementia is generally defined as a persistent disorder of the mental processes characterized by memory dysfunction, personality changes, and impaired reasoning.  Late stages lead to an inability to perform even the simplest tasks such as communicating, feeding oneself, or walking.  There are a number of causes of dementia.

The most common cause is Alzheimer’s disease (AD).  The exact cause of AD remains elusive, but the hallmark of the disease is the presence of abnormal clumps of protein deposits within the brain, called amyloid plaques.  It is unclear why these develop and whether they are responsible for the neuron damage, or whether an underlying disorder of the neurons themselves initiates the problem.  Regardless, as Alzheimer’s progresses, there tends to be an accumulation of these deposits and progressive brain cell damage and destruction.

The other major type of dementia is called vascular dementia.  This is caused when damaged blood vessels in the brain create multiple small strokes.  The underlying process that leads to this is atherosclerosis – the medical term for “hardening of the arteries.”  The factors that promote this include smoking, high blood pressure, high cholesterol, and diabetes.  These conditions predispose people to building up plaque in the arteries, which eventually cause the blockages that create strokes.

A host of other insults can also cause dementia.  Anything that injures the brain falls into this category. This includes head injury, brain infections, inflammatory disorders, tumors, or toxic chemicals.

Genetics are also implicated in some forms of dementia.  There are a few rare genetic disorders that cause people to develop dementia at relatively young ages.  You may have also heard of the APOE genes and their association with dementia.  These are not abnormal genes, but it has been shown that people with certain forms of APOE genes are more likely to develop amyloid plaques.

Dementia in women vs. men

More women than men will develop AD, and this is not simply because women tend to live longer.  It is now being appreciated that menopause – a condition unique to women – may be behind this discrepancy.  Several changes occur during menopause that appear to “jump start” some of the processes that promote Alzheimer’s disease. These include a decrease in the brain cells’ utilization of energy as well as a decrease in the synaptic activity between cells.  Disturbances in these processes affect the brain’s ability to function.

Our understanding of the changes in women’s brains during menopause has come from studies using sophisticated brain imaging.  One type of study measures how avidly the brain utilizes glucose, its main type of fuel.  The more avidly glucose is consumed, the more active the brain is working.  Researchers have performed scans on menopausal women and compared them to scans on men of the same age, as well as to younger premenopausal women.  As demonstrated below, the scan of the premenopausal woman shows more “red” – indicating more glucose uptake.  The scan of the postmenopausal women shows less “red” – indicating less glucose uptake.  What this translates to is that when there is lower glucose uptake, the brain cells are not being adequately fueled. This puts stress on the brain cells and leads to premature aging.  Some studies have demonstrated that these cells then resort to taking up fat instead of sugar.  This leads to the production of the byproducts, such as ketones, which can promote the initiation of amyloid plaques.

In other studies, it has been shown that during the menopausal transition, certain areas of the brain have to “reach out” and engage other areas of the brain to help it function.  It is believed that this extra effort “taxes” the brain, which may further predispose it to premature aging.

Is the loss of estrogen the culprit?

Since the hallmark of menopause is the loss of production of estrogen and progesterone by the ovaries, it is not too much a leap of faith to suspect that the loss of our female hormones is harmful to the brain.  There is a lot of evidence to support this.

• We know that estrogen is critical for normal brain function.  Estrogen plays a role in promoting the delivery and uptake of glucose into the brain cells.  Studies using specialized PET scans (like the one pictured above) have shown that administering estrogen to women improves the brain’s uptake of glucose.
• Estrogen has potent antioxidant and anti-inflammatory properties.  These attributes help protect the brain from damage as well as promote healing if injury occurs.  Studies have shown that lab animals who have had their ovaries removed do not recover from brain damage as well as animals that continue to produce estrogen.
• Estrogen promotes the production of the brain’s neurotransmitters – the chemicals that allow the neurons to talk with each other.  One of these is acetylcholine.  A deficit of acetylcholine is believed to be a factor in AD.  (The medications used to treat Alzheimer’s are basically drugs that raise acetylcholine levels in the brain.)
• Estrogen plays a major role in maintaining good blood flow to the brain.  Estrogen dilates blood vessels as well as protects them from building up plaque.

 

A loss of estrogen would have a significant negative effect on many factors that keep the brain healthy.  It is not unreasonable to assume that the sudden drop of estrogen at the time of menopause would impact brain function, both in the short term and long term.

Does estrogen treatment help?

The million-dollar question is whether hormone replacement therapy will prevent dementia.  Based on the research I’ve described, it seems intuitive that it will help.  Research in lab animals has supported this.  Studies in mice and guinea pigs have demonstrated that estrogen therapy decreases the accumulation of the amyloid plaques.  This was also demonstrated in a recent small study in humans where it was shown that women taking estrogen at the time of menopause demonstrated fewer of these deposits when compared to women not on hormone therapy.

However, before any treatment is recommended, clinical studies need to be done to conclusively demonstrate a benefit.  And while a number of studies have been performed, for a variety of reasons, the results have been inconclusive.  This is mainly because none of the studies have been large enough or reliable enough to provide a definitive answer.

Here is a review of what we know.

In the 1990’s a number of large studies known as observational studies assessed the rates of dementia between hormone users and non-users.  In these types of studies, researchers gathered data on the participants, rather than enrolling them in “head-to-head” trials.  Almost all of these studies indicated that taking estrogen decreased the rate of dementia.

However, these observational studies are not considered “gold-standard” types of studies.  To receive this level of quality, a study needs to be performed where a large number of women are recruited and half are given HRT and the other half a sugar pill.  There has been only one major study of this type addressing HRT.  And this was the 2002 Women’s Health Initiative (WHI).  (See my article to learn more about this study.)

The WHI concluded that HRT increased the risk of dementia.  Because of its “gold-standard” design, the results of the WHI have been considered “the best available science” and women have been warned that estrogen can cause Alzheimer’s disease.  The problem with this study is that it enrolled women way beyond the age of normal menopause – the average age was 62.  We currently believe that initiating estrogen this many years after menopause does not produce the same beneficial effects as when given at the time of menopause.  (For a more detailed explanation, please see this article.)  Despite this, the conclusions of the WHI have been applied to all women, regardless of their age.

There have been several studies subsequent to the WHI that specifically enrolled younger women who were just entering menopause.  These studies did not demonstrate that HRT increased the risk of dementia.  They showed it had no effect one way or the other.  But it must be noted that these studies went on for less than six years.  Since the dementia process develops over many years, more time is likely needed to truly assess the effects of estrogen treatment.  Most of the observational studies mentioned above, which showed a beneficial effect of HRT, analyzed women over a couple decades.

One group of women whose brains do benefit from estrogen therapy are women with premature menopause – such as those who had surgery to remove their ovaries.  These women have an increased risk of developing Alzheimer’s disease.  A study from the Mayo Clinic showed this risk to be double that of women going through menopause at a normal time.  However, if these women are placed on estrogen at the time of their surgery, their risk of dementia is no greater than women going through natural menopause.

The bottom line

Currently none of the HRT guidelines recommend that women take estrogen as a means to prevent dementia.  This is because the WHI study continues to be the dominant study when it comes to assessing the benefits and risks of HRT.  It is likely that the results of the WHI would have been very different had it primarily enrolled younger women going through the menopausal transition.

Whether we will ever see a new study of this nature is uncertain.  It would need to go on for many years because dementia is a process that starts in mid-life and takes twenty or thirty years to manifest.  Funding and following individuals over this long a time would be a colossal undertaking.

The bottom line is that women entering menopause today cannot expect to see a definitive answer in their lifetimes. But we do know that estrogen plays many critical roles in the brain, and the loss of estrogen at the time of menopause undoubtedly will have some adverse effects.  This type of information is important for women to know as they make a decision about whether or not HRT is right for them