University Place Positive Aging Series Craig Atwood, "How to Increase Our Healthy Cognitive Lifespan" 7/19/2010  UP 455   cc >> Welcome to today's session of the Positive Aging Lecture Series. It's sponsored by Continuing Studies at UW-Madison, the SAIL organization, Supporting Active, Independent Lives, and Oakwood Village. Our speaker today is Dr. Craig Atwood. Dr. Atwood is an associate professor in the UW Department of Medicine in the Division of Geriatrics. And he's a research scientist at the Madison Veterans Administration Geriatrics Research Education and Clinical Center. He's research director of the Wisconsin Alzheimer's Institute and the Wisconsin Comprehensive Memory Program. He received his PhD in biochemistry at the University of Western Australia in Perth, Australia, and completed postdoctoral training in neuroendocrinology at the National Institutes of Health. His early faculty appointment was as an instructor of neuroscience at Harvard Medical School, followed by an appointment as an assistant professor of pathology at Case Western Reserve University. Dr. Atwood is a widely acknowledged authority in neuroendocrinology of Alzheimer's disease and has recently proposed a new theory of aging based on the functions of sex hormones. His research interests are aimed at identifying ways to delay the onset or slow the progression of aging related disease like Alzheimer's. 

He has published several seminal papers concerning the pathobiology of Alzheimer's disease and has received research funding from the National Institutes of Health, the VA, the Alzheimer's Association, and the pharmaceutical industry. He has received a Zenith Award from the Alzheimer's Association. Dr. Atwood has been at UW-Madison for about seven years and his topic today is on how to increase our healthy cognitive lifespan. Will you please join me in welcoming Dr. Craig Atwood. (applause)  >> Thank you very much for that introduction. And I thank you for the invitation to be here. But really... "All the world's a stage. And all the men and women merely players. They have their exits and their entrances, and one man in his time plays many parts, his acts being seven ages. 

At first the infant, mewling and puking in the nurse's arms. Then the whining schoolboy, with his satchel and shining morning face, creeping like snail unwilling to school. And then the lover, sighing like furnace, with a woeful ballad made to his mistress' eyebrow. Then a soldier, full of strange oaths and bearded like the pard, jealous in honor, sudden and quick in quarrel, seeking the bubble reputation even in the canon's mouth. And then the justice, in fair round belly with good capon lined, with eyes severe and beard of formal cut, full of wise saws and modern instances. And so he plays his part. The sixth age shifts into the lean and slippered pantaloon with spectacles on nose and pouch on side, his youthful hose, well saved, a world too wide for his shrunk shank and his big manly voice, turning again towards childish treble, pipes and whistles in his sound. Last scene of all, that ends this strange eventful history, is second childishness and mere oblivion, sans teeth, sans eyes, sans taste, sans everything." From Shakespeare's "As You Like It," act two, scene seven. So even Shakespeare understood that we go through various stages through our lives. And the early stages in our lives are characterized by an increase in performance. 

We learn skills. We learn how to eat and how to speak and how to think. And then during adult life, we utilize these learned skills that have developed in the early decades. But then as we move through life, sometimes these skills start to deteriorate. And in the case of cognitive skills, we can see that if it falls below a certain level, we can move into a state called dementia. So today I'd like to give some background on dementia. I'd like to discuss, what is dementia, the stages and symptoms of age-related dementia, the effects of age-related dementia on the brain, the causes of age-related dementia. And then the last half of the talk, I would like to discuss ways of trying to halt cognitive decline. How do we maintain our cognition in our older years? And in this section of the talk, I'm going to discuss hormonal therapies for Alzheimer's disease, but also current treatment options and medications.  So obviously, this is not the optimal situation. 

What we would prefer is to be able to maintain our cognitive performance into our final days. So, let's define dementia. What is dementia? Dementia is defined as the loss of cognitive function that interferes with a person's day-to-day activities. And this could include changes or decrements in thinking, remembering, reasoning, personality, and behavior. As an illustration of how cognition can decline with Alzheimer's disease, I'd like to run through a series of images here. Sketches drawn by William Utermohlen, who in 1995 learned that he had Alzheimer's disease. He was an American working out of London most of his life, and in 1967, he drew a self portrait. And as we can see, he is quite an accomplished artist. And unfortunately, he developed Alzheimer's disease, which is the major age-related dementia in society. So in 1996, he decided to start drawing self portraits. 

And you can see here, this is a painting from 1996. Here is a second painting from 1996. A couple of sketches from 1996. A painting from 1997. Another painting from 1997. A painting from 1998. A painting from 1999, the second to last. And here is the final sketch that he drew in 2000. And so, I think this very adequately illustrates how Alzheimer's disease and other dementias can rob you of your cognitive abilities, and in this case, his ability also to paint. Now, there are other conditions, there are certain conditions that can be confused with dementia. 

For example, it can seem that you've lost cognitive abilities when you take certain medications. Obviously alcohol is known to affect cognition. But also hormones and vitamin imbalances can lead to decrements in cognitive abilities, and also depression. Depression can lead to problems with attention and memory. And it can be confused with a lack of initiation, which is a common early sign of dementia. And it may be seen with or in fact precede dementia. So let's look at some case examples of cognitive loss. Case A. Mrs. R is an 84-year-old retired English professor who over the past year has noticed difficulty with word-finding, misplacing things, and occasionally getting lost while driving. She has started to blame her husband for hiding things from her, and becomes irritated easily when her children express concern about her having gotten lost. 

Case B. Mrs. V is a 76-year-old woman who lives with her husband. Recently she has been referring to the girl who lives in the back room, even though nobody lives with them. When she goes to the grocery store, she will forget to pick up items she needs, but frequently will return with several mustard bottles even though she already has about 12 bottles at home.  In the past four months, she has had a number of falls and one time passed out completely. And physical changes are also a component of cognitive decline. Mr. M is a 65-year-old man who recently had a stroke and since then has noticed some memory loss. Once an avid reader, he now has difficulty following the storyline of books. He has forgotten several recent appointments. Although he used to be very active in several volunteer organizations, he now just sits at home and watches TV. 

When encouraged by his daughter to return to his volunteer work, he says, "They do not need me, it is not worth the effort to get over there." And so this is an example of somebody who is having strokes, or mini strokes, that is robbing them of their cognitive abilities. Dementia terminology. So, dementia can be due to a number of different diseases. Alzheimer's disease is a major form of dementia in society. Lewy Body disease is another common disease. Vascular disease, which is closely related to Alzheimer's disease. Pick's disease, individuals that have contracted HIV, and Parkinson's disease. Older terminology that was being used to describe cognitive decline included Chronic Brain Syndrome or Organic Brain Syndrome, senility, acute confusional state, and hardening of the arteries. So what is dementia? Well, let's focus on Alzheimer's disease. As I mentioned, causes of Alzheimer's disease are very... 

causes of dementia, sorry, are shown here. And Alzheimer's disease, vascular disease, combinations of disease, often vascular disease with Alzheimer's disease, or Lewy Body, similar to Parkinson's and Alzheimer's disease are common. And these make up a large proportion of the cases of dementia. Alzheimer's can form up to 80% of all dementia cases. Its prevalence increases with aging. There are two main forms of Alzheimer's disease. Early onset Alzheimer's disease, which accounts for approximately 5% of cases. Symptoms typically develop before age 60, and this disease is driven by three genes or genetic mutations in these genes that promote cognitive loss. The majority of Alzheimer's disease cases, however, are classified as late onset Alzheimer's. And this makes up about 95% of the cases. 

Symptoms usually develop after the age of 70 and the major risk factor for this late onset Alzheimer's disease is the apolipoprotein E4 gene, together with aging itself. So there are large increases in the prevalence of Alzheimer's disease, and as you can see, there are approximately 5.1 million individuals in the US who have dementia or Alzheimer's currently. This number is expected to increase to around 13 to 14 million by around 2050. The reason for this increase is due to the increased longevity of the population. The average age of women now is almost 80 years of age, whilst the average age of men is a little over 76 years of age. And also, there's an aging baby boomer population, which I also fit into. So, let's look at the stages and symptoms of age-related diseases. So, we have normal cognition throughout our adult life. However, as we move into our last decades of our life, we see a decline in our cognitive abilities. And Alzheimer's disease can be defined as being mild, moderate, and severe. 

So it's a continuum. And it takes a number of years for somebody to become severely demented. The disease process actually starts probably ten to 15, even 20 years before the first clinical signs of the disease. There is also a pre-Alzheimer's disease stage, which is otherwise known as minimal cognitive impairment. And a lot of research is being performed on this particular stage so that it can be diagnosed as well as treated. Treatment at this early stage offers the best potential for preventing cognitive decline. So mild cognitive impairment is characterized by memory complaints, preferably corroborated by an informant, impaired memory function for age and education, preserved general cognitive function, intact social and occupational function, and not demented on your psychological testing. Mild Alzheimer's disease is characterized by short term memory loss, difficulty performing familiar tasks, altered judgment, language changes, changes in mood, behavior, and personality, disorientation to time and place, and problems with abstract thinking. Moderate Alzheimer's disease is characterized by worsening memory loss, difficulty performing familiar tasks, poor judgment, language changes, changes in mood, behavior, and personality, disorientation to time and place - are you getting lost or not keeping appointments? Problems with abstract thinking, changes in sensory perception, and also physical changes. It's becoming known now that there are also physical changes that often accompany the loss in cognitive ability. 

And finally, severe Alzheimer's disease is characterized by little or no short term memory, inability to perform even small tasks, lack of judgment, unable to communicate, and physical decline. So Alzheimer's disease is a slowly progressive disease. Let's look at the effects of this age-related dementia on the brain. So you can see here two brains, one from a control individual, an elderly control individual, and a second from an individual that had Alzheimer's disease. You can see that the gyri are far more narrow and the sulci, shown in the middle here, widens. Suggesting that the brain is shrinking. This can be very easily seen here on the right. A healthy brain compared to a brain that has advanced Alzheimer's disease. So the disease appears to be leading to the loss of neurons and synapses, which connect the neurons and transport the information throughout the brain. There are five major, overt pathological changes that you can see in the Alzheimer's disease brain. 

The first two, neuron loss and synapse loss, I just mentioned. But there is also the deposition of two proteins. One is phosphorylated-tau, which deposits inside neurons and gums up the microtubules within the neurons and prevents them from working properly. And the second is amyloid plaques, which deposit extra --, which I'm sure you've heard about, and are thought to be a major ideological factor in the disease. The fifth major pathological change is a low-grade inflammatory response. So there is a microgliosis. The immune cells in the brain proliferate and they appear to be responding to the neuro degeneration that's occurring. It's probably a response to try and remove the dying and/or dead neurons. So, Alzheimer's disease attacks nerve cells in several regions of the brain. It's not just affecting one region of the brain. 

And it attacks several regions including the cerebral cortex, which is involved in conscious thought and language. It affects the basal forebrain, which is known to be important in memory and learning. And importantly, it affects the hippocampus, which is essential to memory storage, and you can see these regions shown here. So, what are the causes of age-related diseases? We know that aging is the major risk factor for Alzheimer's disease, so it seems logical to think that whatever explains the cause of aging must be related to Alzheimer's disease. And just shown here, obviously we don't develop Alzheimer's disease when we're 20, 30, or 40, at least not the late onset variety. But you can see that there is a doubling in the incidence of Alzheimer's disease from 65 years of age through to 85 years of age, such that by the time we reach 85 years of age, approximately 40% of individuals have some form of dementia. So if we look at the major risk factors for Alzheimer's disease, we can see a trend. And that trend is that many of these risk factors are associated with changes in sex hormone levels. So, as we age, obviously, there are changes in sex hormone levels. Family history's also been shown to be associated with sex hormone levels. 

This protein here, which is the major risk factor for late onset Alzheimer's disease is known to transport cholesterol into cells. Cholesterol is the precursor to the sex steroids, such as estrogen and testosterone. Down syndrome is also known to be associated with Alzheimer's disease, an increased incidence of Alzheimer's disease, and it's also associated with changes in sex hormone levels. And then there are a couple of other factors, likely unrelated to sex hormones, and that is low education level and head trauma with loss of consciousness. So let's explore these hormonal changes. This figure here illustrates the changes in reproductive hormones that occur in our bodies as we age. So shown in this section here on the left, this yellow line, shows the cyclical changes in reproductive hormones during the menstrual cycle of a woman. When a woman hits menopause, these cyclical changes become completely disregulated. Some hormones, such as estrogen, some progestagens, decline to very low levels. Other hormone called inhibin also declines. 

The reverse to these changes are large increases in GnRH and gonadotropins. And also activins. So we're moving throughout our adult life, our hormones are nicely balanced, signaling to all the cells in our body. And then, all of a sudden, we hit menopause and bang. The cells in our body are not receiving the normal signal that they were receiving previously. And these same changes occur in men. But instead of having cyclical changes, our hormones very slowly increase over time and very slowly decrease. Men lose approximately 1% of their serum testosterone levels every year between the ages of 30 and 80. So men go through exactly the same process, but it's more gradual. So we refer to these changes, this disregulation of the axis, as leading to dyotic signaling. 

So there is a decrease sex steroid signaling, but increase gonadotropin, GnRH, and activin signaling. Okay, so what has this got to do with Alzheimer's disease? Well, the Alzheimer's disease brain displays many signals, many characteristics, that the neurons are attempting to provide. These neurons that have been sitting in the brain for the last few decades are all nicely wired up, like train tracks. That's their function, to transmit information, receive information, process that information, transfer that information for storage, but also to be able to retrieve that information when required. When the neurons in the brain receive this dyotic signaling, this altered hormonal signaling, it throws these neurons into the cell cycle. It's basically a signal saying, okay, we're going to divide. Unfortunately, when a neuron that is fully connected up and what's known as "terminally differentiated," it has a function, and doesn't normally divide. When it's told to divide, it tries to do this, but it doesn't do it very effectively. And this leads to a disregulated cell cycle and eventual neuronal loss. So, these hormones here are known to be what's known as mitogenic. 

They're known to drive the neurons to try and divide. These are increasing as we age. And other hormones that are differentiative, or specify function like the sex steroids and activins, generally decline. And what's interesting about these hormones is that they increase many of the changes that we see in the brain. So these hormones are now known to drive the deposition of amyloid in the brain. These hormones are known to promote the phosphorylation of tau, which ends up in these intracellular neuro-- tangles that gum up the neurons. And so this loss of balance in these reproductive hormones can lead to this aberrant reactivation of cell division and this leads to neuronal death. These cell cycle-related events can explain pretty much all the pathology and biochemical changes that we actually see in the brain. So, everybody out there agrees that these events occur in the Alzheimer's disease brain, that there's altered processing of this protein here that leads to the formation of these amyloid plaques. There's phosphorylation of this protein called tau that leads to neurofibrillary tangles. 

There is altered cell cycle protein production required for cells to divide. That there is replication of the DNA in the chromosomes, some very strong evidence that these neurons are attempting to form two daughter cells. There's elevated proteins and mitochondrial DNA for the formation of mitochondria. These are the powerhouses of cells, for the production of energy, but also sex steroids. There's altered signaling pathways and there's oxidative stress. So, there's fairly compelling evidence that cell cycle changes are what are driving these neuropathological and biochemical changes that we can detect in the brain, and there's also fairly compelling evidence that hormones are responsible for signaling for these changes. So what is the evidence that hormones, hormonal changes, are regulating cognitive health and dementia? Well, the first evidence is that there is a female predominance in the population for Alzheimer's disease. For every two women that develop Alzheimer's disease, only one man will. And this is sort of, it's very -- the abrupt earlier loss of gonadal function in women. These hormones are known to regulate biochemical and neuropathological changes associated with Alzheimer's disease, as I've just explained. 

And there is a large amount of data indicating that now. There is an increased risk of dementia in women who have had an oophorectomy. So either one or two ovaries removed. The removal of the ovary has the same effect as menopause in that it causes the hormonal balance to become disregulated and you end up with dyotic signaling. And it's been shown that there are certain relationships between the concentrations of hormones in the serum of those, in the bloodstream, of those with Alzheimer's disease. So for example, the lower the sex steroid levels are in your bloodstream, the more likely you are to develop Alzheimer's disease. Conversely, the higher the concentrations of the gonadotropin hormones, and this is luteinizing hormone and follicle stimulating hormone, the more likely you are to have Alzheimer's disease. So the more disregulated your axis becomes after menopause, the more likely you are to develop Alzheimer's. And I think the most compelling evidence, which we will spend considerable time talking about in the next few minutes, or for the rest of the talk, is that physiological hormone replacement therapies both delay the onset and decrease the incidence of Alzheimer's disease. So hormonal therapies for Alzheimer's disease. 

As many of you would be aware, hormones are used, sex hormones are used to supplement those hormones that are no longer produced by the gonads. In the case of women, supplementation is with estrogens and progestagens, or both, and these are given to replace the hormones that are no longer being produced by the ovaries. Same for men, testosterone or androgens, are given to men during andropause to try and increase testosterone levels that have been declining because of the decreased production of testosterone by the testes. What's interesting is, a number of sources have been used for these hormones. Not only giving back normal human hormones, but also equine hormones and synthetic hormones. So let's look at the clinical trial data for 17-beta-estradiol. 17-beta-estradiol is the major estrogen present in both male and female bodies. And in these treatment trials, where they've taken individuals that have Alzheimer's disease and they've taken individuals that do not have Alzheimer's disease and they have treated them with 17-beta-estradiol, these three studies, three controlled studies, have shown not just a halting of the progression of Alzheimer's disease, but an actual improvement in cognitive performance. In five uncontrolled studies, that is, where there was no control group, but they simply followed the patients over time, it also showed an improvement in cognitive performance. In men, there's only been one study, but again, in this one controlled study, there was an improvement in cognitive function in those that were supplemented with testosterone. 

In prospective cohort studies, or going back and looking at data to see whether or not this has been protective, whether sex steroids have been protective, what they have found is that 17-beta-estradiol reduces the incidence in one study and delays the onset of Alzheimer's disease in older women. In older women that are cognitively normal, they have performed 15 studies with 17-beta-estradiol. In 12 of these 15 studies, even though these women are considered to have normal cognition, they've seen improvements in cognitive function. In three studies, they showed no benefit. So there are 26 different pieces of evidence out there indicating that physiological forms of estrogens and testosterone are beneficial for cognitive health. So let's just go through a couple of these studies in detail. In one study, an estradiol study, elderly women were followed for five years. Those that were not supplemented or treated with 17-beta-estradiol showed an increase in Alzheimer's disease in about 16% after these five years. Those that were treated with 17-beta-estradiol, only 1.7% developed Alzheimer's disease. So in my mind, a fairly protective effect. 

In another study, women that suffered only moderate memory problems, and I'm referring to those 15 studies on the previous slide, they improved their memory while on hormone replacement therapy. So the question becomes, why are we not all taking hormone replacement therapies for the treatment of dementia? Why are we not taking these hormones in the case of post-menopausal women, and why are we not taking testosterone in the case of men? Well, it comes down to some studies that were published over the last ten years, assessing the effects of certain of these hormones on cognitive function. And this gets to the types of sex steroids that are being used in the United States for hormone replacement therapy. So, in many other parts of the world, normal, natural physiological sex steroids are given as hormone replacement therapies. Unfortunately, here in the US, analogs and animal-derived sex steroids have been the major forms of hormones utilized. And if one was cynical, one  might suggest that they were developed for use because you can't make a profit out of using these natural physiological hormones. However, they were initially developed for the treatment of menopausal symptoms and they were continued to then be used. The second point is that there's an increased risk of cancer in taking these hormones. So I'm going to cover these two points in detail. So, the major hormone replacement therapies in the US have been Premarin and Prempro. 

Premarin are conjugated equine estrogens. So these are estrogens that are extracted from mare urine, pregnant mare urine, or as my son would say, "mare wee-wee." (laughter) The second product is Prempro, and this product contains both the conjugated equine estrogens, plus an analog of progesterone called medroxyprogesterone. And these are, in fact, effective in the treatment of menopausal symptoms, and that's great. However, they are somewhat different than these, which are the human sex steroids. Again, the major estrogen in our body is 17-beta-estradiol. In women and men there's also progesterone, and obviously in men, highly levels of testosterone. So no studies have ever shown that these hormones have negative effects, but let's have a look at the conjugated equine estrogens, with and without medroxyprogesterone. So conjugated equine estrogens, there have been a slew of studies that have examined their effects on all sorts of age related diseases, but many have been performed for the treatment of Alzheimer's disease. And approximately 50% of studies improved cognitive performance in healthy older women. So this is not bad, but it's certainly less than the 90% to 95% of studies that have shown, or in fact 100% of studies that have shown estradiol improves cognition. 

Again, conjugated equine estrogens have been shown in about 50% of studies to delay the onset and halt the progression. But again, this is below the 90% to 95% seen using the natural hormones. And a very important study that came out, the Women's Health Initiative Memory Study, out of Boston, showed that women taking estrogen pills with medroxyprogesterone, Prempro, or without, were more likely to show cognitive decline. So this is a negative result. This is a result that threw everybody out, because all of a sudden hormones looked like they were bad. Obviously, you don't want to take something that's going to decrease your cognition. So it appears, from looking at all the data that's out there, that different forms of estrogens vary in their side effects on the brain. So, I'm going to get into a little bit of chemistry here, and you don't have to be a chemistry major at all to understand what I'm about to explain. Here are two natural forms of sex steroids, progesterone and testosterone. And as you can see, the chemical structure of progesterone is almost identical to testosterone. 

You've got a -- here and you've got these aromatic rings here. Hydrogens, methyl groups here, it's all the same. Except there is a -- group here in progesterone and a hydroxyl group here in testosterone. So the structures are almost identical. However, we know that these sex steroids have very different physiological functions. Progesterone obviously required for pregnancy and many other maternal functions, as well as functions on the brain. And testosterone for masculinization and --. So even a small change in the structure of these sex steroids has dramatic consequences for physiology. So let's look at medroxyprogesterone, the major progesterone in Prempro. And you can see here, again, almost identical. 

There's a group down here, methyl group, and a hydroxyl group up here. But other than that, they're identical. But biologically, given what we've seen here, we might expect major difference in physiology, and in fact we do, as I'll explain in a couple of minutes. Here we have 17-beta-estradiol. Again, it's almost identical to testosterone. There's a -- group here, hydroxyl group, but other than that it's essentially identical. Again, estradiol has very different functions to testosterone. And here is the major estradiol that is found in these conjugated equine estrogens. And it's named estrone sulfate. It has a sulfated group here and a -- group here. 

So, undoing the scientific damage. Unlike progesterone, medroxyprogesterone found in Prempro does not protect against toxicity that's induced in neurons. It doesn't protect against traumatic brain injury, so progesterone is very protective of traumatic brain injury. But it does prevent neuronal division, okay? So there is neuronal division in the brain, it occurs on a low-grade basis, but it is essential and necessary, and medroxyprogesterone does not induce proliferation. So giving medroxyprogesterone, at least for these functions in the brain, is essentially like giving placebo, or maybe worse. The conjugated equine estrogens are also known to have different signaling pathways. Biochemical studies have not been performed to tease out the exact differences, but I think over time we're going to also find that these conjugated equine estrogens do not have the neurotrophic properties that estradiol has in the human brain. So the bottom line. We need to be supplementing our bodies with sex steroids that are physiologically relevant to humans, as shown here. "You want to give me what? I don't think so!" Why would you give a horse human estrogens? Why would a human take mare estrogens? And these hormones for women are 17-beta-estradiol and progesterone. 

And for men, testosterone, but also progesterone. So let's look at the second point as to the uncertainty for using hormone replacement therapies. There is an indisputable increase in the risk of breast, uterine, and ovarian cancer in taking hormone replacement therapies, whether it be estradiol, or the conjugated equine estrogens. Obviously, this is not good. However, this risk, this increased risk, does not outweigh the risk from developing Alzheimer's disease, heart disease, or stroke. In fact, those taking hormone replacement therapy live longer. So the risk in taking hormone replacement therapy needs to weigh out depending on your individual cognitive state, but also your family history of Alzheimer's disease and cancer. So let's look at examples. Example one. "I am 80 years of age and have no family history of cancer, but my cognition is declining." You might consider that the risk of cancer is unimportant in the face of memory loss. 

Example two. "I am 65 years of age and have cognitive decline." You might consider risk of cancer unimportant in the face of memory loss. "I am 70 years of age without cognitive loss, but a family history of cancer." You might consider that the risk of cancer outweighs the risks of memory loss. "I am 70 years of age and have cognitive decline. I also have a family history of cancer." Well, I think the risk of developing cancer, or the thought of developing cognitive loss is probably worse than the thought of perhaps even cancer. So this is something that needs to be borne in mind. So let's look at current treatment options and medications. So, the treatment of Alzheimer's disease is multifaceted. It includes education and emotional support to both the patient and their families. A safety review. 

We don't want people driving as they become demented. Caregiver support is also very important. Behavioral interventions are often required. What I'm going to discuss here are medical therapies. FDA approved medications for Alzheimer's disease include two classes of compounds, acetylcholinesterase inhibitors for the treatment of mild to moderate Alzheimer's disease. And here are the four compounds that are currently available. And NMDA receptor antagonists for moderate to severe Alzheimer's disease. And this is a newer product called Memantine or Namenda. So the acetylcholinesterase inhibitors work by blocking the degradation of a neurotransmitter, a chemical called acetylcholin. And this leads to an elevation in acetylcholin levels in the synapse, and this elevates brain function. 

So these chemicals do not get at the disease mechanism, but they do prop up and make the neurons that are there work a little bit better. Cholinesterase inhibitor therapy usually commences in this mild Alzheimer's disease stage, although clinical trials are underway to test it for minimal, during the minimal cognitive impairment stage. And cholinesterase inhibitor therapy stops usually here. These drugs have been shown to delay the progression of memory loss, delay time to nursing home placement, improve behavioral symptoms, and help relieve caregiver burden, so all very important plusses. Memantine, which has been the most recently proved drug, works by preventing the buildup of a neurotransmitter called glutamate, too much of which can cause neuro degeneration. And it's been found to be useful in combination with cholinesterase inhibitors and so has been indicated for moderate to severe Alzheimer's disease. So, if we begin cholinesterase inhibitor therapy here, what we normally see is a stabilization in individuals for around three to six months. This occurs in many individuals, but not all individuals. And then there's a progression that parallels the disease process similar to those that receive no treatment. So it does halt the progression a little bit, but unfortunately we still see a decline. 

In those that take added memantine, again we see a bit of a bump, but after a period of time, this progression is still downward. So obviously there is a major need for new therapies for the disease, and as of a couple of years ago, there were hundreds of drugs in clinical and pre-clinical testing for neuro degenerative diseases. There are 70 drugs in Phase I clinical trial, there were 75 drugs in Phase II clinical trials. 26 drugs have made it through to Phase III clinical trials, the last phase before FDA approval. And of these 26 drugs for all different types of neurological conditions, 13 were in clinical trials for Alzheimer's disease. So what other potential treatments are there? Well, it's been shown in epidemiological studies that those that take nonsteroidal anti-inflammatory drugs have a decreased risk of developing Alzheimer's disease. Unfortunately, in treatment trials these NSAIDs have not proven to halt the decline of cognition. There are clinical trials utilizing strategies to remove the proteins that deposit in the brain with the idea that the deposition of these proteins is detrimental. Unfortunately, these vaccination trials have been failing for reasons you can ask me about later. Antioxidants have been utilized in clinical trials, vitamin E has shown an improvement, or has been shown to improve cognition in those with Alzheimer's disease, but the improvement is very, very mild indeed. 

And then there are numerous nutraceuticals and other compounds. There's phytoestrogens, such as is found in soy, there's isoflavonoids, dietary lignans, there's --, which have been used in Germany for many years for various neurological conditions, and other nutraceuticals such as resveratrol. Resveratrol is very interesting. It's extracted from the skin of red grapes and so it's found in red wine. It's thought to perhaps explain the French paradox that the French have a very fatty diet, but on the whole, they live as long as everybody else. And when this product has been given, at least to mice, they have shown an increase in longevity of about 20% to 30%. It has yet to be tested for age related diseases in humans. Gingko is also thought to have beneficial properties. Green tea leaf extract, ECGC. And curcumin, the Indian spice turmeric. 

So let's just go back to hormone replacement therapies for a minute. There appears to be compelling evidence that sex hormones modulate brain health. Physiologically relevant hormone replacement therapies, in my mind, should therefore be a frontline for the treatment of Alzheimer's disease, providing other factors, such as cancer risk, are taken into account. And so, I would ask the question, do we already have the answer to cognitive loss? So what about other age-related diseases and hormones? Well, it's known that estrogen deficiency resulting from removal of the ovaries is associated with a higher risk of coronary heart disease, stroke, hip fracture, Parkinsonism, dementia, cognitive impairment, depression, and anxiety in a number of studies. And that the removal of endogenous sex steroid production increases disease risk except estrogen deficiency resulting from oophorectomies decreases breast and ovarian cancer, okay? What about males? Well, low testosterone levels but elevated luteinizing hormone levels are associated with frailty, increased prostate cancer, decreased sexual desire, low sperm count, height loss, hot flashes and sweats, plus other less specific symptoms. Support for hormone replacement therapy or maintaining that axis and balance comes from studies demonstrating that the higher the age at menopause, the longer the post-reproductive lifespan in women. So the later you go through menopause, the longer you'll be expected to live. And similarly, advanced age at last reproduction is associated with improved longevity. So if you have children in your 40s or late 40s, you might expect to live longer. Again, because your axis was balanced enough for you to be reproductive. 

And in the Wisconsin Longitudinal Study, we've found evidence indicating that there's a 20% reduction in mortality amongst those who take hormone replacement therapies. So, maintaining sex steroid levels reduces the risk of Alzheimer's disease, stroke, coronary heart disease, osteoporosis. And maintaining sex steroid levels increases the risk of cancer, but it also increases the risk of living longer.  So... What sorts of strategies can we develop to try and keep this reproductive axis in balance to offset our age related disease so that we can live longer? Well, there's a couple of strategies that come to mind. One, pharmacological solutions, i.e., the hormone replacement therapies that I've been discussing. We give back 17-beta-estradiol, we give back progesterone, we give back testosterone. We also give back inhibins, another important hormone that's lost with menopause, but also andropause in men. Unfortunately, we can't give back inhibins, it's not produced, it's a protein, and it's fairly difficult to get into the body. However, these are readily available and can be taken. 

The second way is to replace the gonadal cells that can no longer produce the sex steroids that were produced during our adult life, our earlier adult life. And one way of doing this would be to replace the ovarian and testicular cells, perhaps using human embryonic stem cells injected into these organs. This sort of sounds like science fiction, but in fact the experiment to prove this has been performed already in animals. If you take young ovaries, or ovaries from a 3-month-old mouse, so young ovaries, and you transplant these ovaries into an 11-month-old mouse, so a mouse that is post-reproductive. A mouse lives about two years and it goes through what would be termed menopause at about nine months of age. If you replace the old ovaries with the young ovaries, the mouse not only starts cycling again, so not only does it start its estrus cycles, but it also lives longer. This is obviously not currently possible for humans. But it's interesting to think about --. So, what sort of hormone replacement therapies should we contemplate? Well, obviously we want to be taking natural or physiological sex steroids. We want to be taking 17-beta-estradiol, or even estriol, which is another human estrogen that's used in Europe for menopausal symptoms. 

It's thought to have very little cancer risk, but for reasons that are not clear to me, it's not being utilized in the US. And progesterone. Estradiol is available in patches, in pills, and many other forms. Progesterone is available in creams and pills. And there's various routes by which you can take these hormones. There are various first pass effects through the liver if you take these as pills, so one has to weigh this information also. Do we take estradiol alone or do we couple it, oppose it, to progesterone? Studies have shown, generally, that giving opposed hormones there is a decreased risk of female reproductive cancer. And the timing, duration, and cyclicity. So, obviously, this treatment could be started during menopause for the relief of menopausal symptoms, but it could then be continued to help prevent the development of age-related diseases. What has been found in a number of studies is that there is a critical window. 

Providing these hormones are taken during the first five to ten years post-menopause, it appears that they offer about the same protective effect as if you were taking these hormones for 20 or 30 years. So this immediate post-menopause window is very, very important. In terms of cyclicity, as I showed previously, hormones, at least in the female reproductive system, cycle up and down throughout the menstrual cycle, and there is this notion that menstruating is "normal." Well, it is normal, but historically it actually probably did not occur that often and I can explain those reasons during question time, if you like. So continuous progesterone, estradiol is probably just fine. And continuous progesterone would be useful because it would avoid breakthrough bleeding. So, for men, androgens are available, testosterone is available in various gel preparations, but also just recently being formulated into a spray, so you can spray your armpits and prevent dementia. (laughter) Progesterone is also available, and again the route. Transdermal, you can get patches, creams, or sprays, as I've indicated. You can also take it orally, although testosterone tends not to survive the oral route very well. All right, so let's wind up here. 

Potential preventive therapies. Again, the physiological sex steroids, which you have to weigh up the risks with respect to cancer. Certain of these compounds I feel could be proven in the future to be beneficial for cognitive health, but also preventing other diseases. We need to make sure that heart disease risk factors are treated appropriately. Obviously, exercise should be a part of any regimen. And we need to stay socially and intellectually active with these sorts of games or anything else. So current research. There's a tremendous amount of research into Alzheimer's disease, both internationally and nationally. Here are some of the organizations that can supply information should you need it. There is a very active Alzheimer's disease research group here at the UW-Madison, and in the VA GRECC. 

It performs clinical trials on a number of different compounds. And there are many areas of investigation within the program at the University of Wisconsin, including hormone therapies, functional MRIs for the diagnosis or prognosis of Alzheimer's disease. There are aging studies, statin therapies, so drugs to modulate cholesterol levels. And there are numerous diagnostic and prognostic tests being developed. So I will end there, and thank you for your attendance, and I'll take any questions. (applause)