The Tangled Neuron

Can Insulin-Degrading Enzyme Drain Beta Amyloid From Alzheimer's Brains?

Our roads flood all the time here in Tampa Bay. We’re close to sea level. When it rains, there’s just no place for the water to go, especially at high tide. Storm drains back up, the water level rises, cars stall and traffic stops. The problem isn’t just too much rain, it’s also too little drainage.

Some Alzheimer’s researchers think the same thing may be happening in the brains of people with dementia. According to this theory, the problem isn’t really just too much production of beta amyloid [the sticky protein that forms plaques and is thought to cause Alzheimer’s], it’s also too little “drainage” of that beta amyloid.

Most of the efforts to find a cure for Alzheimer’s have focused on preventing the over-production of beta amyloid. But over the last few years, some scientists have been exploring the idea that in Alzheimer’s brains, the balance between production and elimination of this protein has gone awry.

One of the researchers working to find treatments based on this “drainage” theory is Dr. Malcolm Leissring at The Scripps Research Institute. He is testing various proteases’ [enzymes that break down proteins] ability to destroy beta amyloid and unplug the drain. Much of his research is focused on one specific protease: Insulin-Degrading Enzyme (IDE).

Malcolm Leissring, Ph.D.

Insulin-Degrading Enzyme

“I am interested in all beta amyloid degrading proteases, but IDE is particularly attractive for a lot of reasons,” Dr. Leissring says. “It is one of the few to be linked genetically to Alzheimer’s disease. It appears to be the main protease involved in the degradation of (extracellular) beta amyloid in neurons, because when you delete IDE from cells, you also reduce the amount of beta amyloid degradation by over ninety percent. And there are a lot of tantalizing and unanswered questions about IDE, such as how it gets secreted from cells, which makes it very attractive for research.”

His research fits well with that of other scientists who have found that IDE levels are low in the hippocampus of the brains of people who have been diagnosed with Mild Cognitive Impairment, and even lower in those diagnosed with Alzheimer’s. Low levels of IDE are associated with high levels of beta amyloid.

Progress So Far

Dr. Leissring and his colleagues have shown that mice bred to have increased IDE (or another protease called neprilysin) have reduced levels of beta amyloid in their brains. The increased level of IDE appeared to slow plaque formation in the brains of these mice.

Focusing on the proteases that might increase beta amyloid drainage gives researchers a lot of new possible therapies to prevent dementia. “I don’t think we are anywhere near [human] trials involving IDE,” Dr. Leissring says, “ but there are some exciting results coming out.” One encouraging finding is that increasing the levels of IDE or other proteases (and thereby reducing beta amyloid levels in the brain) might be done via the bloodstream. This could be much safer than attempting to administer a therapy directly to the brain.

Raising levels of IDE will probably not involve adding the enzyme itself to the bloodstream or the brain. According to Dr. Leissring, logistical problems with purifying IDE make it more probable that potential treatments will take a slightly different approach. “All cells make IDE,” he says, “and we can engineer bacteria or other cells to produce it. So it’s easy to produce, but not so easy to purify. I don’t think it will ever be produced on a scale for use in humans. More likely, a drug will be found that affects IDE or influences its expression levels within cells.”

The Insulin Connection

The promise of IDE-related therapies seems to contradict studies that show increasing insulin levels may improve memory for some Alzheimer’s patients. IDE degrades insulin as well as beta amyloid, so increasing IDE levels would be expected to lower insulin levels.

While increasing insulin levels may help some patients in the short term, Dr. Leissring points out that “accumulating evidence suggests that chronically high levels of insulin are not good, neither for diabetes nor for AD. There is a growing body of evidence that suggests that chronically high levels of insulin cause the body to become desensitized to the hormone’s effects---which is exactly what Type 2 diabetes is.”

”Based on our understanding of the causes of Alzheimer’s disease, and the role of IDE in degrading beta amyloid,” he says, “increasing insulin levels would be predicted to increase beta amyloid levels. We actually know that this is true from human studies. But insulin is a potent hormone that has myriad effects on cells, and it just might work for some other reason.”

Some diabetes drugs work to increase insulin sensitivity, rather than raising insulin levels. Researchers at the University of Washington are studying whether these drugs can improve memory in patients diagnosed with Mild Cognitive Impairment.

So, Dr. Leissring thinks simply increasing insulin may not help Alzheimer’s patients. “The approach of using insulin enhancers, on the other hand, seems sound, and there is emerging evidence from animal studies that it might work,” he says.

The Cerebral Amyloid Angiopathy Challenge

Cerebral amyloid angiopathy (CAA) seems to have been the main cause of my father’s dementia and death. In people with CAA, beta amyloid similar to that in Alzheimer’s plaques is deposited on the walls of the blood vessels in the brain. The protein causes the vessel walls to crack, allowing blood to leak out. Every hemorrhage, large or small, damages brain cells and can cause dementia and major hemorrhagic strokes like the one Dad had.

Unfortunately, some therapies that decrease the beta amyloid in Alzheimer’s plaques seem to increase the beta amyloid deposits on blood vessels. In theory, Dr. Leissring says, increasing the elimination of beta amyloid would be predicted to prevent both Alzheimer’s and CAA. But in some studies, attempts to dissolve beta amyloid via vaccination have increased CAA and hemorrhages in animals.

A large percentage of Alzheimer’s patients also have CAA. For them, using drugs designed to dissolve amyloid may be risky. “I think we can definitely hope for a preventative treatment for CAA, but the chances of a cure are less certain and will require much more study,” he says.

The Funding Challenge

Dr. Leissring reports that his research is currently funded by “start-up” money from Scripps Florida, funds from the National Institute on Aging (NIA), and a grant from the Ellison Medical Foundation. But even with this funding, he says he’s only been able to start ten percent of his planned projects.

“We are living in an incredible age, where we can do things in a day that would have taken many months just a few short years ago,” he says. “But it really does simply boil down to money (and lab space, ultimately). The more money, the more scientists we can hire and the more experiments can get done.”

Other Alzheimer’s researchers are experiencing the same problems - government and large organization funding seems totally inadequate. It may be that the only way to fill the gap is with private donations. The McNally family, whose father Richard died of Alzheimer’s six weeks after my dad’s death, has started a non-profit fund to support the research of Dr. Leissring and his colleagues. If you’d like to help, please go to The Unforgettable Fund, read the McNally family’s blog, and click on How to Donate.

Software Versions, Hormones and The Fountain of Youth

The computer industry uses version numbers to track the evolution of software. The first release after trial versions is called version 1.0. Major changes are reflected in the first digit of the version number, as in version 2.0. Any minor changes are reflected in the second digit, as in version 2.1. I’ve recently realized that this labeling scheme could apply to hormones as well. Think of it this way – each decade, along with its associated hormonal changes, is a major version change.

In the midst of writing about Alzheimer’s and dementia, I find myself in Hormones 4.9. So far, the transition into middle-aged versions is reflected more in my mental preoccupations than in any physical manifestations. All I think about is aging and dementia.

These topics dominate my conversations now, partly because most of my friends are somewhere near Version 5.0. My colleague Rebekah and I used to talk about technical specifications and industry gossip. But when she called me from Kansas City the other day, my favorite subjects came up. She was driving her dog Max to his acupuncturist appointment, for treatment of arthritis and irritable bowel syndrome. I told her about my scheme for labeling hormonal stages, and we wondered how it would work for dogs.

Then she told me her father-in-law had fallen at the nursing home. “Nine stitches and a bump the size of a prairie chicken egg,” she said. “I went to visit him yesterday, and said ‘That was really a nasty fall.’ ‘Fall!’ he said, ‘I didn’t fall – I was taken down by a mob in the bathroom! Then the lady who sits on people at football games got me….”

With a sense of humor and an occasional glass of wine, I figure we can handle Hormones 5.0. But I’m more worried about 6.0 and beyond. It seems no one is immune to serious problems such as Alzheimer’s, cancer, and heart disease. Maybe this is why when Gail Rae Hudson (The Mom and Me Journals) and her mother watched the movie Cocoon recently, they decided they would drink from the fountain of youth if they had the chance.

I thought of them when I watched 10 Years Younger yesterday [I had turned on the television for research purposes – really!]. During the program, image experts succeeded in moving a woman’s appearance from Hormones 4.9 back to Hormones 3.9 or so. But what good is looking like Version 3.9 if I can’t remember where I left my car?

Is there anything we can do to decrease our actual version numbers and avoid serious health problems? As far as I can tell, scientists don’t understand aging very well. The most popular idea about why we age is called the Free Radical Theory on Aging. According to this theory, breathing in air allows unstable molecules called oxygen free-radicals to build up in the body. These oxygen free-radicals then combine with other molecules, causing cell damage in a process similar to the way rust damages metal.

Researchers have shown that calorie restriction in mice and other organisms extends their lifespans. Fans of the Free Radical Theory think this may be because reducing food intake decreases the rate of metabolism and thus oxygen intake, and so the amount of free-radicals accumulating in the body also goes down. Some studies have contradicted this hypothesis, though. Even more discouraging, the anti-oxidant vitamins I thought might keep me in the equivalent of Hormones 4.9 for a few more years may not be effective. Maybe the Free Radical Theory of Aging won’t lead to Gail’s fountain of youth.

But Dr. Craig Atwood at the University of Wisconsin thinks a theory called the Reproductive-Cell Cycle Theory of Aging may eventually show the way. As discussed in an earlier post, he believes the same theory explains the chain of events leading to Alzheimer’s disease.

Dr. Atwood’s 2004 paper “Living and Dying for Sex: A Theory of Aging Based on the Modulation of Cell Cycle Signaling by Reproductive Hormones,” explains how calorie restriction might extend lifespans a bit differently than free radical [theorists, proponents]. The paper was co-authored by Dr. Richard Bowen of Voyager Pharmaceutical Corporation and published in Gerontology in 2004. It outlines the idea that when estrogen and testosterone levels go down in mid-life, the body cranks up other hormones (luteinizing hormone and follicle stimulating hormone, for example) in an attempt to maintain fertility.

“The increased levels of luteinizing hormone and follicle stimulating hormone signal bone, muscle, brain and other cells to divide inappropriately,” Dr. Atwood explains, “leading to cell dysfunction and death. This increased cell death leads to tissue dysfunction and disease, thereby killing less fertile older animals or people, preventing them from competing for resources with younger, more fertile individuals.”

Dr. Atwood thinks this theory better explains why stresses like extreme calorie restriction, exposure to cold, and “excessive” exercise appear to be associated with longer life, since calorie restriction has been shown to reduce reproductive hormones in female mammals. It may be the body interprets these stresses to mean that it’s not a good time to reproduce, and so decreases the amount of sex hormones it manufactures.

Maybe hormones hold the key to real anti-aging, rather than just changing appearances. But what about reports that hormone treatments may not prevent disease and dementia in women? In the U.S., the Women’s Health Initiative (WHI) hormone therapy trials were discontinued in 2002 because researchers found somewhat higher rates of some diseases in the group taking hormones. This same study also found that the estrogen plus progestin combination used in the trials didn’t prevent cognitive decline and actually seemed to increase dementia in some women over 65.

I asked Dr. Atwood if the results of the Women’s Health Initiative trials mean I shouldn’t consider taking hormones to decrease my risk of dementia. He said he feels that it’s very misleading to extrapolate the results of this study, in which Prempro and Premarin were used, to all forms of hormone replacement therapy. Prempro is a combination of conjugated equine estrogens and progestin in the form of the synthetic medroxyprogesterone acetate, and Premarin is made up of conjugated equine estrogens.

“Current hormone replacement therapies do not come close enough to replicating normal reproductive hormone levels,” he says, “since conjugated equine estrogens and medroxyprogesterone are not the major forms of sex steroids in the human body.” He points out that the WHI study contradicts results from numerous other animal and human studies showing that natural or bioidentical forms of these hormones protect neurons and may prevent dementia.

Hormones affect men too. A new study by researchers at the University of Washington Veterans Administration Puget Sound Health Care System found that low testosterone levels in men are associated with increased mortality rates. Looking specifically at dementia, the picture seems less clear. Scientists at the University Medical Center Utrecht in the Netherlands studied the link between reproductive hormones and Alzheimer’s disease (AD) in 2,974 men, aged 71 to 93 years for six years. They concluded “testosterone levels are not associated with risk for cognitive decline and AD, whereas higher estrogen levels increase risk for cognitive decline and AD”. In a small study at the University of California Los Angeles, testosterone supplementation in 16 men with Alzheimer’s improved their quality of life as reported by caregivers, but not their cognition.

It doesn’t seem to me there’s been enough research yet to know how various hormone replacement therapies will affect aging in general, let alone the risk of developing dementia. Dr. Atwood agrees that further research is needed. He and his colleagues are studying the neuroprotective effects of different formulations and delivery methods of female sex hormones.

He reminded me that research on aging and dementia has to have a broader focus than simply looking at estrogen and testosterone levels. “There are many other hormones that become dysregulated in the body following menopause and andropause,” he says, “and these have not been studied in any detail. Therefore, the dysregulation of estrogens and testosterone may be only part of the story.”

In the meantime, at least in theory, Gail and her mother could try to fool their bodies into keeping levels of luteinizing hormone and follicle stimulating hormone low by subjecting themselves to some of the stresses listed above. It’s hard to say whether this would slow their rate of progress to higher versions. For his part, Dr. Atwood doesn’t view calorie restriction as very attractive. “Rigorous exercise is the most practical anti-aging strategy until therapies that modulate reproductive hormones are developed,” he says.

I don’t think Gail will starve her mother, or sign her up for an Ironman race and the Polar Bear Club, but I guess this is the place to say that information in this post is not a substitute for medical advice. These measures could have life-threatening ill effects, particularly in older people.

With software, higher version numbers indicate greater stability and added functionality. Could this be true for life? Although I don’t want to develop dementia or another serious disease, I don’t really want to go back to Hormones 2.9 or even 3.9 either. So for now, I’ll watch for more research on the role of reproductive hormones in Alzheimer’s and aging, and head to the gym as often as I can. But I’m rebelling against the idea of looking “10 Years Younger”, and am growing my gray hair out. At least people will understand why I can’t find my car.

Stress, Depression and Alzheimer's, Part 2

In a previous post, I wrote about how a history of depression may increase your risk of developing dementia. This connection is not well understood, and is further complicated by the fact that many Alzheimer’s patients are depressed, even when they have no previous history of depressive episodes. If my father had lived long enough, he might have been dealing with depression as well as cerebral amyloid angiopathy and probable Alzheimer’s.

Dr. George Zubenko, Professor of Psychiatry at the University of Pittsburgh School of Medicine, spent some time last week helping me make sense of all this.

“The rate of depression in people 65 and over is quite low – a few percent,” Dr. Zubenko says. “But somewhere between 30 and 50% of Alzheimer’s patients suffer from depression. Some of that is probably due to the realization that they’re losing mental capacity – major depressive episodes often seem to be triggered by stressful life events. The much higher rates of major depression in AD [Alzheimer’s disease] patients suggest that the emergence of MDD [Major Depressive Disorder] in AD is often the result of the neurodegenerative disorder.

George S. Zubenko, M.D., Ph.D.

It’s obvious that major depression increases the suffering of dementia patients and their caregivers. Dr. Zubenko points out that it also exaggerates the patients’ disabilities, makes institutionalization more likely, and may hasten death. For these reasons, it’s important to diagnose depression in dementia patients. Diagnosis can be tricky, though - doctors don’t agree on the definition of "depression" in AD, and it’s often difficult for dementia patients to communicate their symptoms.

To help diagnose and characterize depression in Alzheimer’s patients, Dr. Zubenko and his coworkers developed a diagnostic interview called Clinical Assessment for Depression in Dementia (CADD). He believes that “major depressive disorder in Alzheimer’s disease” is not the same as major depression in non-demented patients. When the CADD was administered to 243 patients with probable Alzheimer’s disease and 151 non-demented control patients, the data showed that Alzheimer’s-related depression had somewhat different symptoms than “regular” depression. In this study, depressed Alzheimer’s patients were less likely to have sleep disturbances or feelings of worthlessness or excessive guilt than non-demented depression patients, but were more likely to have problems concentrating or making decisions.

The results of this same study confirmed other research showing that the prevalence of major depression did not increase with the severity of Alzheimer’s disease. This may mean that major depression in Alzheimer’s is not related to the overall degeneration of the brain, but rather to degeneration in specific areas. In fact, several studies have shown that major depression in Alzheimer’s disease patients is associated with the degeneration of the areas of the brain stem that produce mood-regulating chemicals such as serotonin, noradrenaline, and dopamine. It’s unclear whether this is relevant for other types of dementia.

Dr. Zubenko is one of a group of scientists proposing that the next update of the Diagnostic and Statistical Manual of Mental Disorders (a reference manual used by doctors in the U.S.) include more accurate characterizations of various psychiatric symptoms in dementia, including depression. Better diagnosis would be another step towards understanding the causes of and treatment for depression in Alzheimer’s.

In the meantime, can doctors help AD patients with depression? Most clinical trials of anti-depressants for depression in Alzheimer’s have been relatively small and short term. At first glance, results look mixed, with some trials showing anti-depressants were more effective than placebo, and some not. In one larger study of 511 patients, an anti-depressant significantly improved both depression and memory. Research currently underway may yield more information. Israeli researchers are conducting a trial of Escitalopram (Lexapro, Cipralex)) for depressive syndrome in various dementias, and there’s also a U.S.-based trial of Zoloft for depression in Alzheimer’s disease.

But the published trial results are really more positive than it first appears, because many show large improvements in the patients taking antidepressants AND in those taking placebos. For example, researchers from the Raul Carrea Institute of Neurological Research in Argentina published the results of a trial of anti-depressants in 41 depressed Alzheimer’s patients. The symptoms of depression went away in 47% of patients treated with the anti-depressant, and in 33% of those treated with placebo. The large placebo effect may be due to non-drug factors such as the attention paid to patients and caregivers during clinical trials, or to the fact that depression in Alzheimer’s patients seems to come and go. Even though it’s not well understood, Dr. Zubenko says this finding means doctors can provide some assistance for AD patients with depression.

“The goals of most controlled clinical trials are somewhat different from the goals of clinical care,” he explains. “Most controlled clinical trials are designed to evaluate whether a particular treatment is effective. To accomplish this, the only difference between the treatment and control groups is the specific treatment whose potential benefit is being evaluated. These controlled trials are important because they provide scientific information from which healthcare professionals and caregivers can decide what treatments work for a particular condition and which do not. Doctors recommend treatment plans for individual patients based on this information, but are not limited to one particular treatment approach. In such cases, we often recommend multiple interventions to maximize the likelihood of a beneficial response, hopefully in an organized way, so that we can also infer which interventions are benefiting the patient. This practical approach is especially important when time is of the essence--e.g the patient's condition is deteriorating in ways that place them in harm's way, they are dangerous to others, or when other practical realities limit the available duration of treatment (such as often occurs in inpatient settings).”

Medications are helpful, but “nonspecific clinical interventions can have valuable effects on optimizing function and minimizing disability,” Dr. Zubenko says. “Patients who are in physical pain or discomfort, or are impaired in other ways by medical problems or medication side effects, commonly have secondary disturbances of mood and cognition. Performing a complete medical evaluation and optimizing general health care can have significant positive effects on level of function and the quality of life. Supportive care is also important-- improving nutrition among malnourished patients, addressing personal hygiene, normalizing and structuring daily activities, providing a safe environment with activities and aids that facilitate memory and promote normal functioning , and reevaluating these plans periodically to ensure that they remain appropriate to the patient's needs. Based on my clinical experience, major depression in AD patients usually responds best to a multimodal treatment approach.

It's also important to remember that the ongoing care of a patient with AD is a challenging task for the caregiver. Over the intermediate and long term, it is necessary to provide support, education, assistance, and resources to the caregivers as well. Proper attention and support reduces the stress on caregivers and decreases or delays the need for institutionalization. Failure to do so results in poorer outcomes for both patients and caregivers alike.”

So, major depression and dementia are closely linked, and our understanding of causes and treatments for both of these diseases is still incomplete. For depression sufferers around the world, there’s an increased risk of AD. And for Alzheimer’s patients around the world, there’s a potential depressive ripple effect, for both patients and caregivers.

Careful medical attention for both the patient and the caregiver may help, but I wonder how many patients and caregivers can get this attention. In my family’s experience, it was difficult to coordinate Dad’s care between his family physician and his neurologist, let alone “optimize” all the factors Dr. Zubenko talks about. If my father had lived long enough to need intensive caregiving, only minimal assistance and resources would have been available to us.

It’s hard to find the silver lining in this research, but Dr. Zubenko put it in perspective for me. “We’re trying to treat a complicated behavioral syndrome in the context of degenerative brain disease – any progress is remarkable, and efforts to optimize treatment are well worth it for patients and their family members,” he says.

Stress, Depression and Alzheimer's, Part 1

For most of his life, my father was calm and happy. “No sweat,” he’d say when the furnace blew up or the car wouldn’t start. Even when his retail lumberyard burned down, or when his parents died, he seemed to take a Zen attitude towards life. But after he retired, I thought he was more pessimistic than usual. Was this somehow related to his later dementia?

I didn’t think much about mood, depression and dementia until I realized it was a topic of discussion on some of the caregiver blogs. In The Yellow Wallpaper, Deb Peterson writes about how her mother’s depression after the death of several family members seemed to mark the beginning of her dementia. Paula Martinac (Dementia Blues) reports both her parents were depressed before their declines into dementia. But many people with Alzheimer’s disease or dementia have no history of depression. Gail Rae Hudson (The Mom & Me Journals), who describes her mother’s condition as “dementia lite,” doesn’t think her mom has ever been depressed.

Was the change in Dad’s mood [I wouldn’t call it depression] a normal reaction to retirement? Or was it an understandable reaction to subtle signs of dementia the rest of us didn’t see? It makes sense that some dementia patients become melancholy when they realize they’re having memory problems.

But rather than dementia causing depression, it seems to be more of a two-way process. Several studies show a history of depression may increase your risk of developing dementia later in life:

• A large retrospective study at the University of Limburg in the Netherlands (published in 1996) and another at the University of Copenhagen in Denmark (2003) found associations between a history of depression and dementia
• When researchers at Rush Alzheimer's Disease Center in Chicago followed Catholic clergy aged 65+ for seven years, they concluded that each depressive symptom reported over the seven year period increased the risk of developing Alzheimer’s disease by an average of 19%, and increased average cognitive decline by 24%.
• Scientists at Boston University School of Medicine found a significant association between depression symptoms and Alzheimer’s in 1953 patients with Alzheimer’s disease and 2093 of their non-demented relatives. The association was most significant when depression symptoms first occurred within one year of the onset of Alzheimer’s, but there was still a modest association even when depression first happened more than 25 years before the onset of Alzheimer’s. [free registration required to view this article]

Other studies have not been as definitive. University of Ottawa researchers found a weak, but not statistically significant association between a history of depression and Alzheimer’s disease after following more than 4600 Canadians aged 65 and older over a five year period.

This year, a team of researchers from the University of Miami Miller School of Medicine and the Wien Center for Alzheimer’s Disease and Memory Disorders at Mt. Sinai Medical Center published the results of a systematic review and analysis of the research on this topic. Analyzing data from over 100,000 patients in 22 studies, the researchers concluded that a history of depression does seem to increase the risk of developing Alzheimer’s, although the absolute risk is still small. Their data also showed relatively long times between depressive episodes and the onset of Alzheimer’s, suggesting that depression may be an independent risk factor for developing Alzheimer’s rather than signaling the onset of the disease.

For dementia patients with a previous history of depression, it’s also likely their dementia will be more severe than that of patients with no such history. In a recent study, pathologists compared the brains of Alzheimer’s patients who had lifelong histories of depression to the brains of Alzheimer’s patients who hadn’t had depression. The pathologists found that the brains of patients with a history of depression had more of the plaques and tangles associated with Alzheimer’s disease than those of patients who hadn’t had depression. This increase in plaques and tangles seemed to correlate with the severity of memory loss.

If depression and Alzheimer’s are linked, then maybe there’s a common underlying cause. Several studies point to cortisol, a stress hormone, as the possible culprit. The thinking is that stress causes the body to release cortisol, and that chronic stress leads to the chronically high levels of cortisol sometimes associated with cognitive impairment and shrinkage of some areas of the brain.

The obvious question is whether lowering cortisol improves memory. I’ve always had trouble navigating, and this problem gets worse when I’m upset. Could I take something to lower my levels of this hormone before I drive an unfamiliar route? It turns out that for rats, lowering cortisol levels does improve their performance in mazes.

I was disappointed to find it’s not so simple for humans. In a small trial of seventeen people, a team headed by researchers from McGill University in Canada found that manipulating cortisol levels did have an effect on memory in some people, but that effect was dependent on historical cortisol levels in each participant or person. If the individual patient had had moderate cortisol levels for a period of five years, blocking cortisol levels actually decreased memory, and adding back cortisol reversed this problem. For patients with historically high cortisol levels and existing memory problems, blocking cortisol didn’t improve memory, although increasing cortisol levels made their memory problems worse. This could be because it’s the cumulative, long-term exposure to high levels of cortisol that hurt the brain, rather than the level at any one time. Some scientists think problems are caused by the malfunctioning of the receptors for cortisol, rather than the hormone itself.

So, the cortisol and stress connection is intriguing, but at least so far, hasn’t yielded the magic formula to fix dementia.

One of reasons it’s hard to untangle the relationship of depression and dementia or Alzheimer’s disease is that both diseases may have multiple underlying causes. “I think the evidence shows that there may be complex relationships among stress, cortisol (and other neuroendocrine substances), inflammatory markers, cardiovascular disease, and cognition,” says Dr. Ray Ownby, Professor of Psychiatry at the University of Miami Miller School of Medicine and the lead author of the scientific review of research on the topic. “Since cardiovascular disease may be related to Alzheimer's disease, it seems quite possible that stress, cortisol, inflammation, depression, and AD may all be related, but we don’t know how.”

Raymond L. Ownby, M.D., Ph.D., M.B.A.

But even if stress, cortisol and depression were only partially responsible for dementia, could they be considered “modifiable risk factors” for Alzheimer’s disease? I asked Dr. Ownby if treating depression could actually lessen a person’s chances of developing dementia.

“The possibility that treating depression might lower your risk for Alzheimer’s disease is intriguing,” he says, “but there simply isn't any evidence that I'm aware of on the subject, other than the possibility that antidepressants can lower levels of some chemicals that may be related to dementing illnesses.”

What about the idea that depression can masquerade as dementia? When I first started researching my father’s memory problems, several web sites mentioned “pseudo-dementia.” According to some of these sites, once you treat the depression, the dementia is reversed. But the diagnosis and prevalence of pseudo-dementia is now in question, and at least one study has shown that many people who seemed to have reversible dementia [their memory problems improved after their depression was treated] later developed [non-reversible] dementia.

Dad didn’t have a history of depression, and it’s pretty clear most of his dementia was related to cerebral amyloid angiopathy. But if he had lived long enough, depression might have been more of a problem. Treating any depression may have helped his dementia, at least for a while. I’ll talk more about that in my next post.

Beta Amyloid in Alzheimer's and CAA: Dr. Jekyll or Mr. Hyde?

Two weeks ago, I met with Dr. Craig Atwood at the University of Wisconsin to talk about the theory that mid-life hormonal changes trigger a chain of events leading to Alzheimer's and similar neurodegenerative diseases.  It turns out this isn't the only area in Alzheimer's research in which his thinking diverges from the mainstream.

During our discussion on reproductive hormones, I gave him Dad's autopsy report to read.

"Hmmm, severe CAA [cerebral amyloid angiopathy].  Well, I would suggest that the amyloid deposits were your dad's brain's attempt to protect itself by sealing off ruptures to prevent hemorrhage.  I don't think the amyloid caused his problems."  He opened a file cabinet and pulled out a copy of a review he wrote on this topic.  Published in Brain Research Reviews in 2003, the article lays out the logic behind the theory that amyloid [the protein found in Alzheimer's plaques and on the brain's blood vessel walls in CAA patients] could be protective, not destructive as most researchers believe.  The logic goes something like this:

• Normally, when damaged parts of the body start bleeding, the blood coagulates, or clots, and this seals off any "leakage," but can prevent blood flow through damaged vessels to neighboring tissue...
• If this happened to the blood vessel walls deep within the brain, the resulting clot would block the supply of glucose and oxygen carried by the blood to that part of the brain, depriving neurons of essential nutrients and leading to dysfunction...
• The brain has developed a different mechanism to stop bleeding:  amyloid aggregates around the blood vessel wall, sealing the lesion and preventing blood from clotting.  This allows continuous blood flow through the damaged vessel, in the way that repairing a corroded or cracked plumbing pipe would allow water to flow through the pipe...
• Amyloid has properties that make it a good sealant...
• The fact that amyloid deposits have been observed near injury sites in the brains of people who have had head trauma [see an early report, for example] can be seen as support for this theory...
• Therefore, amyloid could be a protective molecule that is formed when there is damage to the brain caused by injury, stroke, Alzheimer's or age-related changes to blood vessel walls.

Dr. Atwood is not alone in questioning whether beta amyloid is really the evil Mr. Hyde of Alzheimer's.  The Wall Street Journal summarized the larger controversy in articles published on April 9, 2004 and April 16, 2004.  But the idea that amyloid could be a vascular sealant is in direct opposition to the widely held belief that amyloid is toxic and causes Alzheimer's and brain hemorrhages like Dad's.

The theory that amyloid is a "good" protein is important in the context of researchers' and pharmaceutical companies' efforts to develop vaccines to clear amyloid from the brain.  The first clinical trial of such a vaccine in humans was halted in 2002 after some of the participants developed inflammation of the brain and spinal cord.  Despite the safety issues, the vaccine appeared to have slowed memory loss in twenty of the thirty patients followed after the trial was stopped.  Trials of vaccination against amyloid in mice have had similar results:  University of South Florida scientists report that vaccination clears amyloid plaque deposits and improves memory in mice, but increases amyloid on blood vessel walls and causes hemorrhages.

Researchers are developing new, hopefully safer, ways to vaccinate against amyloid, but Dr. Atwood remains unconvinced that these efforts will succeed.  "If you believe that amyloid is protective, then it's no surprise, that mice and humans develop problems when they are immunized," he says.

Of course, Dr. Jekyll and Mr. Hyde were one and the same.  The evil Mr. Hyde could only be suppressed if Dr. Jekyll continued to take the potion he'd developed in his lab.  Could the beta amyloid in Dad's brain have been somehow both helpful and harmful?  Maybe someday we'll have the magic potion we need to harness its good properties while suppressing the bad.

Hormones, Alzheimer's and the Fountain of Youth

I visited Dr. Craig Atwood at his Laboratory of Endocrinology, Aging and Disease at the William S. Middleton Memorial Veterans Hospital in Madison, Wisconsin last week.  To get to Dr. Atwood's office, I navigated through the hospital's maze of dark hallways and waiting rooms filled with American flags, flickering televisions and mostly older male patients.  It seemed an unlikely setting for a discussion of Dr. Atwood's paper "Living and Dying for Sex:  A Theory of Aging Based on the Modulation of Cell Cycle Signaling by Reproductive Hormones."

Co-authored by Dr. Richard Bowen of Voyager Pharmaceutical Corporation, "Living and Dying for Sex" was published in Gerontology in 2004.  The paper lays out a new theory on aging, along with supporting data.  I wanted to talk with Dr. Atwood because he believes this theory is relevant to the cerebral amyloid angiopathy and Alzheimer's that caused Dad's dementia and death.

An endocrinologist by training, Dr. Atwood is now Research Director of the Wisconsin Alzheimer's Institute at the University of Wisconsin School of Medicine and Public Health.  Many Alzheimer's researchers focus on the pathology of the brain, including the plaques and tangles that are part of the official diagnosis of Alzheimer's.  But as an endocrinologist, Dr. Atwood studies hormones, the glands that produce them, and their role in the body.  Maybe this is why he sees things a little differently.

"This all started when a patient mentioned to Dr. Bowen that her husband's Alzheimer's disease hadn't worsened after he was placed on leuprolide acetate for the treatment of his prostate cancer," Dr. Atwood explained.  "Leuprolide acetate decreases the levels of reproductive hormones in the blood.  This, along with similar anecdotal reports, led us to focus on the hormones that regulate reproduction, including estrogen, testosterone, luteinizing hormone and follicle-stimulating hormone, as possible factors in Alzheimer's disease."

Craig S. Atwood, Ph.D.

"Throughout our reproductive lives, our reproductive hormones are in balance, but at mid-life (during menopause in women and andropause in men), the levels and balance of these hormones change," Dr. Atwood continued.  "Estrogen and testosterone levels go down, and we know from previously published research that levles of luteinizing hormone and follicle-stimulating hormone go up during this time.  We think that as estrogen and testosterone levels decrease, the pituitary gland increases production of these other hormones in an attempt to maintain fertility.  This attempt to maintain fertility is good for the species, of course, but we think it's bad for the individual.  It effectively removes post-reproductive individuals from the population."

Why might these normal hormone changes have been bad for my father or for any other "post-reproductive individual"?  "The answer lies in the cell cycle," Dr. Atwood said, pointing to a poster about the cycle on his office wall.  Cell division allows an organism to grow, and to repair and renew tissue.  The process in which the chromosomes in a cell are replicated and the cell divides into two new cells is called the cell cycle.

In adults, brain cells or neurons don't normally go through the cell cycle.  This may be because they develop extensions called axons and dendrites for transmitting information to other brain cells.  Dr. Atwood explained that if you think of these axons and dendrites as hardwired into the brain's network, you can see that cell division would greatly disrupt brain function.

But in the 1990's, researchers found evidence that Alzheimer's patients' brain cells had been trying to replicate their chromosomes and divide.  It may be this misguided attempt to re-enter the cell cycle that is causing the cells to die.  Scientists don't know for sure why these brain cells are trying to divide, or exactly how the attempted division could cause cell death.

Given that a drug suppressing the reproductive hormones seemed to halt the progression of Alzhiemer's disease in some patients, Dr. Atwood theorized that imblanced or dysregulated reproductive hormones are somehow involved in signaling brain cells to divide.  There are a lot of luteinizing hormone receptors in human brains, and researchers have found the same receptors in areas of rats' brains that correspond to the parts of the human brain typically affected by Alzheimer's.  These observations indicate that luteinizing hormone could play a role in signaling those brain cells to divide.

To sum it all up, Drs. Atwood and Bowen think that mid-life changes in sex hormones signal normally stable neurons, or brain cells, to divide.  According to their theory, the neurons' attempts to replicate chromosomes and divide goes awry somehow, resulting in cell death.  This could be the underlying cause of Alzheimer's and similar diseases.

Research is underway in Dr. Atwood's lab to test this theory, and to develop Alzheimer's treatments based on these findings.  He and his colleagues have already shown that leuprolide improves memory and decreases beta amyloid deposits in mice bred to have Alzheimer's disease.  In addition to these efforts in the lab, Voyager Pharmaceutical Corporation is recruiting patients in the United States, Canada and South America for a Phase III trial of leuprolide acetate in 555 patients with mild or moderate Alzheimer's disease.

In future posts, I'll try to summarize how Dr. Atwood's theory may explain aging in general, and why he believes the beta amyloid protein deposits seen in Alzheimer's and cerebral amyloid angiopathy are protective, not harmful.