The Tangled Neuron

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.

Testing for the Wisconsin Registry for Alzheimer's Prevention

This morning I gave blood and completed the neuropsychological testing for the Wisconsin Registry for Alzheimer's Prevention (WRAP).  Nicole Wright, Research Specialist with the Wisconsin Alzheimer's Institute, met me at the University of Wisconsin Hospital in Madison.  She introduced me to Sue, a nurse who recorded my vital statistics and drew blood.  My blood will be used for genetic testing, and to record levels of substances such as cholesterol that may affect my risk of developing Alzheimer's.

Nurse Sue draws my blood

Then it was off for two and a half hours of neuropsychological testing administered by Nicole.  Here's a list of the tests I took:

• Clock Drawing
• Wechsler Abbreviated Scale of Intelligence
• Boston Naming Test (language and verbal skills)
• Controlled Oral Word Frequency (lexical fluency)
• Wide Range Achievement Test (sub-test of Reading Test)
• Judgment of Line Orientation (visuo-spatial skills and spatial orientation)
• WASI block design sub-test (perceptual-constructional ability)
• WASI Matrix Reasoning (non-verbal abstract reasoning)
• Rey Auditory Verbal Learning Test
• Faces I and II from the Wechsler Memory Scale - III (recognition of unfamiliar faces)
• Wisconsin Card Sort - 64 (working memory and executive abilities - novel problem solving)
• Wechsler Adult Intelligence Scale - III, Working Memory Sub-tests
• Stroop Color Word Test (response inhibition)
• Trail Making Test A and B (psychomotor speed and mental flexibility)

As Nicole predicted, some tests were easy, but others seemed difficult to impossible.  I didn't feel stressed during the testing - it probably helped that we took two breaks. The experience on each test is probably different for every participant, but what's important is how your abilities change over time, not your absolute scores.   

These tests will be my baseline tests, and I'll be back to take them again every four or five years.  I won't know the results of my blood tests or neuropsychological tests (at least as long as WRAP is ongoing), but at least I feel I'm contributing to the effort to find Alzheimer's treatments.

If you're interested in participating in WRAP, you can contact the Wisconsin Alzheimer's Institute at  +1 608-829-3306 or 1-800-417-4169.  You can also email Janet Rowley at jsrowley@wisc.edu.

The Wisconsin Registry for Alzheimer's Prevention

I stopped in at the Wisconsin Alzheimer's Institute today to sign up for their Wisconsin Registry for Alzheimer's Prevention (WRAP).  The institute is part of the University of Wisconsin School of Medicine and Public Health in Madison, the capitol of Wisconsin.

In 2001, WRAP staff began collecting and recording information about the health, lifestyles, genes and cognitive status of adult children of people diagnosed with Alzheimer's.  This information is made available to researchers at the University of Wisconsin and the Madison Veterans Administration Medical Center.  More than 900 people (including control subjects with no family history of Alzheimer's disease) have signed up to participate in the registry, and some findings have already been released:

• 44% of WRAP participants have the APOE e4 gene that is associated with a higher risk of developing Alzheimer's disease (compared with 15% of control subjects)
• WRAP participants with the APOE e4 gene do not score significantly worse on neuropsychological tests of memory and cognitive function than those without the gene
• Moderate alcohol use and exercise are associated with slightly better performance on cognitive tests
• Brains of people whose parents had Alzheimer's react less to stimulation than brains of people with no family history of the disease.

If I'm accepted into the program, I will need to come back to Madison every four or five years so any changes in my health or cognitive status can be recorded.  I may also have the opportunity to take part in future studies.

Adult children of Alzheimer's patients are eligible to participate in WRAP if they are between 40 and 65, and can document that a parent had Alzheimer's disease.  I took a copy of my father's autopsy as proof that he had Alzheimer's, but if a parent is still living, medical records showing a clinical diagnosis would be required.

Nick Weber and Nicole Wright of Wisconsin Alzheimer's Institute

During my appointment today, Research Specialists Nick Weber and Nicole Wright helped me fill out consent forms as well as a detailed health history.  On Friday, I'll go to the University of Wisconsin Hospital to have blood drawn, blood pressure taken, etc.  Then I'll go through two and a half hours of neuropsychological testing with Nicole.  This should give me a better understanding of what Dad went through during his neurologist visits!

The Cost of Alzheimer's and Dementia Care

In her blog The Yellow Wallpaper, Deb Peterson lists financial worries as the number one stress in caring for her mother, who suffers from dementia.  "If I knew that my mother was assured of the care that she needs, right up until the end of her life, I might feel less stress," Deb writes.

She's in good company.  Researchers from the Karolinska Institutet in Sweden told attendees at the International Conference on Alzheimer's Disease and Related Disorders Sunday that they estimate worldwide costs for dementia care at US$ 248 billion per year.  Even averaging in lower costs for developing countries, that's almost $9000 per person per year.

In the U.S., costs are probably higher, and much of the burden is carried by families.  Here's some estimates on U.S. costs from the Alzheimer's Association:

• Cost of Alzheimer's care                                                                $100 billion per year
• Percent of Alzheimer's patients living at home                                  70
• Percent of care for those patients provided by families                       75
• Average annual cost of paid home care for remaining 25% of care      $19,000 (most paid by families)
• Average cost of nursing home care per year                                     $42,000
• Average lifetime cost of care for an Alzheimer's patient                    $174,000

Contrast these numbers with the proposed federal spending on Alzheimer's research for fiscal year 2007:  $645 million.

No wonder Deb and others who face these costs every day are stressed out about finances.

Cerebral Amyloid Angiopathy and Alzheimer's Disease: Evil Twins?

A couple of posts ago, I mentioned that my father had both cerebral amyloid angiopathy (CAA) and Alzheimer's disease.  This isn't unusual - one study estimates 25% of people with Alzheimer's have moderate to severe CAA.

It turns out that the protein in the deposits on CAA patients' blood vessel walls is closely related to the protein seen in the plaques associated with Alzheimer's.  Researchers don't understand why excess levels of these proteins build up in some people's brains, or exactly what the connection is between CAA and Alzheimer's.

One recent study shows that a kind of CAA concentrated in small capillaries, rather than in larger blood vessels, is linked to Alzheimer's disease.  But Dad's CAA was not concentrated in his capillaries.  In fact it seems his CAA and Alzheimer's were not really connected.  "The burden of CAA in the brain vastly exceeds that seen in even the most severe and advanced cases of AD [Alzheimer's disease], indicating that this is likely to have been an independent disease process," Dad's autopsy report says.

There's growing recognition that CAA can cause or contribute to dementia, as well as cause hemorrhagic strokes like the one my dad had.  The fact that cerebral microbleeds, which can be caused by CAA, were common in Dutch memory clinic patients in a recent study seems to support this.

Whether or not CAA and Alzheimer's disease are evil twins, they were double trouble for Dad.