The Tangled Neuron

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.

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.

Cerebral Amyloid Angiopathy and Alzheimer's Disease: Dad's Double Burden

     Five years after Dad first had memory problems, we're starting to understand what caused his dementia.  Seven months after he died, we know what caused his hemorrhagic stroke.  I'm both relieved and sad to have a diagnosis.

     Last week I got a report from the Neuropathology Lab at Massachusetts General Hospital, where we sent some of Dad's brain tissue.  The report says he had severe cerebral amyloid angiopathy, or CAA.  In people with CAA, a destructive protein 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, difficulty speaking, or even paralysis.  Some CAA patients, like Dad, die of these hemorrhagic strokes.

     In a way, it's a relief to know that researchers don't yet understand what causes CAA, or how to treat it.  As Dad's memory problems slid into full-blown dementia, I felt like there was an answer, but we just couldn't find it.  This diagnosis means no one - not me, not my family, not his doctors - could have done anything to help him, no matter how hard we tried.

     My father also had a "moderate number" of the plaques and tangles characteristic of Alzheimer's disease in some areas of his brain.  According to the neuropathology report, these "contributed to his neurologic difficulties."  It's sad to think about him entangled by both Alzheimer's and CAA.

     On my birthday last year, Dad stayed on the phone with me longer than usual.  It was hard for him to find words, but he wanted to talk.

        Dad, Beau and Mom

     "Things are different here now," he said.  "But when I nap, Beau [their dog] stays with me.  He climbs up on me so I feel better. And Mom and I still push on each other [give each other backrubs], so that's good."

     "You've got a lot of good things, Dad."

     "Yes.  Hi from me to you...happy birthday," he said.  "I'm still older than you are!"

     Struggling under the double burden of CAA and Alzheimer's, Dad kept both his gratitude and his sense of humor.

The APOE Gene, Alzheimer's and Dementia

     Going through the thick folder containing Dad's medical records, I found the results of a genetic test:

Apolipoprotein E Genotype:  2 and 3.  Interpretation:  This individual does not possess an apoe 4 allele.  This result does not indicate whether this individual's dementia is due to Alzheimer's disease or other cause of dementia.

     The APOE or apolipoprotein E, gene makes a protein that carries cholesterol and other fats through the blood to be processed.  The three common variations of this gene are called e2, e3 and e4.  Everyone has two copies of this gene; Dad had one e2 and one e3 copy.  If you have one or two copies of the e4 variation, you may have a somewhat higher risk of developing Alzheimer's disease.

     But the connection between the APOE gene and Alzheimer's is not very strong.  Some people who don't have the e4 variation have Alzheimer's, and some people with Alzheimer's don't have the e4 variation.  My father didn't have the e4 variation, but still developed dementia.  The e2 variation he had is actually associated with a lower risk of developing Alzheimer's disease in some studies.

     The APOE gene may also influence the age at which people develop Alzheimer's.  People with the e4 variant who have Alzheimer's tend to develop it at a much earlier age than those who have Alzheimer's but not the e4 variant.  Even this influence is weak - in an article published in The American Journal of Human Genetics in 2000, researchers estimate that only 7 to 9% of the age of onset of Alzheimer's is explained by the e4 variation.

     Dad did not have the gene variation associated with higher risk of Alzheimer's

     Because the connection between the APOE gene and Alzheimer's or dementia isn't very strong, environmental factors and/or additional genes must play a role in determining whether someone develops dementia, and at what age.  The search for other genes involved with dementia is an intimidating task.  An overview of presentations at a recent conference on Alzheimer's notes that the AlzGene database of studies on genes and Alzheimer's contains information on over 300 candidate genes and 800 common variations.  So far, no one has found another gene that plays as significant a role as APOE.

     It could be a combination of genes determines whether or not someone will develop dementia.  For example, a study of 180 Alzheimer's patients and 120 non-demented volunteers identified three different gene combinations, each of which appeared to increase the risk of developing Alzheimer's by 800 percent for study participants.

     The US National Institute on Aging is sponsoring ongoing research to identify genes involved in Alzheimer's.  The study is recruiting siblings, at least one of whom must have been diagnosed with the disease.

     If the link between genes and dementia were better understood, genetic tests could be used to predict, diagnose and maybe even treat Alzheimer's and other dementias.  In the meantime, the association between the APOE gene and Alzheimer's isn't strong enough to be useful.  Testing for the e4 variation of the APOE gene didn't help us understand Dad's dementia at all.

Microbleeds in memory clinic patients

     A new article on cerebral microbleeds in memory clinic patients was published in the May 9 issue of Neurology.  Microbleeds are the small hemorrhages that doctors could see signs of on the MRI of my father's brain.  Thes microbleeds happen when the blood vessel walls in the brain thicken, harden and then crack, allowing blood to seep into the brain.  This can be caused by high blood pressure or by deposits of a protein called amyloid on the vessel walls (cerebral amyloid angiopathy).

     The Neurology article describes how researchers from the Department of Neurology/Alzheimer Center at the Vrije Universiteit (VU) Medical Center in Amsterdam looked for cerebral microbleeds in 772 memory clinic patients.  They found microbleeds in 65% of vascular dementia patients (whose dementia is caused by problems with blood supply to the brain), 18% of Alzheimer's disease patients and 20% of patients diagnosed with mild cognitive impairment.  While these percentages are lower than those of hemorrhagic stroke patients (estimated at 68% in one study), they are higher than the percentages found in the general population.  For example, as part of the Framingham study in the US, researchers found microbleeds in 4.7% of 472 participants with a mean age of 64 years, only two years younger than the mean age of the Dutch memory clinic patients.

     The VU scientists' findings raise some questions about the relationship of microbleeds and vascular disease to Alzheimer's.  Currently, vascular dementia and Alzheimer's are viewed as separate conditions.  But some researchers wonder whether vascular disease causes or contributes directly to Alzheimer's.

    For an expert opinion on these issues, I checked in with Dr. Philip Scheltens, Professor of Cognitive Neurology, Director of the Alzheimer Center at the Vrije Universiteit Medical Center and co-author of the new study.  His study concludes that the relatively high proportion of microbleeds in Alzheimer's disease and mild cognitive patients "provides further evidence for the involvement of vascular factors in neurodegenerative disease such as Alzheimer disease."

Dr. Philip Scheltens

     I asked Professor Scheltens whether he thinks microbleeds might actually cause or contribute to Alzheimer's.  "I think they are yet another phenomenon that occurs alongside Alzheimer's," he says, "and certainly do not cause it but may precipitate the clinical picture."

     Could microbleeds cause dementia independent of Alzheimer's?  "That we don't know yet," Professor Scheltens says, noting that there are not enough large studies on this topic to come to a firm conclusion.  "My view is that AD is a clinical label to which many pathologies can contribute; there are pure cases and cases where degenerative and vascular pathology go together and one may influence the other."

     I'm waiting for an analysis of Dad's tissue that I hope will provide more clues as to what caused his dementia, and whether he had cerebral amyloid angiopathy and/or Alzheimer's.  In the meantime, studies like Professor Scheltens' are providing more clues about the relationships among these conditions and diseases.  That may help researchers better understand the causes of dementia and eventually lead to the development of more effective treatments.

Did genetic mutations associated with iron overload cause Dad's dementia?

More than two years ago, one of my father’s neurologists determined that Dad had low levels of B-1 in his blood, and said this was the major factor in his dementia. “We think iron overload causes B-1 deficiency,” he told me. “Genetic tests show he is an iron overload carrier – he has one copy of the C282Y mutation in the hemochromatosis gene that causes iron overload when present in two copies. Being a carrier is typically a silent condition, but it is not with your dad – he does have high levels of iron. Iron overload may be a factor causing his dementia.”

Did I inherit Dad's iron overload gene mutation along with his good looks?

This neurologist was not alone in thinking there might be a connection between the genes associated with iron overload or hemochromatosis and Alzheimer’s. The results of a University of Toronto study published in 2000 showed that these genetic mutations predisposed men to Familial Alzheimer’s Disease, but might actually be somewhat protective for women. Subsequent studies have had mixed results.

When I found the results of Dad’s hemochromatosis genetic test in his records, the write-up was so long and technical I couldn’t begin to interpret it. Two genetic mutations other than C282Y were listed: H63D and S65C. Did he have all three mutations?

I called the American Hemochromatosis Society for help, and they suggested I contact Kimball Genetics, Inc. a DNA diagnostic lab in Denver, Colorado. The company’s President and Laboratory Director, Dr. Annette Taylor, was kind enough to help me interpret Dad’s tests.

“There really is a lot of technical information in the report,” she said, “but the final interpretation is that your father was heterozygous (had a single mutation) for ONLY the C282Y mutation associated with iron overload. A double mutation is strongly associated with iron overload, but most heterozygotes have only slightly increased iron. Only about 1% of people with hemochromatosis have just this single mutation.”

“Other genes may also be involved in leading to iron overload in C282Y heterozygotes,” she continued, “but your dad was negative for the H63D and S65C mutations.”

Before I talked with Dr. Taylor, I sent a DNA sample to Kimball Genetics to see if I had the same mutation Dad had. I used their collection kit to swab the inside of my cheek, and sent the swabs to the lab. “Your genotype is fine,” she assured me. You got your Dad’s normal gene.”

Now that I have a copy of Dad’s blood test results, I’m not sure he really had high levels of iron anyway. I’ll talk more about that in my next post. In the meantime, it’s looking less likely to me that inherited iron overload caused his dementia.

Do cerebral emboli cause Alzheimer's and vascular dementia?

In a recent study at the University of Manchester in the UK, researchers found that participants with Alzheimer’s and vascular dementia had significantly more blood clots in their brains than those with no dementia. The scientists used ultrasound testing to look for clots in the brains of 320 people.

These clots, or emboli, are formed outside the brain, then travel to the brain through the bloodstream. Once the clot is in the brain, it blocks the blood flow cells need to function. The researchers explain that a large clot can cause a stroke, but many small clots over the years may cause brain damage and dementia, without any symptoms of stroke. The clots are often caused by problems with heart rhythms or by carotid artery disease. The carotid arteries are the large arteries running up through the neck to bring blood to the head.

The study is interesting because if further research confirms this association between clots and dementia, testing for clots could be used to identify people at risk for dementia. If these clots actually are found to cause dementia or Alzheimer’s, it might be possible to treat patients with medicines that keep clots from forming.

We don’t know if my father had the cerebral emboli found in this study – this type of ultrasound testing is not typically performed on patients. His medical records say that his carotid arteries were clear. But what about problems with his heart?

“All of our dementia patients get heart checks,” says Dad’s last neurologist, Dr. Frank Fleming of East Carolina Neurology, “but not necessarily rhythm monitoring for extended times.” But Dad was monitored for 24 hours to check for this type of heart problem, and although his heart beat was slow, there were no major problems with the rhythm.

Dr. Fleming notes that it isn’t clear yet what the advantage would be of monitoring the heart function of every dementia patient for these extended periods. In this new study, in fact, 40% of the dementia patients with these clots showed no signs of heart or carotid artery problems. The researchers hypothesized that dementia and clots might have a common cause, rather than a cause and effect relationship.

We’ll have to wait to see if further research confirms this association between clots and dementia, and then try to understand what the relationship means for screening or treatment.

 

The MTHFR gene and Alzheimer's

One of the test results I found in Dad’s records was for a mutation in a gene called MHTFR. His medical records say:

Methylenetetrahydrofolate reductase (MHTFR) FRET genotype analysis to identify the C677T polymorphism. Genotype result: A/A (Normal)

The U.S. National Library of Medicine has a Genetics Home Reference site written for consumers who want to know more about genetic conditions. Information on that site says mutations in this gene are associated with cardiovascular disease and elevated levels of an amino acid called homocysteine. Elevated levels of homocysteine in the blood are thought to increase the risk for cerebrovascular disease and Alzheimer’s disease.

Some researchers have suggested a possible association between a particular mutation of the MHTFR gene and Alzheimer’s disease or vascular dementia, but recent studies have not found any strong association, except in Japanese and Chinese populations.

Even if this genetic mutation were a problem, Dad didn’t have it. His homocysteine levels were also normal. None of his doctors ever mentioned this genetic test or homocysteine levels, so I guess they didn’t feel this was likely to be a factor in his dementia.

Genetics, Alzheimer's and Dementia

Looking back through Dad’s medical records, I found the results of some genetic tests. Did his genes explain what happened to him? Were his dementia and death already set in stone the day he was born? Or maybe by the time this picture was taken?

 

I remember that one of his neurologists had said that my father didn’t have the gene that may increase the risk of developing Alzheimer’s. To see if I could get a better understanding, I thumbed through Dad’s records looking at all the pages with the words “gene” or “genotype”.

Here’s what I found:

• Apolipoprotein E Genotype: 2 and 3
• Methylenetetrahydrofolate reductase (MHTFR) FRET genotype analysis to identify the C677T polymorphism. Genotype result: A/A
• Analysis for C282Y mutation, H63D mutation and S65C mutation…

The Apoliprotein E Gene is the one the neurologist told me is associated with Alzheimer’s Disease. The C282Y, H63D and S65C mutations are associated with iron overload, which this same neurologist suspected might be a problem. But I have no idea with the C677T polymorphism is, or what all of this means. I’ll try to find some answers, and will post any results.