The Tangled Neuron

Detecting Alzheimer’s and Other Memory Disorders Before Symptoms Appear: The FDDNP-PET Scan

Summary: PET scans using a compound called FDDNP show promise for detecting Alzheimer’s and other neurodegenerative diseases before symptoms are apparent. If follow-up studies confirm the accuracy of this imaging technique, researchers will be a step closer to the vision of early detection and treatment to delay progression.

When my father complained about memory problems, his family doctor told him there was nothing wrong.

Head Injuries And Alzheimer's

Summary: a head injury may increase your risk of dementia, or cause dementia to develop at an earlier age. Head injuries also have some of the same pathologies as Alzheimer’s disease. This means that treatments developed to reduce brain damage caused by head trauma may help those whose dementia is not associated with an injury.

Dolly Knowles fell last week while she was walking the dog. She hit her head on the pavement, and has two black eyes and a broken rib. Dolly, 85, is John’s father Bud's girlfriend, and an important part of our family.

Dolly and Bud

She tells me this isn’t the first time she’s bumped her head. When she was living by herself in Wisconsin, she hit her head on the corner of an antique wardrobe. “The next thing I knew, I was on the floor and it was dark outside. Must have knocked me out. I wasn’t sure what had happened,” she says, “so I just went to bed.” Her doctor checked her over and said she was fine.

But Dolly thinks that blow to her head three years ago may have caused her to lose her sense of smell. She’s also starting to have trouble with short term memory and with finding words. “I think that’s just age,” she says. But it may also have something to do with her run-in with the furniture.

Professional Athletes, Head Injuries and Dementia

Researchers have long known that boxers have a high rate of dementia. Playing other sports where head injuries are common may also increase the risk of developing dementia, or perhaps cause it to develop at an earlier age. In an article published in NeuroSurgery in 2005, University of North Carolina scientists tested more than 2500 retired professional football players. They found those with three or more concussions were five times as likely to have Mild Cognitive Impairment and three times as likely to have significant memory problems compared to retirees without a history of concussion.

“Although there was not an association between recurrent concussion and Alzheimer's disease, we observed an earlier onset of Alzheimer's disease in the retirees than in the general American male population,” the researchers wrote. “Our findings suggest that the onset of dementia-related syndromes may be initiated by repetitive cerebral concussions in professional football players.”

Football players who haven’t suffered concussions may still have an increased risk of cognitive problems. In 2006, University of Pittsburgh researchers published case studies of two former football players who didn’t have a record of multiple concussions, but did have cognitive impairment. Both men also had “Major Depressive Disorder.”

The prevalence of dementia among football players was highlighted this year by the retirement of Ted Johnson of the New England Patriots at age 34 due to the memory loss, depression and other problems his doctor says were caused by repeated head injuries. And last week, a New York Times article profiled the efforts of the wives of two retired professional football players to encourage the National Football League to help pay for the care of their husbands and other retired players with dementia. The NFL has now established a fund for this purpose.

Not Just for Professional Athletes

What about those of us who don’t box or play professional football? Recent studies of general populations show that moderate to severe (but maybe not mild) head injuries may increase the risk of dementia:

- "Head injury with loss of consciousness, although uncommon in this sample, was associated with increased risk of Alzheimer's disease. "University of Washington, 1997 study in which 32 of 349 people with probable Alzheimer’s had had head injury, as compared to 16 of 342 control subjects

- “This study suggests that mild head trauma is not a major risk factor for dementia or AD in the elderly.” Erasmus University, The Netherlands, 1999 review of data from The Rotterdam Study of more than 6000 people

- “Moderate and severe head injuries in young men may be associated with increased risk of AD and other dementias in late life. However, the authors cannot exclude the possibility that other unmeasured factors may be influencing this association.” Duke University, 2000 study of the medical records of approximately 1800 retired military personnel, 548 of whom had had head injuries

- “Head injury is a risk factor for AD. The magnitude of the risk is proportional to severity and heightened among first-degree relatives of AD patients.” Boston University, 2000 review of data from over 2000 persons with probable Alzheimer’s and over 14,000 of their family members from the Multi-Institutional Research in Alzheimer Genetic Epidemiology project.

The APOE Connection

Researchers are still working to understand why some people with head injuries don’t develop memory problems. More than twenty years ago, scientists found a possible link between APOE4 (the genetic variation associated with an increased risk of Alzheimer’s) and higher rates of dementia after head injury, as well as a higher risk of increased accumulation of beta amyloid plaques. But the link isn’t clear - none of the population studies above found a significant link between APOE4 and an increased risk of dementia in people with head injuries.

How might APOE status make a difference? Dr. Daniel Laskowitz, Associate Professor of Medicine and Director of the Neurovascular Laboratories at Duke University Medical Center, says he thinks there’s a synergistic relationship between APOE4 and head injury. “I think it’s likely that inflammation (perhaps exacerbated by amyloid deposition) plays an important role in neuronal injury…. APOE4 predisposes to inflammation, which causes neuronal injury and cognitive loss. Head injury associated with inflammation accelerates this process.”

Daniel Laskowitz, MD

In his lab, Dr. Laskowitz is working to understand how the brain is damaged after head injury, and to develop new treatments for both patients with head injuries and those with various types of dementia. In an article published in Neuroscience last month, he and his colleagues describe how a treatment based on a protein similar to the APOE protein [produced according to instructions contained in the APOE gene] reduced inflammation and Alzheimer’s-like pathology in mice following head injury. But in their experiments, mice bred to have the APOE4 variation didn’t have the same physiological and functional improvement after treatment as those with APOE2 and APOE3 did. More work is needed to confirm the role of this gene in determining the effectiveness of treatment.

“The data suggests that there may be a pharmacogenomic interaction between the APOE therapy and E4 - you may, for example, need higher doses of drug if you have E4…the bottom line is that it is too early to tell,” Dr. Laskowitz says. Pharmacogenomics is the study of how your genes affect how you respond to drugs.]

What does this have to do with Alzheimer’s and other types of dementia? “We used head injury as a model to accelerate Alzheimer’s disease pathology,” he explains, “but the results would be relevant to those without injury, as well as those with other forms of injury (bleeds, etc) that may have provoked the inflammatory response, regardless of genotype.”

If my father were still living, treatments based on this research might have been able to reduce the brain damage from microbleeds caused by his cerebral amyloid angiopathy. Drugs might be available for people with head injuries like Dolly’s if brain damage is detected. But these treatments will probably not be available in her lifetime, and maybe not within mine.

As with most Alzheimer’s research, funding is a major obstacle. At this point, Dr. Laskowitz says, “there is not much forward movement on this…. If there were funding, it could be put in preclinical development tomorrow, and be ready for clinical testing within several years.”

I just came back from the Alzheimer’s Association’s Public Policy Forum, during which several hundred of us went to Capitol Hill to ask for increased NIH funding for research on new Alzheimer’s treatments like this. Maybe that will make a difference for the next generation.

Dreaming About A Cure, Talking About Care: Part 1 of 4 - Is Alzheimer's Really A Disease?

Last night, I dreamed Dad was getting better. He called to say he was back home, and sounded upbeat. He was finding words more easily than when we last had talked. I immediately started thinking about things we could do to speed his recovery: green tea, meditation, maybe even a little red wine. More than a year after Dad died, I'm still dreaming about a cure.

I'm not alone in my dreams. "I really thought that we would have a cure before I had to worry about onset. I was terribly wrong," says Chuck Jackson, a former employment counselor whose mother and nine of her siblings had early onset Alzheimer's. Four of his cousins have died of the disease, and how he, his brother and three of his cousins have been diagnosed with it.

This talk of a cure is echoed around the world in hundreds of labs and millions of homes. But I don't think we're anywhere close.

If you are diagnosed with Alzheimer's today, your doctor may prescribe Aricept, Namenda or other medicines. The most these drugs will do is delay symptoms in some people; they have no effect in others. Treatment won't change the underlying degeneration of your brain, or halt progression. If your family can't care for you, there's little chance you'll get good care in a nursing home, at least in the US.

This bleak reality has prompted Chuck Jackson and other members of the Dementia Support and Advocacy Network (DASN) to speak out about Alzheimer's. The majority of DASN members are persons with dementia or their care partners. Individual members of the group are working with organizations, the media and lawmakers to raise awareness about Alzheimer's.

"If doctors themselves would be more aware, I think they'd find there are a lot more afflicted with Alzheimer's disease than they realize," says Sarah Christianson, a DASN member and former office manager diagnosed with early onset Alzheimer's and frontotemporal dementia.

Sarah Christianson

But Dr. Peter Whitehouse advocates something different: a complete redefinition of Alzheimer's and how we treat it.

Dr. Whitehouse is Director of Integrative Studies and Professor of Neurology at Case Western Reserve University, and author of the forthcoming book The End of Alzheimer's [St. Martin's Press]. He is one of several scientists and doctors who have mentioned to me that they don't think Alzheimer's is a single disease.

Peter J. Whitehouse, M.D., Ph.D

"People suffer enormously from what I used to call Alzheimer's," he says. "But as a clinician, I'm aware of the variability of dementia symptoms and progression, so I'm suspicious of the claim that this is one disease and that it's different than aging."

Expressing doubts about Alzheimer's status as a disease is controversial, both among researchers and among persons with dementia. "Terribly wrong-headed," says Jay Smith, a DASN member from California who is working to organize a conference for people with dementia. "That kind of thinking (simplistic, not based in reality) is just dangerous." Jay was forced to leave his job when he was diagnosed with early onset Alzheimer's.

Jay Smith

Lisa Genova, another DASN member, neuroscientist and author of Still Alice, a novel about a fifty-year-old cognitive psychology professor diagnosed with Alzheimer's. "This IS a disease," she says, "œand not just a normal part of aging."

"Alzheimer's doesn't just happen to people in their 70's and 80's; it happens to people in their 40's & 50's and younger," says Jaye Lander, a Pennsylvania-based former Wall Street executive diagnosed with early onset dementia of the Alzheimer's type. "I turned 60 on Thanksgiving but have had brain tissue atrophy visible in MRI's for several years. As long as our brains start disintegrating on us in our primes, I think it is a terrible disease and not just a normal function of aging."

Many researchers assume early onset and late onset Alzheimer's disease are similar, but Dr. Whitehouse's comments were not meant to address early onset Alzheimer's. "Of course, if people are getting it in their 40s and 50s, it's hard to say that's aging. It's more reasonable to call what these people are suffering from a disease," he says.

He is much less certain about whether late onset dementia is really one disease. "As a clinician, I now avoid using the word Alzheimer's," Dr. Whitehouse says. "But what do I put on a billing form, and what do I say to a patient? The answers are more complicated than we like."

Alzheimer's Plaque-Buster?

For years, Dad had a night job. By day, he ran our family’s retail lumberyard. By night, he ran a mouse relocation program. Our house was full of mice. They scampered through the attic and ran down plumbing and electrical ducts, nabbing cotton balls and Kleenex to build their nests. They got into our food, and left droppings along the baseboard.

The situation came to a head when my mother went into the kitchen to get a plastic bag full of garbage she had left on the counter. “There was a mouse sitting inside the bag, stuffing his face,” she says. She called Dad into the kitchen. He carefully closed the bag, carried it outside, and let the mouse go.

That night, my father brought home a small Havahart trap, baited it with peanut butter, and set it in the laundry room. A quivering brown mouse was in the cage the next morning. On his way to work, Dad drove his passenger down a dirt road, and released him in the woods.

Dad reset the trap that night, and another mouse was there in the morning. This went on for months – almost every morning, another mouse. And almost every morning, Dad would head down the dirt road to his mouse drop-off spot.

“They’ve posted a sign,” he joked, “free peanut butter and a ride.” My parents kept a tally - after four months, Dad had transported 123 mice. They seemed to be multiplying faster than he could clear them out.

Breaking Down Beta Amyloid

Scientists think the same thing may be happening with beta amyloid, the protein that makes up the plaques found in Alzheimer’s. The protein is constantly produced by the body, then cleared from the brain. It may be that in people with Alzheimer’s, the beta amyloid is building up faster than it can be eliminated, and the excess protein is toxic to brain cells.

Researchers have found several enzymes that break down beta amyloid, including insulin degrading enzyme (IDE). Increasing the amount of these substances in the body could help speed up the elimination of excess beta amyloid.

Dr. Jin-Moo Lee, Assistant Professor of Neurology at Washington University School of Medicine in St. Louis has shown that another enzyme called matrix metalloprotease-9 (MMP-9) also degrades beta amyloid. Dr. Lee found that MMP-9 is able to break down the fibrils that make up the plaques found in Alzheimer’s. MMP-9 and other enzymes break down a free-floating kind of beta amyloid that hasn’t formed into plaques. But in Dr. Lee’s lab, the other enzymes didn’t seem to degrade fibrils the way MMP-9 did. These results suggest that MMP-9, already found in the body, may be helpful in clearing plaques from the brain.

Jin-Moo Lee, M.D., Ph.D.

There’s more evidence that the enzyme may help regulate beta amyloid levels. Dr. Lee and his colleagues found that turning off the gene for MMP-9 in mice increased the levels of beta amyloid in their brains.

MMP-9’s Role In Other Diseases

Harnessing MMP-9 to break down beta amyloid will be a delicate task. High levels of the enzyme are associated with cancer and arthritis. Even worse in terms of dementia, Dr. Lee has shown that high levels of MMP-9 near blood vessel walls in the brain are associated with cerebral amyloid angiopathy (CAA). In CAA, beta amyloid is deposited on blood vessel walls in the brain. The walls then thicken, harden and crack, allowing blood to leak out into the surrounding tissue. My father’s autopsy showed severe CAA, and it’s likely that the disease and resulting microbleeds caused his dementia. He died last year of a massive hemorrhagic stroke, probably due to CAA.

So MMP-9 may clear Alzheimer’s plaques, but may also be involved in CAA and brain hemorrhages. Is MMP-9 good or bad for the brain?

“MMP-9 is neither ‘good’ nor ‘bad,’ Dr. Lee says, “but may have different responses and activities in different cells and different locations. We have hypothesized that MMP-9 may play a role in weakening the vessel wall in CAA (though this is far from proven)…. We have shown that MMP-9 and -2 can degrade Abeta [beta amyloid] in the brain. These are two different locations and two different activities.”

The fact that increased levels of MMP-9 have been found in the brains of ischemic stroke patients provided a clue to MMP-9’s role in brain hemorrhages. “MMP-9 is upregulated after ischemic stroke,” Dr. Lee explains, “and likely plays a role in converting an ischemic stroke into a hemorrhagic stroke (by weakening the vessel wall). This is why it is so intriguing that MMP-9 is upregulated in CAA vessels, with the thought that CAA vessels may have increased MMP-9 which might eventually lead to weakened vessels.”

Dr. Lee is working to confirm the role of MMP-9 in CAA. He has a study underway to see if lowering MMP-9 levels in mice with CAA reduces the frequency of brain hemorrhages. “This data will be far more convincing,” he says.

More Research Needed

Adding to the uncertainty of MMP-9’s role in dementia, it’s not clear what effect breaking down the beta amyloid fibrils will have. “Again, this may be "good" or "bad," Dr. Lee explains. “Recent reports suggest that smaller aggregates of Abeta (oligomers) may be toxic or inhibit neurotransmission. It is possible that MMP-9 may break down fibrils into these smaller aggregates, which might be even more toxic than fibrils. On the other hand, it is possible that MMP-9 could degrade both fibrils and oligomers rendering them non-toxic. We are currently investigating this.”

It’s also not clear whether drugs designed to increase or decrease levels of MMP-9 could stop brain degeneration and dementia, or what any side effects would be. One possibility for therapy stems from the fact that MMP-9, like many other enzymes, requires the presence of zinc to work. So in theory, reducing the amount of zinc in the body via chelation therapy might inactivate MMP-9 and reduce damage to blood vessel walls. It’s unclear what this might do to the beta amyloid plaques in other areas of the brain, though, and there could be severe side effects. “Removing zinc would likely be detrimental to other systems,” says Dr. Lee.

The connection of MMP-9 to both Alzheimer’s and CAA is intriguing, but still murky. More research is needed before any treatments can be developed. “I think we are far from therapies at this point,” Dr. Lee says. “One must remember that at this level of research, we are trying to understand molecular mechanisms, and we are somewhat removed from therapies. However, our goal is to identify potential targets for the development of therapies. It’s too early to say whether MMP-9 will provide us with viable targets, but therapies to ameliorate disease are always on our minds.”

Calcium Channel Blockers and Alzheimer's

Every day, in Alzheimer’s labs and clinics around the world, researchers conduct target practice. One of their targets is beta amyloid, the sticky protein many scientists think causes Alzheimer’s. This target practice is somewhat of a trial and error process, involving educated guesses about which weapons might work against beta amyloid and other substances and conditions implicated in Alzheimer’s.

One such target practice is directed from the Roskamp Institute, only thirty miles south of where I live. Working with the Trinity College Institute of Neuroscience in Dublin, Ireland, Dr. Michael Mullan and his colleagues are conducting a clinical trial of the calcium channel blocker Nilvadipine to see whether it reduces beta amyloid and improves memory in Alzheimer’s patients.

Calcium channel blockers are drugs used to treat high blood pressure and other diseases. Some studies have shown that these medications might be useful in preventing or treating dementia. A follow-up to the Systolic Hypertension in Europe trial showed that for people with high blood pressure, long term use of a calcium channel blocker may cut the risk of developing dementia by 55%. This makes sense, because scientists have observed toxic levels of calcium in Alzheimer’s brains. “Calcium overload in cells is lethal, says Dr. Mullan, “and this is the final pathway by which cells may die in Alzheimer’s.”

It’s not clear whether calcium channel blockers as a group help preserve memory. Results from the Canadian Study of Health and Aging showed that people taking these drugs were more likely to suffer from cognitive decline. Another study concluded that patients taking blood pressure medicines, including calcium channel blockers, performed worse on cognitive tests than did those taking other drugs. The conflicting results of these studies might be because each drug in this class has different effects.

The fact that Nilvadipine is a calcium channel blocker may be irrelevant anyway. “Nilvadipine's anti-amyloid effects do not seem to be due to the calcium channel blocking of drugs,” says Dr. Mullan. It’s not clear how Nilvadipine might reduce amyloid in Alzheimer’s brains, but it may be related to increased blood flow.

“This drug increases cerebral blood flow in rodents and humans, and we wonder whether there is a link between the two,” Dr. Mullan says. “It could be that there is increased clearance of amyloid from the brain due to increased blood flow. If that is the case, we don't know what the mechanism would be. However, the most likely reason that we see reduced amyloid in the brains of mice is that Nilvadipine directly reduces amyloid production. We've seen this effect in a number of cell types.”

The trial of Nilvadipine in 150 people diagnosed with mild to moderate Alzheimer’s is being carried out in Ireland, where the drug is available by prescription [it’s not currently approved for use in the US]. Doctors will measure the level of amyloid in these patients’ blood. If the levels of amyloid are higher in the blood of patients taking Nilvadipine compared with those not taking the drug, this may mean that it is clearing amyloid from the brain. Doctors will also monitor any changes in blood flow in the brains of trial participants, as well as blood pressure and performance on cognitive tests.

In the US, the Roskamp Institute is also looking for volunteers who have been diagnosed with Alzheimer’s. These volunteers won’t receive any medication, but will give blood to provide data to be used in the trial.

When my father had mild dementia, I wondered whether increased blood flow to his brain would help his memory. I asked Dr. Mullan if Dad would have been eligible for this trial, given that his pulse rate and blood pressure were low, not high. “It's possible (although there are many alternative reasons why your father may have had his cardiovascular signs) that increasing cerebral blood flow would have been beneficial. However, the blood pressure lowering effect of Nilvadipine would probably have precluded him from the study,” he says.

Dad also had cerebral amyloid angiopathy (CAA), and it’s not clear how Nilvadipine and other drugs thought to reduce amyloid would affect CAA patients. In CAA, beta amyloid similar to that in Alzheimer’s plaques is deposited on the walls of the blood vessels in the brain. The protein deposits cause the vessel walls to crack, allowing blood to leak out. Every hemorrhage, large or small, damages brain cells and can cause dementia as well as major hemorrhagic strokes like the one Dad had. “The vessel walls are weakened by amyloid and removing it (depending on how it is removed) might weaken them further,” says Dr. Mullan. “This is a very difficult area to predict, and clinically we will see when we have potent anti-amyloid drugs.”

Memory Pharmaceuticals is testing a similar drug called Mem 1003, and this trial is currently recruiting patients in the US. The company hasn’t responded to my request for information. [11/01/06 Note: Memory Pharmaceuticals says that Mem 1003 works by modulating the amount of calcium that enters neurons in the brain. This seems to be a different mechanism for treating dementia than the potential anti-amyloid action of Nilvadipine.]

It’s too late for my father, but I hope all this target practice means that multiple treatments for Alzheimer’s and dementia will be ready in time to help others who have dementia now. With its established safety record, Nilvadipine could be available fairly quickly. But first it must be proven effective in this study and in future trials.

Should You Be Tested For Memory Problems?

When Dad started having trouble finding words, he went to see his family physician. The doctor dismissed his concerns. “I’d know it if you had problems,” he said. He was wrong about Dad, and studies published this year show he may have been wrong in general.

In the May issue of Archives of Neurology, Mayo Clinic researchers published the results of their analysis of the brains of 15 people who had died while they had a diagnosis of Mild Cognitive Impairment. The researchers compared the brains to those of 28 people who had had no memory problems and 23 who had been diagnosed with probable Alzheimer’s disease. The level of pathologies in the brains of the people with Mild Cognitive Impairment was in between that of patients diagnosed with probable Alzheimer’s disease and that of those with no memory problems. The study authors concluded that their findings suggest Mild Cognitive Impairment is “a transitional state of evolving AD [Alzheimer’s disease].”

In the September issue of Neurology, scientists at Dartmouth Medical School in Hanover, New Hampshire wrote about their study of brain volume in patients diagnosed with Mild Cognitive Impairment. They performed MRI scans on the brains of 40 people who had normal scores on neuropsychological tests, but complained about memory problems. The researchers compared these scans to those of two other groups: 40 people diagnosed with Mild Cognitive Impairment and 40 healthy volunteers with no memory complaints. In the group with normal test performances but memory complaints, the decrease in gray matter volume was similar to that in those diagnosed with Mild Cognitive Impairment. The greater the memory problems reported by participants, the more volume had been lost.
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The idea that abnormal brain degeneration starts long before people have clinical signs of dementia isn’t really new. Scientists at Vrije Universiteit in Amsterdam had previously found that brain volume in people diagnosed with Mild Cognitive Impairment seemed to be at an intermediate stage between that of healthy volunteers and those diagnosed with Alzheimer’s.

If my father’s doctor had ordered an MRI when Dad first mentioned memory problems, the scan might have shown signs of atrophy. But what good would that have done? There’s no drug to stop the progression of either Alzheimer’s or the cerebral amyloid angiopathy (CAA) Dad had. There’s not even agreement about what should be included in the criteria for diagnosis of Mild Cognitive Impairment.

This lack of understanding is exactly why I think you should be tested if your memory isn’t what it used to be. Whether or not your test results show a problem, you might be able to contribute to Alzheimer’s and dementia research. Try to have your testing done at a memory clinic, university or an Alzheimer’s Disease Research Center that will use your results in studies.

Especially if you’re in the US, don’t forget to ask how much you will be charged for any testing. You might be able to find programs you can participate in at no cost. We sent Dad’s MRI scans, other medical records and brain tissue to Dr. Steven Greenberg to get a second opinion on autopsy results and to try to help with his research on CAA and Alzheimer’s. This summer, I went through the testing for the Wisconsin Registry for Alzheimer’s Prevention. There was no charge for participating in either of these research efforts.

Someday doctors will be able to accurately diagnose and treat degeneration of the brain. Until then, participating in research programs is one way we can help.

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.

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.

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.