The Tangled Neuron

Dr. Rudolph Tanzi's Talk on Alzheimer's Genetics and Treatments

Summary: Genetic variations linked with Alzheimer’s provide clues on potential treatments. Many drugs currently in trials are based on these clues.

With advances in technology, software and the Human Genome Database, Dr. Rudolph Tanzi is optimistic about the future for personalized medicine, where prevention and treatments could be tailored to a person’s specific genetic profile.

Because an estimated 70 percent of Alzheimer’s genetics is still unknown, researchers have a lot of work to do before this vision can be realized.

Scientists study genetic variations and how they are linked with pathologies and symptoms to determine who is at risk for developing diseases. But there’s another important reason they study genetic variations: to look for clues about potential treatments.

To understand why genes might hold clues about treatments, it helps to know that genes contain the blueprints for making proteins, which carry out most of the functions of a cell. If one or more of the thousands of proteins working in a cell is missing or malfunctioning, disease can result. So studying the genes associated with Alzheimer’s disease may lead to a better understanding of the proteins those genes encode, and how they might go awry. These proteins are then “targets” for potential treatments – by manipulating them, we may be able to treat or even prevent Alzheimer’s.

This search for potential Alzheimer’s treatments through the study of genes was the focus of Dr. Rudolph Tanzi’s keynote speech at the Alzheimer’s Association Wisconsin Annual State Conference in May. Dr. Tanzi is Professor of Neurology at Harvard University, and the author of Decoding Darkness. He also runs the Genetics and Aging Research Unit at Massachusetts General Hospital.

Rudolph Tanzi, Ph.D. (center) with conference attendees Cambria Anderson and Chuck Jackson

Dr. Tanzi’s Brief History of Alzheimer’s Gene Research

In the early 1980’s, Dr. Tanzi says, he was working with Dr. James Gusella who discovered the Huntington Disease gene. Dr. Tanzi was inspired to try to accomplish the same thing with Alzheimer’s; eventually his lab would be involved with the discovery of all three of the early onset familial Alzheimer’s genes.

In the mid-1980’s, two different teams of researchers found that the plaques in Alzheimer’s brains are made up of a protein called beta amyloid. One of the researchers, George Glenner, found that the plaques in Alzheimer’s are similar to those in Down Syndrome. “Because people with Down Syndrome have three (instead of the usual two) copies of Chromosome 21, Glenner predicted that beta amyloid was made from a gene found on Chromosome 21,” says Dr. Tanzi.

A few years later, researchers did in fact find a gene called amyloid precursor protein (APP) on Chromosome 21. “APP is a long protein, and when it gets cut apart, it results in beta amyloid,” Dr. Tanzi explains. Later research linked variants of APP to early onset Alzheimer’s disease.

By the mid-1990’s, two more gene variants, called presenilin 1 (PSEN1) and presenilin 2 (PSEN2) had also been linked to early onset Alzheimer’s disease. The PSEN genes are related to the presenilin enzymes [proteins] that cut APP to make beta amyloid.

With these discoveries, scientists knew that variations in three genes were linked to inherited or familial early onset Alzheimer’s disease. But even these genes don’t account for all familial early onset Alzheimer’s. Twenty-one mutations have been identified in the APP gene, accounting for seven percent of familial Alzheimer’s. One hundred sixty-five mutations in PSEN1 account for about 40%, and eleven mutations in PSEN2 account for three percent. This means that rare variations in these three genes account for only about 50 percent of familial early onset Alzheimer’s.

For late onset Alzheimer’s, variations in one gene is a confirmed risk factor. “As you probably know, the APOE4 variant increases the risk of developing Alzheimer’s,” Dr. Tanzi says. “About ten percent of the population carries two alleles or copies, which is associated with a tenfold increase in risk. Another 20 percent carry one allele, which brings threefold increase. About 75 percent of us carry the APOE3 variant, which is neutral with regards to risk of Alzheimer’s, and about two percent have the APOE2 variant, which in combination with APOE3 decreases the risk.”

What Alzheimer’s Genes Tell Us About Treatments

“All four genes point to excessive accumulation of beta amyloid peptides [proteins] in the brain as a common event,” Dr. Tanzi says. “Either you produce too much, and this may be early onset, or you clear too little, which may be the case with late onset. Normally, beta amyloid is produced by the brain and eight minutes later, cleared out. APOE variants affect how rapidly you can clear it out.”

But does this accumulation of beta amyloid really cause Alzheimer’s? “You will have heard that the amyloid hypothesis might not be correct,” says Dr. Tanzi. “The problem is that plaques are end-game stuff. You have to back up to where a single beta amyloid peptide is made. At that point, it’s neutral. But if it binds with zinc or copper, it forms assemblies called oligomers. These assemblies lodge in the synapses, and cause short-circuits in synaptic function. It looks more and more like this is what causes the problem. If the oligomers clump together, you get plaques. Maybe way before the plaques, oligomers cause cognitive problems. In the end, Alzheimer’s is a disease of the synapses. It’s really the loss of connections between nerve cells that causes problems.” This view is the basis for drugs under development by his company, Prana Biotechnology.

According to Dr. Tanzi, most drugs currently in trials are based on newer discoveries linked to APP, PSEN1 and PSEN2. Here’s his rundown of some of the treatments being tested:

Vaccines - This approach traps beta amyloid in the blood using antibodies. A new approach, passive immunization, involves making antibodies in lab. Vaccines are being tested in Phase 2 trials.

M1 Muscarinic Agonists - “First, you need to know that you can’t remove beta amyloid intact, but a ‘good’ enzyme – alpha secretase – cuts beta amyloid in half.” Dr. Tanzi says. M1 muscarinic agonists work to activate alpha secretase.

Gamma and Beta Secretase Inhibitors - “There are also ‘bad’ enzymes – beta and gamma secretases – that release beta amyloid. Developing gamma and beta secretase inhibitors is a huge industry. The problem is that both of these enzymes have to clip other proteins too. Gamma secretase can make two forms of beta amyloid – either AB40, which may have a normal role, or AB42, which is more likely to form oligomers. Now there are gamma secretase modulators that instead of eliminating the enzyme, tweak it to produce more AB40 than AB42. But a great concern is that in trials, this has caused problems with microhemorrhages.”

Substances That Reduce the Trace Metals [Zinc and Copper] Needed to Form Oligomers - Dr. Tanzi’s company is working to develop a Metal-Protein Attenuating Compound (MPAC) based on this approach. “It’s not a chelator, because you need metals for other things,” he says. “It just prevents oligomers from forming. One candidate, Clioquinol, showed a 50 percent reduction in beta amyloid in mice, but there were problems with a contaminant,” he says. “PBT2, a second generation MPAC, reduces beta amyloid levels, rescues communication among nerve cells, and improves mouse cognition after five days of treatment. It’s now being tested in Alzheimer’s patients in Sweden”

According to Dr. Tanzi, other possible approaches include:

*increasing blood flow to the brain which turns on the gene for an enzyme called neprolysin, which degrades beta amyloid. It’s not clear whether this can be done safely.

*preventing hypoxia, or lack of oxygen, to regulate beta secretase activity.

*ACAT inhibitors (his wife’s research) – these cardiovascular drugs lower beta amyloid levels, and can be administered nasally.

There’s a lot of work to do. Dr. Tanzi estimates 80 percent of all cases of Alzheimer’s are inherited, but 70 percent of Alzheimer’s disease genetics are unknown. He heads up an initiative called the Alzheimer’s Genome Project, which is working towards identifying that elusive 70 percent.

“We’re seeing the next wave of genetics,” he says. “There have been huge advances the last two years in technology, software and the Human Genome Database. The ultimate goal is to target drugs to your specific genes that put you at risk. This is called pharmakinetics, pharmagenetics or personalized medicine.”

One obstacle to progress, at least in the U.S., is the fear that genetic information could be used to deny employment or insurance. Because of this, an important first step towards preventative medicine in the U.S. is to pass the Genetic Information Nondiscrimination Act, and to add long term care insurance to the bill.

“By 2050,” says Dr. Tanzi, “we will not wait for life-threatening illness to strike.” That seems like a long way off. In the meantime, let’s hope he and other researchers identify new genetic variations linked to Alzheimer’s, and that these discoveries lead to effective treatments.

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.

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.

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.

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.

The Eye Exam Every Dementia Patient Should Have?

After reading that problems with blood vessels in the eye might be a sign of similar problems in the brain, I asked Mom to get Dad’s eye exam records. 

A study published in the January issue of Stroke showed that for people with high blood pressure, abnormalities of the blood vessels in the eye are associated with small strokes that can be detected only with an MRI .  Patients and their families might not notice any one of these strokes, but the combined effect could cause dementia.

These same abnormalities may mean a patient has a higher than normal risk of having a stroke (see http://www.thelancet.com/journals/lancet/article/PIIS0140673601062535/abstract - this  requires free registration to The Lancet).

My father did not have high blood pressure, but because his autopsy results had tentatively shown “hypertensive arteriosclerosis” (thickening of the blood vessel walls associated with high blood pressure),  I thought it might be helpful to know if the blood vessels in his eye showed any problems.

Tien Wong, MD, PhD is co-author of the new study in Stroke and the two other studies I linked to above.  He sent me this photograph below as a sample of the retinal blood vessel disease an eye doctor might see.  The red spots are retinal hemorrhages and aneuryisms, he explained, while the yellow spot indicates a mini-stroke.

Retinal photograph courtesy of Tien Y Wong, MD, PhD, Centre for Eye Research Australia, University of Melbourne

It turns out that the blood vessels in Dad’s eyes were normal.  I’m not sure if that would lead his neurologist to suspect my father’s microbleeds were not caused by hypertensive arteriosclerosis.  Either way, I would think anyone with dementia would want to ask his eye doctor to check for signs of retinal blood vessel abnormalities, and report the results to his neurologist and other doctors.

The MRI every dementia patient should get?

At the neuroconference, Dr. Fleming put up a slide of images from Dad’s MRI.  He pointed to several small dark spots.

“When we look on the T2* GRE sequence, we can clearly see microbleeds.  But you have to do the correct MRI sequence to detect these bleeds!  The GRE or Gradient Refocused Echo takes only an extra 45-55 seconds.”

“I went to the American Society of Neurological Imaging meeting this weekend, and kind of had a bee in my bonnet about this.” He then went through several slides on technical aspects of MRIs.   “At every coffee break, I talked with my colleagues about it.  Turns out at some centers, every brain gets a GRE, but at many top centers, they don’t routinely do it.  When I asked why they don’t, people shrugged.  ‘Well, if we find them, what are we going to do,’ they asked.  I say, if we don’t find out what’s going on first, we can’t figure out what to do.”

“A sizeable part of the population will have these bleeds,” Dr. Fleming pointed out, bringing up a slide referring to studies showing an estimate 3-12% of various populations have microbleeds.  The older you get, the higher the risk, according to this research.

It seemed to me he made a good point about the importance of documenting the microbleeds, even if there’s no treatment yet. Maybe some patients with “probable Alzheimer’s” diagnoses have dementia caused by microbleeds.  And maybe there are certain prescription and over-the-counter medicines that should be avoided or used with caution for these patients.  I’ll try to find out whether there are any guidelines about this.

Thickened blood vessel walls probably caused Dad's microbleeds

“The question we were asked was ‘What was the etiology of the dementia?’” the pathologist took up where Dr. Fleming left off.  A slide showing a cross-section of Dad’s whole brain was up on the screen. I hoped Mom was OK, but was afraid if I looked at her, it would get us both upset.  I concentrated on taking notes, and tried not to think about it. 

“So here’s the brain - you can see the large hemorrhage on the right side.” I was relieved when he moved on to a slide showing a microscopic view.  He moved to the next slide and another pathologist spoke up.  “I looked at these slides with Joe.  This shows thickening of the vessel walls….” 

He launched into a detailed discussion of why it was hard to figure out what caused Dad’s blood vessel disease.

Fifteen minutes into the presentation, I started to see why the cardiovascular surgeon on the plane had warned me not to expect a lot of answers.    The pathology slides showed that Dad’s microbleeds were probably from thickening and degeneration of the walls of the small blood vessels in his brain.  But it wasn’t clear what caused that problem or whether the microbleeds caused his dementia.

Are all dementia autopsies so complicated?

At the neuroconference

Today, Mom and I sat down with twenty doctors around a conference table at Pitt Memorial Hospital in Greenville, North Carolina.  They were neurologists, neurosurgeons and pathologists from East Carolina Neurology and from the Brody School of Medicine at EastCarolinaUniversity.  All of us were here for Dr. Frank Fleming’s presentation of my Dad’s case.

One of the doctors gave us the handouts for the presentation – 85 slides!  I felt really good that Dr. Fleming had taken my questions on Dad’s dementia and his autopsy report so seriously.  But this was the first time I’d been back to Greenville and the hospital where Dad died, and if it was painful for me, it must have been worse for my mother.  We agreed that if she got upset, she would step out of the room, and I would stay and take notes. 

“OK, let’s get started,” Dr. Fleming said.  “Today I’m going to talk about microbleeds and discuss the case of a 73 year old gentleman who unfortunately died of a hemorrhagic stroke in November. Something quite unusual for these Neuroconferences – we have the family here today…”

                                                                                                                                          

The first few slides were about Dad’s medical history.  He started having problems finding nouns about four years ago.  By March 2004, he was having “minor trouble with arithmetic” and had difficulty drawing a clock.  Shortly before he died in 2005, he struggled to find any words, and was increasingly confused.

Tests showed my father had normal or low blood pressure, no thyroid problems, no “clinical stroke event.” His cholesterol was low, the arteries in his neck weren’t blocked, and he didn’t have the APOE4 gene associated with a higher risk of Alzheimer’s.  In short, there weren’t a lot of clues about what might have caused Dad’s dementia.

“But now we look at these images from his MRI in October 2005,” the doctor said.  “You see a dark area on the right side, a spot in the cerebellum here – all these hyperintensities are old hemosiderin deposits.”  He was telling us Dad’s brain had been bleeding for a long time.

.

I invited myself to a presentation on Dad's case

Dad’s neurologist, Dr. Fleming, called today.  “I want you to know we’re still working on your questions about your Dad’s autopsy.  We’ve gone back to the pathologist to try to get some answers, and I expect they may have to go back and do some stains on tissue and so forth.   I don’t know when we’ll have the results.”

 

“I remember that your Dad’s mother died of a stroke,” he continued.  “Do you know if it was a hemorrhagic stroke?  If there’s anyone still alive you can talk with to find out, that would be very interesting for us to know.”

 

I promised to try to get more information for him.

 

“The microbleeds your Dad had are so interesting that we plan to discuss his case – without using his name, of course - at our Neuroconference sometime in March.  Most likely I’ll be presenting the pathology slides myself.”

 

“Would it be possible for me to attend this conference and listen to your presentation?” I  asked, half expecting him to say he’d rather I wouldn’t.  “Yes, that would be fine,” he answered. “I’ll let you know when we schedule the presentation.”

 

I’m really excited about this – maybe now we’ll start to get some answers about what caused Dad’s dementia!

Why did Dad have thickened blood vessel walls in his brain?

“This shows thickening of the vessel walls – could be from CAA  or from hypertension,” the pathologist said.  “We saw frequent plaques – enough to make a diagnosis of Alzheimer’s, but not enough to make a diagnosis of CAA.  When I showed this to other pathologists, they thought it was more hypertensive, although clinical correlation was needed.  But it’s interesting to note that problems from hypertension are usually in more central areas of the brain.”

“So, we would favor a diagnosis of hypertensive arteriosclerosis,” the first pathologist summarized, “although it would have been helpful to be able to examine the entire body.”  He was referring to my family’s request to limit the autopsy to the brain only, and I can see how that handicapped him.

“Given the utter absence of hypertension, though, wouldn’t that push you towards another diagnosis?” asked one of the neurologists.

“Not necessarily.  In an autopsy, we often see changes consistent with hypertension even if the patient was not hypertensive.  These changes might be caused by other factors – cardiovascular, for instance.”