The Tangled Neuron

Alzheimer's Research at a Crossroads: a new conference report

Summary: A new conference report from the U.S. National Institute on Aging summarizes the presentations, discussions and recommendations of top Alzheimer’s researchers. From my layperson’s point of view, the report shows three reasons why Alzheimer’s research is at a crossroads:

1. We don’t really understand what causes memory loss and dementia.
2. Every brain is different, and multiple factors and diseases may underlie any one person’s memory problems.
3. Overall, research to date has not yielded the hoped-for answers.

Of the many recommendations made to the NIA, the ones involving broadening the concept of Alzheimer’s and collaborating with scientists in other fields make the most sense to me. The NIA meeting and report seem like good first steps towards consensus on which road to take.

Over the weekend, I’ve been reading through an excellent report on a conference on Alzheimer’s convened by the U.S. National Institute on Aging (NIA). The conference took place in October 2006, on the 100th anniversary of Dr. Alzheimer’s discovery of plaques and tangles in the brain of his patient Auguste D.

Education, Cognitive Reserve and Alzheimer's

Summary: A recent study confirms that higher levels of education seem to delay cognitive decline, but may increase the rate of decline once it starts. The results of this study don’t mean much for any one person. But they do mean that memory loss might not be readily apparent in people with Alzheimer’s, especially those with more education. The findings point to the need to detect changes in the brain before the symptoms of Alzheimer’s and other dementias appear. This will be especially important when treatments to delay progression are available.

The title of a recent press release from the American Academy of Neurology (AAN) caught my eye – “Educated People Who Develop Dementia Lose Memory At A Faster Rate.” The press release was based on study results published in the October 23, 2007 issue of the AAN’s journal Neurology.

Participating in Alzheimer's Clinical Trials in Sun City, Arizona

Summary: A trial volunteer and a doctor talk about how the close relationship between the community of Sun City, Arizona and Alzheimer’s researchers at Sun Health Research Institute benefits everyone. For Alzheimer’s research to move forward quickly, more people with and without memory problems need to participate in clinical trials.

Ruthann Welander flew from Arizona to New England last month to take part in a cultural exchange program. When she got off the plane, her leg started to hurt. When the pain got worse, her host drove her to the emergency room. All signs pointed to a life-threatening blood clot, but she wasn’t worried about dying. She was worried about donating her brain.

“I’m in a research study and if something goes haywire here – everybody’s gotta go sometime, what’s the difference - I just want you to take this little stamp on my driver’s license and call that number,” she told the woman she was staying with. “That’s Dr. Sabbagh at the research center in Sun City, Arizona and he will tell you where to take my brain.”

Fortunately, Ruthann didn’t have a blood clot. But she does have a family history of dementia. She watched her father, a professor, sink into confusion before his death. And although Ruthann does not have memory problems, her two older sisters had dementia before they died. So when Dr. Marwan Sabbagh, Director of Clinical Research at the Cleo Roberts Center of Clinical Research (part of the Sun Health Research Institute) came to talk to her Kiwanis club a few years back, she paid close attention.

Marwan Sabbagh, MD

“At the end of his talk, he urged any of us who had family members with Alzheimer’s to come and see him at his office,” Ruthann remembers, “because he was just getting started on the ADAPT study [Alzheimer’s Disease Anti-Inflammatory Prevention Trial]. I beat him back to his office, and I’ve been working with him ever since.”

“She’s the poster person for who we want to see as a trial participant,” says Dr. Sabbagh. “Ruthann’s in lots of programs, including ADAPT and our brain and body program. She’s an enthusiastic supporter of the research institute.” Besides participating in several clinical trials, Ruthann arranges for Dr. Sabbagh to speak at meetings of the many community organizations she belongs to.

His talks cover the wide range of Alzheimer’s research going on at Sun Health, from basic science to clinical trials. “Our portfolio is very rich,” says Dr. Sabbagh. “It includes studies involving diabetic medications, gamma secretase modulating drugs, active immunization, passive immunization, secretase inhibitors and gamma globulin therapy. We are doing no fewer than six separate biomarker studies, and we were the first ones to propose statins to treat Alzheimer’s.”

Trials like these don’t happen without volunteers, both with memory problems and without. But it’s not so easy recruiting these volunteers. “It takes years and years to get these drugs to market,” Dr. Sabbagh says, “and part of the reason is that it’s really challenging enrolling participants. You will see some studies take six months to recruit, some take two to three years. You know, if you want things to move quickly, it involves people willing to participate.”

Encouraging Participation in Alzheimer’s Research

What would make persons with dementia and their families more likely to participate in research? “I think they need to see that it’s not futile,” says Dr. Sabbagh. “They need to know that there are limitations in the treatments that are currently available and the only way you’re going to get past the limitations is to consider the possibility of participating in clinical trials - not necessarily for posterity, but because it has the potential to help the people who are involved.”

“I’ll give you a great example of that,” he says, “although it’s somewhat controversial. You know about the AN-1792 study – you heard that they had 19 cases of encephalitis, no doubt. [The trial of this vaccine was halted due to this serious problem.] But what you didn’t hear about is the long term follow-up data - it got buried in obscurity. These drugs can work.” In a follow-up of 30 trial participants, researchers found “significantly slower rates of decline of cognitive functions and activities of daily living” in twenty patients who responded to the vaccine. Researchers are now assessing as many trial participants as possible. Five years after the study began, preliminary data seemed to show the vaccine helped some in this larger group, although no final analysis has been published yet.

Of course, taking part in a trial doesn’t guarantee a benefit - trial drugs are not always effective, and do involve risks. Some participants receive placebos. But, argues Dr. Sabbagh, “the bottom line is that every drug you and I take, every pill we put in our bodies, was at one point experimental. People have to understand that when I offer them an opportunity to participate in a clinical trial, I’m trying to add value. The current tools we have are limited, but we can do something more than wait for the eventuality. So it adds hope.”

It seems that Dr. Sabbagh and his colleagues have been successful making this case to residents of Sun City and the surrounding communities. He says more than a thousand people have donated tissue for research through the Institute’s brain and body donation program, and another thousand, including Ruthann Welander, have signed up to donate tissue at death. Recently, the Arizona Alzheimer’s Consortium, a group of institutions including Sun Health, set up a clinical trial registry to recruit and screen participants before they’re needed for trials. According to Dr. Sabbagh, he and his colleagues have screened several hundred people for this registry.

Why is there so much support for Sun Health and for Alzheimer’s research in Sun City? Maybe because volunteers feel that the researchers truly have their best interests in mind. “We’re really committed to the bench to bedside approach,” says Dr. Sabbagh. Through the center he directs, patients receive treatment and care based on the latest research. This gives people like Ruthann some comfort about taking part in trials. She was hesitant to stop taking ginkgo biloba, a requirement of one trial she enrolled in. But, she says, Dr. Sabbagh’s staff told her that if she showed any signs of Alzheimer’s, she would immediately be taken off the study and be given whatever treatment they thought would be most helpful. “So, I thought, what have I got to lose?” she says. “And when they ask me to take other studies, I say if he recommended it, sure, the answer is yes.”

Dr. Sabbagh’s research and the lives of Sun City residents seem intertwined. “We are begotten by our community,” he says. “Our institution is built by gifts from Sun City, and so I get to know them, they get to know me, I get to be part of their lives, they get to be part of my life. These are our brain donors, financial donors, clinical trial participants and private practice patients, so we get to know them. When somebody passes on, I get sad, but I’m perpetually full of hope. I tell everybody my goal in life is to work myself out of a job. I’m more determined than ever, and what better place to do it than Sun City, Arizona?”

Herpes Simplex Virus Type 1 and Alzheimer's

Summary: A British scientist, Dr. Ruth Itzhaki, has shown that the combination of latent Herpes Simplex Virus Type 1 (HSV1) in the brain and the type 4 form of the APOE gene could account for 60 percent of all cases of late onset Alzheimer’s disease. Almost all elderly brains are infected with HSV1, which often causes no symptoms. Dr. Itzhaki’s lab found the virus in areas of the brain most damaged by Alzheimer’s, and has data relating HSV1 to plaques and tangles.

The idea that a viral infection could underlie Alzheimer’s is part of an emerging understanding of the role of bacteria and viruses in chronic diseases. This kind of research is neither well-accepted nor well-funded, so don’t expect any Alzheimer’s treatments targeting HSV1 to be on the market anytime soon.

I have only a vague understanding of viruses and bacteria. Most of what I know is based on personal experience and on what little I remember from high school biology class. I know that viruses and bacteria are infectious, and that illnesses caused by them are often short-lived. Until recently, I thought scientists understood and could control most harmful viruses and bacteria.

The leading causes of death in the U.S. seem to be in a different category: the top ten list is dominated by chronic diseases like heart disease and stroke, cancer, and diabetes. Alzheimer’s has moved up to number seven on the list. These illnesses are not infectious, not short-lived, not well-understood and not well-controlled.

But it looks like the two categories might overlap more than I knew - the idea that viral or bacterial infections might contribute to chronic diseases not previously linked to infections is gaining ground. One bacterium called helicobacter pylori has been found to cause ulcers, and another called Chlamydophila pneumoniae (Cp), is linked to coronary artery disease. Human papillomaviruses are now recognized as the major cause of cervical cancer.

These discoveries hint at the possibility of a fundamental shift in the way we view diseases, including Alzheimer’s. In his book Plague Time: The New Germ Theory of Disease, Dr. Paul Ewald, Professor of Biology at University of Louisville in Kentucky, argues that bacteria and viruses are behind many chronic diseases, including Alzheimer’s, cancer and some forms of mental illness.

Herpes Simplex Virus Type 1 Linked to Alzheimer’s

For almost twenty years, Dr. Ruth Itzhaki, Professor of Molecular Neurobiology at the University of Manchester in England, has been exploring possible links between viruses and Alzheimer’s. Viruses are tiny infectious particles that attach themselves to and penetrate cells, then use the capabilities of those cells to reproduce. They can cause diseases like colds, flu and AIDS, or they can just sit there, remaining dormant or latent for long periods of time. A latent virus can become active when triggered by stress, other infections or environmental factors.

Ruth Itzhaki, Ph.D.

For a virus to contribute to the development of Alzheimer’s, Dr. Itzhaki reasoned, it would have to be very common in humans. And because Alzheimer’s appears to develop over a long period of time, it would make sense to look for a virus that has long periods of latency, but could periodically be reactivated and cause damage.

One family of viruses fits her criteria: herpes. There are over 100 types of herpes, of which eight infect humans, causing diseases ranging from chickenpox and shingles to cold sores and mononucleosis. Most people have some type of herpes, even though they may have no symptoms.

When Dr. Itzhaki and her colleagues examined the brains of older people, they found signs of latent Herpes Simplex Virus Type 1 (HSV1) in the areas most affected by Alzheimer’s. Traces of the virus were present in both Alzheimer’s and non-Alzheimer’s brains. Because HSV1 is not prevalent in the brains of younger people, the researchers hypothesize that the virus infects the brain in older age, as the immune system declines.

HSV1 is especially common in humans. The virus, which can be transmitted via skin contact and saliva, infects approximately 58% of people between the ages of 14 to 49, and in older people, almost everyone. Often, there are no symptoms.

Even though the presence of the virus in areas of the brain damaged by Alzheimer’s was intriguing, it was clear that not everyone with HSV1 develops Alzheimer’s. “‘Infect’ doesn’t always mean ‘affect,’ Dr. Itzhaki notes. “With many sorts of infection, some people show no symptoms.” As with other viruses, perhaps an unrelated illness or stress could activate latent HSV1. But Dr. Itzhaki wondered if a combination of HSV1 and some other factor could be involved.

The APOE Connection

The APOE4 genetic variant has already been identified as a risk for developing Alzheimer’s, but is “neither necessary nor sufficient to cause Alzheimer’s,” Dr. Itzhaki points out. She wondered if HSV1 and APOE4 could together trigger a series of events leading to brain damage and degeneration. The idea that APOE status could determine the effect of a virus not new. For example, studies in her own lab had determined the risk for cold sores from HSV1 is higher in people with the APOE4 mutation. Also, her lab found that APOE status determines susceptibility to, or severity of, infections in various other diseases.

When Dr. Itzhaki and her colleagues tested for both HSV1 in brain tissue and APOE4, their data indicated that the combination of these two factors could account for 60 percent of all sporadic Alzheimer’s cases (late onset Alzheimer’s that does not run in families).

It’s interesting that a small study of the brains of three people with familial Alzheimer’s disease by scientists at Aichi Medical University School of Medicine, Aichi, Japan showed signs of active HSV1 in areas with beta amyloid deposits. This would suggest that HSV1 is involved with the type of Alzheimer’s that runs in families, not just the sporadic Alzheimer’s Dr. Itzhaki studied.

How Does HSV1 Damage the Brain?

Just how HSV1 might damage the brain is not known. It could be via inflammation and oxidation. Oxidation is when unstable molecules called oxygen free-radicals combine with other molecules. In the same way that rusting damages metal, oxidation can damage brain cells. Dr. Itzhaki says that oxidation has been found in HSV1 infected cells in the lab and in brain cells harboring latent HSV1.

“We think inflammation must be a major factor,” she says. She lays out the hypothesized chain of events: “When HSV1 is latent (i.e. in a dormant state) in the brain, it can be activated by inflammation of the brain. The latter can occur when somebody has an infection, or is stressed, or immunosuppressed. The virus then augments the inflammation there. So other viral or bacterial infections (not necessary in the brain) can cause indirect trouble.”

What About Other Herpes Viruses?

Dr. Itzhaki and her team have investigated whether other types of herpes might be linked to Alzheimer’s. Their research shows HSV2 (genital herpes) and a type of herpes called cytomegalovirus are not as prevalent as HSV1, and not associated with Alzheimer’s disease. However, cytomegalovirus was found to be present in a high percentage of brains of people who had had vascular dementia. More research is needed to understand this connection.

HSV6 (a virus that is common in infants, but often causes little or no illness), was prevalent in the brains the researchers tested, and was associated with Alzheimer’s. Because it overlapped with the presence of HSV1, it’s not clear whether HSV6 could be a cause or a consequence of Alzheimer’s.

A Unifying Theory?

Dr. Itzhaki’s theory that a combination of HSV1 and the APOE4 genetic variant underlies many cases of Alzheimer’s is appealing because it could explain several factors already linked to an increased risk of the disease:

*Age (the older you are, the more chance you have of having HSV1 in your brain)
*APOE4 (see above)
*Cholesterol (HSV1 is associated with increased cholesterol levels)
*Beta amyloid (Dr. Itzhaki has data [not yet published] linking HSV1 to increased levels of beta amyloid. In addition, increased cholesterol levels seem to increase formation of beta amyloid plaques.)
*Tau (Dr. Itzhaki also has unpublished data linking HSV1 with abnormal tau, the protein in Alzheimer’s tangles).

The hypothesis is also appealing to me because it addresses possible underlying causes of the plaques and tangles that have been the focus of Alzheimer’s research for more than 100 years.

Before this theory is widely accepted, more research in Dr. Itzhaki’s lab and in other labs is needed. Money is tight for any Alzheimer’s research now, with only a small percentage of proposed studies funded. For a theory that’s not “mainstream,” funding is even more difficult.

Future Treatment

What if Dr. Itzhaki’s hypothesis about HSV1’s role in Alzheimer’s proves to be true?

“It would have enormous consequences,” she says, “as antiviral agents, which are currently available and which have relatively small side effects and are cheap, could be used to treat patients and should stop further deterioration.”

A good way to test of the role of HSV1 in Alzheimer’s “would probably be to use antiviral treatment for a year,” Dr. Itzhaki says, “and measure cognitive decline during that year and compare the rate with the patient’s rate a year before and a year after treatment. This would take into account the different rates of decline in different people. Scanning too would be very useful in indicating the course of brain damage during each of the three years.”

This type of clinical trial of antiviral drugs sounds good, but “as antiviral agents are off-patent, pharmaceutical companies have little profit motive in using them thus, especially as trials are hugely costly,” she points out.

In addition to antiviral drugs to stop progression of Alzheimer’s, vaccination against HSV1 could potentially prevent the disease. Dr. Itzhaki and colleagues have shown that vaccination of mice can protect against latent HSV1 infections of their brains.

But right now, she says, there’s no interest in developing Alzheimer’s therapies targeting HSV1. It’s a kind of “Catch-22” – more research is needed to confirm HSV1’s role in dementia, but there’s no funding for that research without confirmation of that role. “The trouble again is not just cost, but also the hostility of many people in the field…as a result, neither we nor others who want to repeat our research can get adequate or even any funding. It’s incredibly frustrating and disheartening. But until funds are available to extend the work, resistance to it will continue,” Dr. Itzhaki says.

Cholesterol, Statins and Alzheimer’s, Part 2 of 3

Summary: In a small pilot trial, Lipitor (a statin), seemed to improve scores on neuropsychological tests, especially for patients with mild Alzheimer’s, high cholesterol and the APOE4 genetic variation. The results of two large trials of statins for treatment of Alzheimer’s should be published in 2008. Whether or not statins prove to be effective against Alzheimer’s, this research adds to the evidence of a connection between heart disease and some dementias.

In my last post, I wrote how recent research has dampened hopes that the cholesterol-lowering drugs called statins can reduce the risk of dementia. But what about people who’ve already been diagnosed with dementia?

Two large trials of statins to treat Alzheimer’s are underway. Dr. Larry Sparks, Head of the Ralph & Muriel Roberts Laboratory For Neurodegenerative Research at the Sun Health Research Institute in Arizona, is a lead investigator for one of these trials. He’s enthusiastic about exploring the connection between cholesterol and Alzheimer’s.

“Think about it,” Dr. Sparks says. “APOE4 [the genetic variation linked to increased risk of Alzheimer’s] leads to elevated cholesterol. I don’t think cholesterol causes Alzheimer’s, but I believe it negatively influences it, or causes it to progress faster. There’s definitely a vascular influence.”

Earlier in his career, Dr. Sparks was a Medical Examiner in Kentucky. While performing autopsies of non-demented people with coronary artery disease, he noticed they had amyloid plaques similar to those in people who had been diagnosed with Alzheimer’s. Later, working at the Sun Health Research Institute, he found that rabbits fed high cholesterol diets developed amyloid plaques in their brains. This plaque build-up was reversed when the cholesterol was removed from the rabbits’ diet.

Now, in a small pilot trial, Dr. Sparks and his colleagues have shown that a statin called Lipitor may actually improve scores on neuropsychological tests for some people with Alzheimer’s. In an article published last year, they wrote that Lipitor seemed to help the most in patients with mild Alzheimer’s, high cholesterol and the APOE4 genetic variation.

So reducing cholesterol to treat Alzheimer’s seems logical, right? Nothing is that simple with Alzheimer’s and dementia.

First, some scientists think statins might work by reducing inflammation in the brain, rather than by reducing cholesterol. Second, brain cells produce cholesterol because they need it to function. While bringing down cholesterol levels in the blood might prove helpful for Alzheimer’s, decreasing cholesterol in the brain may harm neurons. Three statins, Mevacor (Lovastatin), Zocor (Simvastatin) and Baycol (Cerivastatin – now off the market in the US) appear to work in the brain as well as in the blood. Two trials at the University of Pittsburgh testing the effects of Mevacor and Zocor on cognitive functioning in people with high cholesterol showed the drugs may have caused a small decrease in performance on some neuropsychological tests. While the effect of these statins on the brain is unknown, Dr. Sparks thinks a safer approach is to influence the brain indirectly by using statins that reduce cholesterol in the blood rather than in the brain.

Finally, a new study shows a late-life drop in cholesterol may actually be associated with an increased risk of Alzheimer’s. I’ll talk about that in my next post.

The results of the two large trials of statins for treatment of Alzheimer’s [CLASP (testing simvastatin or Zocor) and LEADe (testing atorvastatin or Lipitor)] should be published in 2008. Whether or not statins prove to be effective against Alzheimer’s, this research adds to the evidence of a connection between heart disease and some dementias. Dr. Sparks puts it this way: “if you’re sufficiently resilient that you don’t succumb to cardiovascular disease, then you’re looking down the barrel of dementia.”

Alzheimer's, Tangles and Tau

Summary: The tangles seen in Alzheimer’s brains are made up of a protein called tau. Tau is involved in Alzheimer’s and other neurodegenerative diseases, but scientists don’t yet understand its role. In the long run, understanding how tau contributes to brain cell death may help researchers develop new Alzheimer’s treatments.

More than a year after Dad died, I’m still trying to understand what caused his dementia and death. His primary diagnosis was cerebral amyloid angiopathy, but “it is likely that the presence of plaques and tangles contributed to his neurologic difficulties,” his autopsy consultation report says.

These plaques and tangles are signs of Alzheimer’s disease. A lot of Alzheimer’s research focuses on plaques and on beta amyloid, the protein that makes up those plaques. Several drugs aimed at preventing the build-up of beta amyloid are being tested. But what about tangles?

The tangles, also found in the brains of people with Pick’s disease and Parkinson’s, are made up of a protein called tau. Tau is found in “normal” brains, and helps stabilize the small tubes that are part of cells’ skeletons. These microtubules transport nutrients through the cells.

Much has been written about the disagreement between scientists who believe beta amyloid causes the brain degeneration seen in Alzheimer’s [“baptists”] and those who believe that tau is the culprit [“tauists”]. But it’s not really an either/or situation - we need to understand the role each protein plays and how they may work together.

Do Tangles Harm Brain Cells?

Were the tangles found in Dad’s brain really harmful to his brain cells? “We’re not certain,” says Dr. Lester Binder, Professor of Cell and Molecular Biology at Northwestern University. “It may be that they’re somewhat protective.”

Lester I Binder, Ph.D.

“Evidence indicates that tangles persist in some neurons for 25 to 35 years,” he says. “Eventually, these cells die, but perhaps not nearly as fast as some other non-tangle bearing neurons.”

In 2005, the results of two studies added to the evidence that tangles might not be causing cell death. Researchers at the University of Minnesota found that when they suppressed tau in mice bred to have human tau, memory improved and cell death stopped, but the tangles continued to form. Another study at the Albert Einstein College of Medicine showed that the presence of tangles in mouse brains didn’t always lead to cell death – instead, it appeared that cell death was caused by brain cells abnormally attempting to enter the cell cycle. The cell cycle is the process in which the chromosomes in a cell are replicated and the cell divides into two new cells. This re-entry into the cell cycle is not normal for adult brain cells, and has previously been linked to neurodegenerative diseases.

Do Changes to Tau Cause Cell Death?

If the tangles themselves don’t cause cell death, then what does? This “whodunit” mystery is more complicated than a game of Clue. In Clue, Mr. Boddy has been murdered, and players must consider six suspects, six possible murder weapons, and nine rooms in which the murder could have been committed. In Alzheimer’s, Mr. Brain Cell is dead, and scientists must consider hundreds of suspects, possible weapons and crime scenes. Those investigating tau are dealing with a lot of uncertainties. Possible tau-related weapons include:

- changes in the form of tau, perhaps when a phosphate gets added to the protein
- changes in the level of tau
- changes in the ratios of types of tau .

There’s uncertainty about who or what causes the changes in tau, too. The list of suspects includes:

- beta amyloid (the protein that makes up Alzheimer’s plaques)
- alpha-synuclein, another protein found in Parkinson’s disease and Alzheimer’s of the Lewy Body type
- impaired glucose metabolism
- a combination of genes plus exposure to toxic metals through diet causing oxidation.

Researchers are also trying to narrow down the location where tau-related cell death might start. Maybe death originates in the microtubules, which could be destabilized by changes in tau. Maybe it was in the cell cycle, but what was Mr. Brain Cell doing there anyway?

In the game of Alzheimer’s, players researching tau and tangles are a long way from winning.

Measuring Tau May Help with Diagnosis

Back in the real world, measuring levels of tau may be useful for diagnosing degenerative brain diseases. Along with levels of beta amyloid, levels of abnormal tau in spinal fluid might predict conversion from mild cognitive impairment to Alzheimer’s or help diagnose Alzheimer’s. Innogenetics, a company based in Belgium, has developed a test to measure tau levels.

Using PET (Positron Emission Tomography) scans and other imaging techniques to map tau in the brain may also help with diagnosis in the future. In late 2006, researchers at UCLA reported that when they injected a substance called FDDNP into 83 people with memory problems, it stuck to both plaques and tangles and could be seen during a PET scan. [If you really want to know, FDDNP stands for fluorescent probe 2-{1-[6-(dimethylamino)-2-naphthyl]ethylidene}malononitrile.] The amount of plaques and tangles shown by FDDNP correlated with the severity of cognitive impairment. The study authors concluded this scan could be used as a tool to differentiate among people with normal memory, those with mild cognitive impairment, and those with Alzheimer’s.

In the future, measuring and mapping tau before and after a treatment may be one indicator of whether that treatment is working.

Potential Alzheimer’s Treatments Targeting Tau

As with beta amyloid, scientists are looking for ways to prevent or treat Alzheimer’s by tinkering with tau. Dr. Binder and his colleagues have shown that an enzyme called puromycin-sensitive aminopeptidase degrades tau in the lab. Scientists at the University of British Columbia are studying how thrombin, a protein involved in blood coagulation, degrades tau, and University of California researchers have found that removing beta amyloid may clear certain forms of tau.

Besides eliminating or reducing tau, other approaches include:

- preventing changes to tau (using lithium or other substances)
- protecting the microtubules in brain cells (using an enzyme called Pin1, the cancer drug Taxol or a compound called NAP, developed by Allon Therapeutics Inc. and now in early clinical trials).

Some scientists think tinkering with beta amyloid could do more harm than good, and tau is no different. I asked Dr. Binder if potential therapies could remove too much tau, since the protein is needed for normal brain function. “This isn’t known as yet,” he says. “Tau knockout mice [bred to have no tau] survive, but it’s not clear how normal they are.”

If removing tau might be dangerous, would it be better to try to regulate the sequence of events leading to changes in tau, or the formation of tangles, rather than remove tau or tangles?

“Perhaps,” says Dr. Binder. “Unfortunately, we are somewhat uninhibited by facts here,” he notes, referring to all the uncertainties about tau. He is sure, however, that investigating tau is worthwhile. “Tau is certainly part of the problem in Alzheimer’s disease and certain inherited frontal lobe dementias,” he says, “and the link between amyloid and tau is currently being explored by both baptists and tauists alike.”

I put Dad’s autopsy report back in the file cabinet for a while. It may be a few more years before I can understand what the tangles were doing in my father’s brain.

SORL1: New Alzheimer's Gene

Summary: A new study shows variations in a gene called SORL1 are associated with an increased rate of late onset Alzheimer’s. The effect of this gene on your risk of developing the disease is probably modest, and researchers don’t know which variations of the gene could increase that risk. The results of this study will not lead to a simple genetic test for increased risk of Alzheimer’s, at least not anytime soon. But the discovery, along with related research, may generate new ideas for Alzheimer’s treatments.

I’ve been taking a break from blogging about Alzheimer’s and dementia. But when I picked up the newspaper from our driveway Monday morning, the top headline screamed “Gene linked to Alzheimer’s.” “More than 40 scientists worldwide find an inherited flaw that can lead to the disease,” the subtitle said.

I’m tired of headlines announcing Alzheimer’s breakthroughs, but decided to check it out anyway.

The headline referred to a new study that shows variations in a gene called SORL1 are associated with an increased rate of late onset Alzheimer’s. Results of the study, conducted by researchers from fourteen universities and institutes, were published online in the February edition of Nature Genetics.

Despite my skepticism about the headline, this study is intriguing. But it doesn’t mean a simple genetic test can tell you if you’re at increased risk of developing Alzheimer’s, at least not anytime soon.

To understand why the study is important, you have to look at related research results published in the last few years.

SORL1 in the Alzheimer’s Brain

Some of the early clues that SORL1 might be involved in Alzheimer’s came from physiological, rather than genetic, studies. First, scientists found that the level of the protein SORL1 was lower in the brains of people who had late onset Alzheimer’s than it was in “normal” brains.

How is a protein related to genes? The information stored in our genes is used to make proteins. Variations in genes (either inherited or that happen during a person’s lifetime) change how proteins are made. The theory is that variations in the SORL1 gene change how the corresponding protein (also called SORL1) is made, perhaps by regulating levels of the protein.

With the new study, there is now evidence that SORL1 may contribute to the risk of Alzheimer’s on both a physiological and a genetic level.

SORL1 Affects Levels of Beta Amyloid

Dr. James Lah is Assistant Professor of Neurology at Emory University, and co-author of the study linking SORL1 protein levels to Alzheimer's. Last year, he and his colleagues found that decreasing levels of the SORL1 protein increases the amount of beta amyloid near cells in lab tests. Beta amyloid is the sticky protein that makes up the plaques found in the brains of Alzheimer’s patients.

James J. Lah, M.D., Ph.D.

This finding is exciting for researchers who think beta amyloid causes Alzheimer’s, and are working on treatments targeting that protein.

“The available data support an important role for LR11 [SORL1] in AD pathogenesis and identify this receptor as a potential novel therapeutic target for treatment of late-onset sporadic AD,” Dr. Lah and his colleagues wrote in their paper published last year in the Journal of Neuroscience.

SORL1 Is a Receptor for APOE

In addition to the link between SORL1 and beta amyloid, there’s a connection between SORL1 and the APOE gene already known to influence the risk of developing Alzheimer’s. The protein SORL1 is a receptor, which means when a specific molecule is nearby, SORL1 binds itself to that molecule, and then causes a reaction within a cell. The specific molecule it binds to is APOE.

APOE is a kind of protein involved in processing cholesterol and other fats. A variation in the corresponding APOE gene, APOE4, has been linked to Alzheimer’s disease. Given this link, APOE variations change the effect of SORL1 variations on Alzheimer’s risk, or vice versa?

“When we began studying LR11/SorLA our first efforts were directed at finding a relationship between it and APOE,” says Dr. Lah. “Their interactions have been surprisingly elusive. However, in my opinion, it is difficult to believe the functional links are merely coincidental. I expect that further work will define the nature of their interactions at both genetic and physiological levels. With the added attention that will follow the Nature Genetics paper, I expect this will come out pretty quickly.”

Intriguing, But More Research Needed

So, why won’t these discoveries lead to a simple genetic test for increased Alzheimer’s risk anytime soon?

While it’s too early to tell how much the SORL1 gene affects the chances of developing the disease, the co-authors of the new paper write that they believe the effect will be “modest.” There are several reasons for this.

First, SORL1 and APOE are just two of many genes suspected to affect the risk of developing Alzheimer’s. In an article published in the January issue of Nature Genetics, researchers at Massachusetts General listed 13 other “potential Alzheimer disease susceptibility genes.”

Second, scientists involved in the new genetic study couldn’t identify which variations of the SORL1 gene might increase the risk of Alzheimer’s. “In sharp contrast to APOE (where APOE e4 is associated with Alzheimer disease in most data sets), no single SORL1 SNP [common variation] or haplotype is associated with increased risk for Alzheimer disease in all six data sets,” they wrote in the article published this week.

Third, the study didn’t show an association between variations of the gene and increased rates of Alzheimer’s in two of the sample populations studied: Caucasians from the MIRAGE (Multi-Institutional Research in Alzheimer's Genetic Epidemiology) study and another set from the Mayo Clinic in Rochester.

This does not necessarily mean that SORL1 is not a risk factor for the populations the people studied represent. “One possible explanation for lack of association in these data sets is genetic heterogeneity,” says Dr. Lindsay Farrer, one of the study’s authors and Chief of the Genetics Program and Professor of Medicine, Neurology, Genetics and Genomics, Epidemiology, and Biostatistics at Boston University School of Medicine. The problem is that multiple variations in the SORL1 gene may contribute to increased risk. “Specifically, in these samples representing perhaps many ancestral European populations there is no one SORL1 SNP variant or haplotype sufficiently enriched to show an association,” he says.

Dr. Farrer also says perhaps the groups in which no association was found just weren’t big enough, especially given the conservative statistical approach used in this study. It may also be that other causes of Alzheimer’s (genetic or not) were somehow over-represented in these groups.

Despite these uncertainties, the results from this analysis of the genetic material, family relationships and medical histories of over 6000 study participants “suggest that inherited or acquired changes in SORL1 expression or function are mechanistically involved in causing Alzheimer disease,” wrote Dr. Farrer and his colleagues.

The scientists supplemented their genetic findings with research on the physiological level by testing for levels of SORL1 in the blood of participants. Those diagnosed with Alzheimer’s had blood levels of SORL1 less than half that of non-Alzheimer’s participants. But this finding had its own uncertainties: only about 14 percent of that difference was accounted for by SORL1 variations.

They also showed in lab tests that decreasing SORL1 in cells increased the production of beta amyloid. This confirmed the earlier research described above, and the results of these new tests will add detail to the hypothesis about the mechanism by which SORL1 may affect beta amyloid.

Something Dr. Lah said helps clarify the connection between the genetic and physiological research for me. “I believe we are entering a new period in which we will be identifying genetic influences on the common late-onset forms of Alzheimer's which individually modify risk more modestly than the very, very potent effects associated with APOE,” he says. “However, these new findings are likely to shed light on physiological pathways that will lead to development of new and more effective treatments for Alzheimer's disease.”

More study on both genetic and physiological levels is needed. “My co-investigators and I encourage other researchers to evaluate association with SORL1 in other datasets,” says Dr. Farrer. “We predict that many, perhaps most, but not all data sets of reasonably large sample size will demonstrate association with one or more SNPs [common variations]. While confirmation is certainly important, in light of our results in which we could not identify any of the SNPs showing association with AD to be functionally or biologically relevant, more intensive interrogation of other variants in this gene is warranted.”

Dr. Lah is a bit less cautious. “I am admittedly biased,” he says, “but I believe that the SORL1 genetic association will hold up, and that LR11/SorLA in Alzheimer's disease will emerge as an important aspect of the disease.”

Reading through the study again, I realize it’s a good example of why there’s often a disconnect between optimistic Alzheimer’s headlines (which set our expectations too high) and the realities of research. The study is big, hard for a non-scientist to understand, and full of twists and turns. Nothing is simple in Alzheimer’s research. But that isn’t the researchers’ fault. We need to have realistic expectations, and support those who are willing to work in this difficult area. I guess I’ll get back to blogging.

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.

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.

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.

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We just don't know much about the brain...

I’m learning a lot from my “seatmates” on this trip to meet with Dad’s doctors.  On the puddle-jumper flight from Charlotte to Greenville,  I sat next to a cardiovascular surgeon.  He had come to North Carolina from Wisconsin to learn how to use the new robot his hospital had bought for heart surgery.

“What brings you to Greenville?” he asked.  I told him I was looking for answers on my Dad’s dementia, and that his doctors were presenting the results of his autopsy. 

“Don’t expect a lot of answers,” he warned me.  “We just don’t know much about the brain.”

“But I thought you could get a definitive answer about whether someone had Alzheimer’s by looking for plaques and tangles in the brain during an autopsy.”

“Well, the problem is that when you do an autopsy, you see the endpoint, but you don’t see the process.  The endpoint might look the same for a lot of different diseases.”

“Hmm, so maybe Dad’s autopsy would show plaques and atrophy whether he had Alzheimer’s Disease, vascular disease, or something else?” 

“Yes, possibly, but I’m not a neurologist.”  I got the feeling he was happy to be working on hearts rather than brains.

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!

Questions about Dad's autopsy

I’ve spent days going through Dad’s autopsy report, and I’m really disappointed.  I don’t think it answers any of the questions we listed on the autopsy request. For example, I thought the autopsy would give a firm diagnosis of Alzheimer’s if Dad's brain had a lot of plaques and tangles .  Tangles aren’t addressed at all in this report, and the two statements about plaques seem contradictory to me.

I’ve sent Dad’s neurologist a list of questions hoping he can answer them.

Autopsy Report

I got Dad's autopsy report in the mail today.  It's four pages long, full of medical jargon, and depressing.  It's hard to imagine that your thoughts and emotions could one day be reduced to phrases like "right temporal cavity lesion" and "the cingulate gyrus appears prominent."

It will take a lot of work with a medical dictionary to try to make sense of this - I'll update you on my progress.

Requesting an autopsy

My family and I sat around the table in a cold conference room down the hall from where Dad had died about an hour before.  It was three o’clock in the morning and we’d said our goodbyes to him.  Mom had to sign some paperwork before we could leave.

“We’d like to request an autopsy,” she told the doctor who had come to sign my father’s death certificate.  We had decided that an autopsy could help researchers, and might show if Dad’s dementia was caused by something my siblings and I could inherit.

“I’ll see if I can find the form,” the doctor said and left the room. 

Ten minutes later, he came back with a piece of paper and handed it to Mom. 

“Can we be specific about what we want them to look for?” she asked him, pointing to the line that said Reason for Autopsy.  He hesitated.  “I don’t have much experience with this – I’m actually a psychiatry resident.”  

We decided to draft a few words ourselves based on some of Dad’s diagnoses.  The words went something like:

Determine the cause of dementia, to include possible Alzheimer’s Disease, iron overload or cerebral amyloid angiopathy.

“What do you think about this?” I asked the doctor.  “I’ll just call the pathologist and check,” he said, dialing zero on the conference room phone.  “Do you have the number for autopsy service? Thanks.”  He dialed again.  “This is Dr. X.  We’re preparing a request for an autopsy report, and the family has some specific requests.  I’d just like to read it to you to make sure…oh,sorry.”  I wondered if he’d woken the guy up.  He read our wording, then hung up the phone and said “that will be fine.”

Maybe if Dad’s death hadn’t been so sudden, we could have made these arrangements earlier.  Either way, I hope we can somehow use the autopsy results to help others dealing with 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.”