The Tangled Neuron

Flurizan, Lipitor and Alzhemed: Negative Study Results

On Monday, Myriad Genetics Inc. announced the failure of Flurizan in Phase III trials.  This news follows the results from the LEADe study showing the cholesterol drug Lipitor did not benefit Alzheimer's patients, and the failure of Alzhemed in Phase III trials last year.

With all this disappointing news, it seems more important than ever for professionals, with input from patients and their families, to talk about new approaches to Alzheimer's research and care.  Maybe implementing some of the ideas discussed at the National Institute on Aging 2006 conference would help.  I'll be at ICAD (the International Conference on Alzheimer's disease) in late July - it will be interesting to see whether new approaches are widely discussed.

Ibuprofen, Naproxen and other NSAIDs for Alzheimer’s

Large observational studies have linked regular use of painkillers such as ibuprofen (Advil) and naproxen (Aleve) with lowered risk of Alzheimer’s, but clinical trials have not backed this up. The publication of the results of two new studies this month didn’t do much to resolve this issue. In the first study, Boston University researchers analyzed the medical records of hundreds of thousands of military veterans, and found long-term use of NSAIDs (non-steroidal anti-inflammatory drugs), particularly ibuprofen, was associated with a reduced risk of Alzheimer’s.

A detailed analysis of the results of the second study, ADAPT (Alzheimer's Disease Anti-inflammatory Prevention Trial), was published this month. It showed that neither naproxen nor another NSAID, celecoxib, improved thinking and memory in more than 2000 men and women 70 years and older who had a family history of Alzheimer’s. Naproxen actually seemed to worsen cognition. The trial was stopped early because scientists worried about the side effects of the two painkillers.

Differences in study design could explain these conflicting results.

Constantine Lyketsos, MD, MPH

The various studies tested different NSAIDs at different dosages in different populations for different lengths of time. It’s also possible that there were “confounding factors” in the population studies – maybe people who take NSAIDs had later onset of Alzheimer’s because they had higher education levels or better overall health, for example.

So, what DO we know about NSAIDs and memory loss? “After the onset of dementia, anti-inflammatory treatment does not seem to work,” says Dr. Constantine Lyketsos, one of the researchers involved in ADAPT. “The data are pretty strong.” Dr. Lyketsos is Director of the Memory and Alzheimer’s Treatment Center at Johns Hopkins University and Chairman of the Department of Psychiatry at Johns Hopkins Bayview Medical Center. 

If treatment with NSAIDs does not seem to be effective, what about prevention?

Amyloid Inhibitors for Alzheimer's: Less Promising Than Thought?

Summary: Amyloid inhibitors, a type of Alzheimer’s drug under development, may not be as promising as once thought. A cheap and easy test early in the drug development process should help researchers focus on the most promising compounds. This finding does not apply to the vaccines being developed to clear amyloid.

If you’re one of the millions waiting for Alzheimer’s drugs now under development, you’ll want to know that researchers at the University of California, San Franciso (UCSF) have come to some interesting conclusions about one type of potential treatment. Which do you want first - the good news or the bad?

UCSF researchers Brian Shoichet, Ph. D. (left) and Robert Fletterick, Ph.D

Let’s start with the bad news. It looks like “amyloid inhibitors” may not be as promising as once thought. Some Alzheimer’s researchers are focused on developing these compounds to prevent beta amyloid proteins from clumping together to form the fibrils and plaques thought to be harmful to your brain. But as with other diseases, the trick is to find compounds that will affect only the beta amyloid “target,” without affecting other proteins your body and brain might need.

Research conducted in the lab of Brian Shoichet, a professor in the Department of Pharmaceutical Chemistry at UCSF, suggests that amyloid inhibitors often affect too many other proteins to be safe and effective Alzheimer’s treatments. The results of his work on this topic were published in late January in Nature Chemical Biology online.

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.

Keep Byrd Institute Startup Funding; Encourage Citizen Involvement

My father had dementia. His illness and death made me feel helpless, and left me with a lot of questions. In the two years since Dad died, I’ve been talking with Alzheimer’s researchers, looking for answers.

I’m especially interested in the research in my home state of Florida. An estimated 450,000 Floridians have Alzheimer’s disease, more than any other state except California. And because the population is older, we have a high prevalence of Alzheimer’s here in the Sunshine State. With the large number of Alzheimer’s cases here, what better place for research on prevention and treatment of the disease?

When I went to the grand opening of the new Byrd Alzheimer’s Center and Research Institute here in Tampa Bay a couple of weeks ago, I was pleased to hear about their plans to expand Alzheimer’s research in Florida. In addition to its own research projects, the Byrd Institute provides an infrastructure for collaboration among researchers statewide, as well as administrative services for Florida’s only federally funded Alzheimer’s Disease Research Center. Most of the work will be carried out in the new building, which has lab space, computers for patient databases, and a clinic for seeing patients. The Institute also has employees in Memory Disorder clinics around the state.

State Funding Cuts Threaten Progress

But as I toured the new facility, state budget cuts were announced. The latest proposal would cut funding for the Byrd Institute in half – from $15 million to $7.5 million. Yes, Florida has budget problems, and they’re likely to get worse. But the state’s budget will not drop fifty percent, like the proposed Byrd funding. Maybe this over-sized cut is due to politics and personalities. Or maybe it’s just that cutting funding for a start-up Alzheimer’s research institution is relatively painless. For obvious reasons, people with Alzheimer’s are not active lobbyists, and their families are too busy caring for them to take the time to advocate on their behalf.

Without adequate startup funding from the state, the Byrd Institute’s labs and clinics will sit empty. Private donors are unlikely to write checks to support a vacant building.

Citizen Involvement

Ultimately, this lack of support is part of a larger problem: the disconnect between medical research and patients. Few Floridians know anything about the research going on in labs around the state, and many researchers do not interact with people who have the disease. More citizens affected by the disease should be key players in Alzheimer’s research at the Byrd Institute and other facilities.

Nationwide, there is a trend towards greater patient and consumer participation in research and health care. In some cases, patients and their families now have a say in how research is prioritized, funded and managed. With donations of time and money, they also support that research.

For scientists to find ways to prevent and treat Alzheimer’s, we need this kind of two-way relationship between research facilities and the community. But it takes time to establish this kind of cooperation. Maintaining startup funding levels for the Byrd Institute will give Alzheimer’s patients all over the state increased opportunities to work with researchers, participate in clinical trials and receive treatments based on the latest science. This should increase Floridians’ direct support of Alzheimer’s research, and over time, lessen the Institute’s reliance on state funding. More than 17 million people live in Florida. If each of them eventually donated just one dollar per year, there would be no need for the state to allocate startup funding.

What You Can Do

If you live in Florida, please call, write or email your legislators and let them know you oppose funding cuts for the Byrd Institute. Give the Institute time to recruit researchers and doctors and work with the community before startup funding is cut off. If $15 million dollars sounds like a lot of money, consider the $155 million the state allocated last year to bring the Burnham Institute for Medical Research to Orlando, or the $310 million of state funds spent to create Scripps Florida.

Then find the Alzheimer’s research facility nearest you, and ask for a schedule of events. Learn more about the work they’re doing, and make sure you meet their scientists. Contribute what you can. Chances are their work will benefit someone you love.

The Alzheimer's Research Registry

Summary: Alzheimer’s researchers say it’s difficult to recruit participants for clinical trials. Whether or not you have memory problems, joining the Alzheimer’s Research Registry is one way you can help move research forward.

In a post about Alzheimer’s research at Sun Health Research Institute, I wrote about the difficulties researchers face in recruiting participants for clinical trials. This can delay a study by months or even years.

To address this problem, the Arizona Alzheimer’s Consortium, a group of Arizona research institutions, has set up a clinical trial registry to recruit and screen participants for current and future studies. The Alzheimer’s Research Registry was launched in March of this year to screen people with and without memory problems for studies and trials including:

- treatment studies for people with probable Alzheimer’s
- non-treatment studies for people with Alzheimer’s
- treatment studies for people with mild cognitive impairment
- planned (but not yet available) prevention studies for cognitively normal people
- non-treatment studies for cognitively normal people.

Why Screen Potential Participants Before A Study Starts?

“People sometimes ask why the Arizona Alzheimer’s Consortium is evaluating potential study participants for studies that may not exist yet,” says Dr. Pierre Tariot, Associate Director of the Banner Alzheimer’s Institute. He and Dr. Marwan Sabbagh of Sun Health Research Institute co-founded the registry. “The reason is that the field anticipates a wave of both treatment and prevention studies in the coming months and years. There are likely to be literally hundreds of studies. From prior experience with a large prevention trial, as well as treatment studies, Dr. Sabbagh and I learned that waiting until a study is completely ready to start can result in considerable lost time. We and our Arizona Alzheimer’s Consortium colleagues chose to anticipate this surfeit of trials, so that as soon as they become available we can immediately refer significant numbers of prospective participants. We want to be able to turn the key and go, without losing precious months.”

Pierre Tariot, M.D.

People in the registry are already participating in trials. “About 150 have been referred to current studies,” Dr. Tariot says, “not all of which are clinical trials. These include biomarkers studies, imaging studies, and several treatment studies for people with probable Alzheimer’s. The last category has included the ADCS DHA trial, two rosiglitazone trials, a cognitive enhancer trial, and an immunotherapy trial.” Since the registry’s launch, approximately 1100 people have contacted the registry. About 500 have been screened, and another 50 await screening.

Joining the Registry

You must be over 50 to be in the registry. Joining is free, and can be done by mail and telephone [call 602-239-6500 or email registryinfo@azalz.org to get the necessary forms]. After the initial screening, depending on the study involved, further medical evaluation may be needed to clarify your cognitive status or diagnosis.

People who live outside Arizona can join the registry, says Dr. Tariot, but they must be able to travel to the state. “Frequency of travel depends greatly upon the particular study,” he says, “ranging from as little as a one or two day visit for the simplest non-treatment study to roughly twice a month in the most intensive studies. Studies involving treatment often average about one visit every month or two. Also bear in mind that studies with higher potential for risk, such as immunotherapy, might not be a good choice for someone living at a great distance.”

If you want to see Alzheimer’s research move forward, joining the Alzheimer’s Research Registry is one way to help.

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?”

Folate, Folic Acid and Alzheimer's

Summary: It’s unclear whether folate or folic acid supplementation can help prevent or treat Alzheimer’s and other dementias. Some evidence actually suggests the opposite: an association between high folate intake and increased cognitive decline. In more positive studies, the link between high folate and lower risk of Alzheimer’s may really be due to exercise.

Folic acid supplements can mask symptoms of Vitamin B12 deficiency, especially in older adults. The U.S. National Institutes of Health warns people 50 years of age or older to have their B12 status checked by a doctor before taking supplements containing folic acid.

Pretend you haven’t read the summary above, and take this short quiz:

1. Folate, a B vitamin found in leafy green vegetables and other foods is good for the brain.
_____Yes _____No _____Maybe

2. Folic acid, the synthetic form of folate found in supplements, is also beneficial.
_____Yes _____No _____Maybe

3. Taking a folic acid supplement can help prevent dementia.
_____Yes _____No _____Maybe

4. It’s OK to take a folic acid supplement just to be sure.
_____Yes _____No _____Maybe

A few days ago, I would have checked yes for every question. But it turns out the correct answer for all these questions is “maybe.” This is surprising, given the press reports:

“Folate shows promise in preventing Alzheimer’s” (USA Today, August 14, 2005)
“Higher Folate Levels May Lower Alzheimer's Risk: Study” (Forbes, January 9, 2007)
“Folic acid boosts elderly brains” (BBC, January 19, 2007).

With headlines like these, it’s no surprise that people worried about brain health have been taking folic acid supplements. When a news feed picked up a story on a study by Dalhousie University researchers in Canada suggesting folate may not reduce the risk of Alzheimer’s, this started an online discussion among members of Dementia Advocacy and Support Network International (DASN). One member wrote “I take folate and have had ‘cerebrovascular events’ in the past, now having vascular dementia.” She wondered what the study results meant for her. Several other members (most diagnosed with Alzheimer’s or dementia) responded that they take folic acid supplements in amounts ranging from 400 micrograms to 5 milligrams.

Some of the DASN members are taking folic acid on the advice of their doctors, or because they’ve heard it might be helpful for dementia. But what evidence is this based on?

Theories About Folate and Alzheimer’s

Scientists aren’t sure by what mechanism, if any, folate may prevent or treat Alzheimer’s. Theories about why folate may be linked to a lower risk of the disease center around homocysteine. Some studies have linked high blood levels of this amino acid to heart disease and Alzheimer’s. In 2001, an analysis of data for 1092 people in the Framingham Study by Boston University researchers showed that a high level of homocysteine in the blood was a strong risk factor for developing Alzheimer’s or other dementia. Folic acid appears to help lower homocysteine levels. So if there’s any protective effect from folate, it could be from lowering homocysteine levels.
There’s also a possible link among folate, homocysteine and beta amyloid, the protein many researchers think causes Alzheimer’s. Scientists at the U.S. National Institute of Aging have shown that brain cells without folate, or with added homocysteine, appear to be more vulnerable to damage from beta amyloid.

Lab studies and theories are tantalizing, but what do studies involving humans show?

Folate or Folic Acid for Prevention of Alzheimer’s?

The results of the study from Dalhousie University that generated discussion among DASN members were published in an article in the Journal of the American Geriatric Society. The lead author of the article, Laura Middleton, is a Ph.D. student studying the effects of lifestyle on the risk of Alzheimer's disease and dementia, with a particular focus on exercise.

Laura Middleton

“In our study, we looked at folate levels in the blood,” she says. “Low folate levels are associated with an increased risk of Alzheimer's disease. Conversely, supplementation with folic acid has not been consistently shown to decrease this risk, suggesting that there may be other factors at play. We suggest in our article that exercise may explain this paradox. In our study group, there were no exercisers who had extremely low folate levels. Folate levels may be associated with the risk of Alzheimer's disease because people who exercise both have higher levels of folate and less risk of Alzheimer's disease.”

Ms. Middleton doesn’t think other factors were at work. “We controlled for a number of other variables,” she says, “including age, sex, education, vascular risk factors, and folate/B12 supplementation.”

Folate’s effect on the risk of developing dementia has been the subject of several large studies, and the results have been mixed. Some studies tracking people’s food consumption, folate levels in the blood and health over several years have shown an association between higher folate intake (or higher levels of folate in the blood) and lower risk of developing Alzheimer’s. In 2001, the results of a study by researchers at Karolinska Institutet in Sweden were published in Neurology. The study found that people with low levels of folate in their blood had twice the risk of developing Alzheimer’s. In an article published in 2005, analysis of data from the Baltimore Longitudinal Study of Aging by the U.S. National Institute on Aging, the U.S. Department of Agriculture (USDA), Johns Hopkins University and the University of California showed a high folate intake was associated with a reduced risk of Alzheimer’s. Early this year (2007), a study by Columbia University researchers followed the dietary intake of 965 persons aged 65 or older over several years. These scientists also concluded that a higher folate intake was associated with a decreased risk of Alzheimer’s.

But as the Dalhousie University study suggests, just because high folate intake is sometimes associated with lower rates of Alzheimer’s doesn’t mean there is a cause and effect relationship. Researchers involved in the Baltimore Longitudinal Study of Aging caution that “additional studies are necessary to investigate whether folate or other(s) [sic] unmeasured factor(s) may be responsible for this reduction in risk,” and the authors of the 2007 article on the Columbia University study note “these results require confirmation with clinical trials.”

A systematic review of 24 studies by Tufts-New England Medical Center scientists published this month (July 2007) questions the value of some of these studies due to quality problems and to variations in the way cognitive function was measured and B-vitamin status was categorized.

Some recent studies have shown either no link between folate intake and the risk of developing dementia, or, more worrisome, that increased folate intake is actually associated with increased cognitive decline. At Rush University Medical Center in Chicago, Dr. Martha Clare Morris studies diet and dementia. She co-authored an article published last year in the Journal of Alzheimer’s Disease that describes a Rush study testing whether folate and other B vitamins can protect against Alzheimer’s. Using data from the Chicago Health and Aging Project (CHAP), she and her colleagues tracked 1041 people age 65+ for a median 3.9 years, and found no association between folate intake and the risk of developing Alzheimer’s.

Martha Clare Morris, Sc.D., Associate Professor, Internal Medicine, Rush Institute for Healthy Aging
Assistant Provost for Community Research, Rush University Medical Center

“We have much research to do in this area,” Dr. Morris says. “There is growing evidence to indicate that perhaps too little folate or too much folate can be harmful to our health…. There are some recent studies including our CHAP study that observed greater cognitive decline with high levels of folate intake.” These studies looked at the risk of developing Alzheimer’s; Dr. Morris and her colleagues plan to study the effect of folate on vascular dementia in the near future.

Can Folic Acid Treat Alzheimer’s and Dementia?

Evidence on the use of folic acid to treat dementia is as mixed as that about its use for prevention. A 2003 Cochrane Review of four double blind, placebo controlled, randomized trials found no beneficial effect of 750 micrograms of folic acid per day on measures of cognition or mood in people with mild to moderate cognitive decline and different forms of dementia.

A 2004 review by (London-based) King’s College researchers of six studies that met certain quality criteria concluded that “the evidence does not support a correlation between serum vitamin B (12) or folate and cognitive impairment in people aged over 60 years. Hence, there is little evidence to justify treating cognitive impairment with vitamin B (12) or folate supplementation.”

The results of two studies published in 2007 are more encouraging. In the first, a small trial of folic acid supplements with cholinesterase inhibitors in 57 patients with Alzheimer’s was conducted by researchers at the University of Dundee. They found adding folic acid to cholinesterase inhibitors improved the ability to carry out activities of daily living and “Social Behaviour” scores, but did not improve scores on the MMSE [Mini Mental State Exam]. In the second, Dutch researchers studied 818 participants in FACIT, a trial testing the effect of folic acid on hardening of the arteries. Their results, published in the January 20, 2007 edition of Lancet, showed that “folic acid supplementation for 3 years significantly improved domains of cognitive function that tend to decline with age.”

But in an editorial accompanying the Lancet article, Dr. Morris and her colleague Christine Tangney question whether the results of the FACIT trial apply to everyone. “By design,” they write, “the trial was focused on people whose folate status was inadequate…. The trial was well designed and unique in its approach of targeting individuals who might benefit from folate supplementation. But how well do the folate intakes of these highly selected trial participants correspond to intakes in more representative samples of the population?” They point out problems with measuring folate intake, as well as our lack of knowledge about what folate and homocysteine levels are optimal, and call for more randomized clinical trials.

Risks of Folic Acid Supplementation for Older Adults

So, the benefit of folic acid supplementation for dementia is unclear, and some studies show a link with increased cognitive decline. Are there other risks involved?

The U.S. National Institutes of Health warns in its folate fact sheet “Beware of the interaction between vitamin B12 and folic acid:”

Intake of supplemental folic acid should not exceed 1,000 micrograms (μg) per day to prevent folic acid from triggering symptoms of vitamin B12 deficiency. Folic acid supplements can correct the anemia associated with vitamin B12 deficiency. Unfortunately, folic acid will not correct changes in the nervous system that result from vitamin B12 deficiency. Permanent nerve damage can occur if vitamin B12 deficiency is not treated.

It is very important for older adults to be aware of the relationship between folic acid and vitamin B12 because they are at greater risk of having a vitamin B12 deficiency. If you are 50 years of age or older, ask your physician to check your B12 status before you take a supplement that contains folic acid. If you are taking a supplement containing folic acid, read the label to make sure it also contains B12 or speak with a physician about the need for a B12 supplement.

Many of us don’t know how much folic acid we get. Because low levels of folic acid are associated with certain birth defects, in the U.S., Canada and some other countries, folic acid is added to flour, breads and other grain products. “With the folic acid fortification program that was instituted in 1998, folate insufficiency is a rare occurrence in the U.S.,” says Dr. Morris. In addition, anyone taking a multivitamin is likely to be getting folic acid - mine contains 400 micrograms, the recommended dietary allowance for folate in the U.S.

So, what does all this mean for DASN members and anyone worried about brain health? It’s been hard to prove that folic acid or any supplement can prevent or treat Alzheimer’s and other dementias, but exercise may be helpful.

“So far, food sources of vitamin E and other antioxidant nutrients look promising for the prevention of dementia,” says Dr. Morris. But, she says, “there is little evidence to support protective benefit through vitamin supplement sources, except perhaps if one is deficient in dietary intake of certain nutrients. There are also a number of animal and observational studies that have shown that fish and n-3 fatty acids are protective against dementia. Verification of these relations through randomized clinical trials is needed before we can confidently recommend dietary intake of these foods and nutrients for dementia prevention.”

Laura Middleton points to the benefits of exercise instead of supplements. “In our studies to date, we have found that exercise not only delays dementia but can also slow the progression and increase the chances of improving even after you have been diagnosed with Alzheimer's disease,” she says. “It is never too late to start exercising. As little as walking three times a week can significantly reduce your risk of Alzheimer's disease and can slow or even pause cognitive decline.”

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.

Cognitive Rehabilitation For People With Alzheimer's and Dementia

Summary: Results of a small trial show cognitive rehabilitation can help people with mild Alzheimer’s improve their ability to perform practical tasks. Unlike cognitive stimulation programs, cognitive rehabilitation is designed to improve specific skills. Rehabilitation may help people with memory loss stay functional and independent, but more research is needed.

Morris Friedell was diagnosed with Alzheimer’s disease in 1998. “I had a feeling that all I could do was wait for the axes to fall, one after the other,” the retired sociology professor wrote in his year 2000 essay “Potential for Rehabilitation in Alzheimer’s Disease.” “I’d lose my ability to drive, to budget, to speak coherently, to dress myself, to use the toilet. I thought: I must plan to die when I can still do so with dignity. I still believe that’s a meaningful challenge, but the greater challenge is how to live as fully as I can until that time. And that’s where rehabilitation comes in.”

Morris F. Friedell, Ph.D.

A former sociology professor, Morris adapted techniques from traumatic brain injury rehabilitation programs and from psychotherapy to develop his own rehab plan. His efforts seem to have paid off, although it’s hard to know what led to his improvement. This is because Morris’s diagnosis is tentative, as are the diagnoses of many others with early stage dementia. “Since 2001,” he writes, “my neuropsychological testing has shown an absence of clinical dementia (although, in real life, conversations and TV sitcoms continue to move too fast for me). Perhaps my rehabilitative efforts have been more or less successful, or perhaps (despite the indications from PETs, MRIs and a qEEG) I never did have brain pathology, or even perhaps neither.”

Morris is running a bit ahead of science. Cognitive rehabilitation for dementia is a fairly new idea, and not much funding has been allocated towards research in this area. Maybe that’s because we tend to write off people with dementia.

Early Studies of Cognitive Rehabilitation Show Promise

“Until recently, there was an unfortunate bias that Alzheimer’s disease patients could not learn,” says Dr. David Loewenstein, director of research and neuropsychology at the Wien Center for Alzheimer’s Disease and Memory Disorders and professor of Psychiatry and Behavioral Sciences at the Miller School of Medicine at the University of Miami. In an article published in the American Journal of Geriatric Psychiatry in 2004, he and his colleagues described results of a trial showing that systematic cognitive rehabilitation can help people with mild Alzheimer’s disease carry out specific tasks.

In his study, twenty-five people with mild Alzheimer’s participated in twenty-four sessions of cognitive rehabilitation. They were trained in tasks including face-name association, object recall, making change, paying bills, orientation to time and place, and the use of a memory notebook.

Participants were tested on tasks similar to (but not the same as) those trained on at three points during the study: before rehabilitation, just after the twenty-four sessions, and three months after the sessions had ended.

With the exception of the bill-paying task, their performance on tasks similar to (but not the same as) those trained on improved significantly after rehabilitation. These improvements were maintained three months later. The study authors speculate that no improvement was seen in the bill-paying task because participants did well on this task before rehabilitation began, so there wasn’t much room for improvement.

While their ability to complete tasks increased, study participants’ scores on unrelated neuropsychological tests did not improve.

Everyone enrolled in this study was taking cholinesterase inhibitors, such as Aricept or Razadyne, but rehabilitation may also be helpful for persons with mild Alzheimer’s who are not taking these medicines. “Since the publication of the 2004 paper,” Dr. Loewenstein says, “we have done work that indicates that even those persons not on cholinesterase inhibitors benefit from the cognitive intervention program. We have not, however, conducted a controlled study examining the extent to which the effects of the cognitive intervention may have been augmented by different types of medications.”

There’s no research yet to indicate whether or not rehabilitation would help people whose dementia has progressed beyond the mild stage. “Our studies are on mild and very mild Alzheimer’s,” Dr. Loewenstein says, “and unfortunately at this time are not generalizable to moderate or severe Alzheimer’s disease.”

And what about aging baby boomers? Could rehabilitation help those of us who have problems finding the right word or navigating unfamiliar streets? It’s too early to tell, says Dr. Lowenstein. “Our program is dedicated to Alzheimer's disease, although we have an NIH grant proposal out looking at the effects of cognitive interventions on the abilities of normal elderly adults.”

Cognitive Rehabilitation – Not The Same As Cognitive Stimulation or Brain Fitness

Cognitive rehabilitation should not be confused with cognitive stimulation or brain fitness. Several companies offer cognitive stimulation programs, marketed mostly to healthy baby boomers hoping to stave off dementia. These typically involve memory exercises and games meant to ramp up overall brain activity. Some studies have shown that cognitive stimulation is useful for persons with mild Alzheimer’s, and I’ll write about these in another post. But cognitive stimulation is not the same as cognitive rehabilitation, which aims to improve performance on specific skills.

These differences were addressed in the University of Miami trial, where an additional 19 people with mild Alzheimer’s disease participated in twenty-four sessions of a “mental stimulation” program. The program did not focus on specific tasks, but instead consisted of interactive computer games involving memory, concentration, and problem-solving skills.

The group participating in the stimulation program did not show improvements in functionality comparable to the rehabilitation group, and in fact scored progressively worse in some tasks. “Directly trained skills showed improvements in the intervention group relative to the mental stimulation group,” Dr. Loewenstein says.

Working Around Memory Loss

As with Morris Friedell, rehabilitation for brain injury was a starting point for Dr. Loewenstein. “Dr. Amarilis Acevedo and I developed the cognitive rehabilitation paradigm because we had been successful rehabilitating stroke and traumatic brain injury in our outpatient treatment center,” he says. But unlike Morris, they did not find brain injury rehabilitation techniques to be helpful. “Unfortunately, the existing cognitive and functional treatments for these conditions were not useful for Alzheimer’s,” he says. “The cognitive and functional interventions that we use with Alzheimer’s disease patients employ different learning strategies.”

Just what are those strategies? The University of Miami researchers tested a combination of three specific techniques for rehabilitation of people with mild Alzheimer’s:

- Spaced retrieval – a method of learning in which the time between learning information and retrieval of information is progressively increased. The goal of spaced retrieval is to help people remember information over long periods of time.

- Dual cognitive support – in this technique, cues or ways to remember information are provided both when the fact is learned and when it is remembered or retrieved.

- Procedural memory training – a method in which tasks are practiced repeatedly, rather than trying to memorize the steps necessary to complete those tasks. This technique takes advantage of the fact that although persons with early stage Alzheimer’s may have problems with explicit memory [knowledge of facts, knowing what happened when], they tend to retain their implicit or procedural memory [unconscious knowledge of how to do something; skills]. Using this preserved procedural memory may be key to cognitive rehabilitation.

“What cognitive [rehabilitation] interventions provide is a way for Alzheimer’s patients to take preserved skills (implicit memory, procedural knowledge, motor memory) and apply them to work around cognitive and functional deficits,” Dr. Loewenstein explains.

The actual exercises used in the University of Miami trial were:

- Learning face-name associations using spaced retrieval and dual cognitive support
- Practicing time and place orientation using a calendar and other parts of a memory notebook during rehab sessions and at home
- Manipulating objects as though participants were using them (procedural memory training)
- Pressing mouse buttons in response to various shapes and information that appeared on a computer screen
- Making change for a purchase from a $20 bill
- Paying bills and balancing checkbooks.

“A take home message from our research is that cognitive and functional rehabilitation in early Alzheimer’s should target meaningful real-world cognitive and functional skills by using procedures that bypass the episodic memory deficit (e.g., procedural learning, spaced retrieval),” Dr. Loewenstein says. “The potential for keeping older adults functional and independent for longer periods of time is quite exciting.”

The basis for the improvements seen from cognitive rehabilitation is not clear, he explains. “A number of people tout brain plasticity, but there is no evidence at this time that cognitive rehabilitation affects plasticity in the Alzheimer’s brain and it would be difficult to argue that any biological process in the brain is altered.”

New Trials

Dr. Loewenstein and his colleagues are now conducting a much larger cognitive rehabilitation trial as part of the Florida Alzheimer's Disease Research Center funded by the U.S. National Institute on Aging. “A number of the same techniques in the original study are being employed,” he says, “but we have also focused on more functionally relevant tasks for very mild Alzheimer’s patients including using an ATM machine, using automated telephone menu systems (interacting with a utility company) and even doing simple searches on the internet.” Although this is a five year study, he hopes to have some initial results to report in twelve to eighteen months.

Participants receiving cognitive rehabilitation in the previous study continued to show improved performance in the tasks tested three months after rehabilitation ended. But researchers don’t know how long after that the benefits might last. “In our current studies, we include booster sessions after the initial treatment (two times per month) for six months in an effort to maintain treatment gains. We would like to obtain funding to study the effects of longer booster sessions” says Dr. Loewenstein.

Researchers at the University of Wales are also conducting a trial of cognitive rehabilitation for early stage Alzheimer’s. The trial includes fMRI imaging to help them understand how rehabilitation affects the brain.

Will Your Doctor Write a Prescription for Cognitive Rehabilitation?

Will doctors eventually write prescriptions for cognitive rehabilitation for people diagnosed with dementia? “I think that this is premature at the time given that this field is in its early stages,” Dr. Loewenstein says. “I believe that the future for cognitive and functional rehabilitation is bright and promising but I think that we need more evidence for effectiveness before these types of interventions are considered for clinical practice.

But I would say that we have poured billions of dollars into pharmacological agents that often have very modest cognitive and functional benefits. I think that it is appropriate to study and to develop cognitive approaches which may have even greater impact on certain functional skills and capacities.”

In the meantime, Morris Friedell continues his own rehabilitation program. “I believe that an important reason patients go downhill the way they usually do is because society sends them a devastating message that their lives are already over,” he writes. He has chosen to reject that message, and is working towards his vision of “recovery of autonomy, competence and quality of life after diagnosis with dementing disease.”

Cholesterol, Statins and Alzheimer's: Part 3 of 3

Summary: A new study shows that a decline in total cholesterol may be associated with the early stages of dementia. More research is needed to understand what this means.

When Dad was in his mid-60’s, the results of his annual physicals were straight out of an advertisement about healthy aging. His weight and blood sugar were normal, and his blood pressure and cholesterol were low.

Now it seems Dad’s low cholesterol levels weren’t such a good sign after all. Some research links high cholesterol in mid-life to increased risk of heart problems and dementia. But later in life, low cholesterol levels, not high, are linked to increased risk of dementia and even death.

A new study, published in the Archives of Neurology, shows that a decline in total cholesterol may be associated with the early stages of dementia. Researchers at King’s College London Institute of Psychiatry looked at 26 years of total cholesterol readings for over 1000 Japanese American men participating in the Honolulu-Asia Aging study. They found that “cholesterol levels in men with dementia, and, in particular, those with Alzheimer disease had declined at least 15 years before the diagnosis and remained lower than cholesterol levels in men without dementia throughout that period.”

What do the results of this study mean? I fired off a list of questions to the study’s lead author, Dr. Robert Stewart, Head of Section of Epidemiology at the Institute of Psychiatry at King’s College.

Robert Stewart, MD, MRCPsych

Q: Should Dad have been worried about his low cholesterol readings? Could the drop in cholesterol seen in the new study be a “biomarker” for Alzheimer’s or dementia?

Dr. Stewart: This is a possibility. However, the drop in cholesterol in our study occurred quite a long time before the onset of dementia and so you would have to wait a long time to know if such a ‘biomarker’ was accurate. This is a finding that needs further investigation.

Q: Did the men in the Honolulu-Asia Aging Study who developed dementia have high cholesterol levels at the beginning of study?

Dr. Stewart: The analysis was designed to measure change in cholesterol over time, so it’s not strictly possible to comment on differences in initial levels. There have been a few studies which have suggested that high cholesterol levels in middle age may predict a higher risk of developing dementia later on in life, but this is still a slightly controversial issue.

Q: Is a drop in cholesterol an underlying cause of dementia and death, or simply a sign of some disease process such as heart disease or a disease process in the brain?

Dr. Stewart: We really can't be sure what it was due to. In the paper we mention that a drop in cholesterol can be caused by an inflammatory event or possibly a nutritional deficit, but you are right in that it could be secondary to cardiovascular disease or secondary to some early brain change. We simply don't know and need to investigate this issue further.

Q: Finally, what does this study say about the potential use of statins to treat dementia?

Dr. Stewart: I don't think that our findings have any particular implication for statin trials. It is likely that the drop in cholesterol in our study was secondary to other processes and was not a direct cause of later dementia. It is also highly unlikely that it was related to cholesterol lowering treatment as these medications were not widely available at the early stages of this study when the cholesterol decline occurred.

We may never know whether Dad’s low cholesterol was a bad sign, or whether taking Mevacor affected his dementia. With the ongoing studies on the use of statins to treat Alzheimer’s, and further research into late-life drops in cholesterol, we should have a better picture of the relationship between cholesterol and dementia in the next few years.

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, Ulcerative Colitis and the Poetry of Donald Rumsfeld

My brother James called from his hospital bed in New Mexico to ask me to research cyclosporine, a potential treatment for his ulcerative colitis. He is weak and has lost more than thirty pounds. The beeping in the background means his IV system needs attention. I hold on while the nurses add steroids, morphine and the solution he gets his nourishment from.

James at Dripping Springs, Las Cruces, New Mexico

As with Alzheimer’s, no one is sure what triggers ulcerative colitis. And although medicines for ulcerative colitis are more effective than those for Alzheimer’s, there are not a lot of studies about treating an acute case like my brother’s. This is probably due to the fact that most people in the midst of painful, severe, life-threatening ulcerative colitis attacks don’t volunteer for clinical trials.

I pulled up the prescribing information for cyclosporine, and sorted through the few articles I could find. I looked up terms I didn’t understand (“parathesia” is a tingling or numbness, “renal insufficiency” is a fancy term for kidney failure). I checked the size of the studies on cyclosporine for ulcerative colitis (small, with around 50 participants). I marked some pages, and made some notes.

Then I called my brother back. “Did I wake you up?”

“That’s OK.”

“Cyclosporine is an immunosuppressant.” I was looking at Mayo Clinic’s site.

“Mmmmm,” he said. I think he already knew this.

“This potent drug is normally reserved for people who don't respond well to other medications or who face surgery because of severe ulcerative colitis,” I read to him. I flipped to a list of side effects I found in a study published in 2003. “Irreversible liver damage, kidney damage in 23% of patients, infections in 20%, seizures in 3%.”

“I don’t want that drug.” By then, he was wide awake. His doctor planned to start the cyclosporine within a couple of days if James didn’t get better.

The rush to research is a reflex action for me. But I don’t think all my compulsive research helped my father deal with his dementia, and I worry it won’t help my brother. I can only evaluate information from a layperson’s point of view. Am I influencing James and his wife Katya to refuse a treatment he needs? I’m getting an uncomfortable sense of déjà vu.

This is the way it goes when doctors and patients have to deal with a lot of unknowns. I was still thinking about this when the Alzheimer’s Research Forum posted a table called “What We Know, What We Don’t Know” for discussion and comment. Under the What We Know column, the editors listed research findings and achievements. There are 41 entries in the What We Know Column. But for every entry in the What We Know column, there is a corresponding entry in the What We Don’t Know column.

This makes me wonder if I should keep blogging about Alzheimer’s research, when there is so much “unknown.” But I think many of us want to understand what’s in the What We Know and What We Don’t Know columns when we’re weighing treatment options for various diseases. And who knows what we’ll find out about Alzheimer’s in the next few years? Maybe there will be a “breakthrough” discovery that really improves prevention or treatment.

Maybe this is what Donald Rumsfeld meant during a February 12, 2002 news briefing when he said:

As we know,
There are known knowns.
There are things we know we know.
We also know
There are known unknowns.
That is to say
We know there are some things
We do not know.
But there are also unknown unknowns,
The ones we don't know
We don't know.

I’ll update you on my brother’s progress. In the meantime, maybe we need to add a third column to our tables: What We Don’t Know We Don’t Know. It’s that Rumsfeld column that keeps me blogging about Alzheimer’s.

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.

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