The Tangled Neuron

CADASIL: Young Onset Dementia Caused by a Stroke Disorder

Summary: CADASIL is a type of stroke disorder that can cause young onset dementia. Two web sites have been developed by women whose families are affected by the disease.

Billie Duncan-Smith’s husband Steve’s first symptom came when he was 38. He woke up with an excruciating headache, and started vomiting because the pain was so bad. Over the next few years, he would suffer many such migraines, some lasting for several weeks. An MRI of his brain showed a high number of white matter lesions, but Steve’s doctors weren’t sure what was causing his headaches.

Billie and Steve in 2004

While Steve suffered, Billie searched the internet and contacted medical experts all over the world. She sent his records and test results to those who offered to help. Finally, someone at the U.S. National Institutes of Health called her to suggest Steve might have CADASIL (Cerebral Autosomal Dominant Arteriopathy with Sub-cortical Infarcts and Leukoencephalopathy), a type of stroke disorder.

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.

The Myth of Alzheimer's?

We seem to be rethinking everything right now - the energy we use, the pollution we create, the foods we eat. Peter Whitehouse, a prominent Alzheimer’s researcher and doctor, is also rethinking the disease we call late onset Alzheimer’s.

In his new book, The Myth of Alzheimer's: What You Aren't Being Told About Today's Most Dreaded Diagnosis, written with Danny George, Dr. Whitehouse questions just about everything we think we know about Alzheimer’s and memory loss. Their book comes at a time when I’ve started to rethink my late father’s dementia after two years of blogging about Alzheimer’s research.

Creativity and Memory Loss

Are people with memory loss more creative? It seems many have taken up painting, writing or playing an instrument. Donna Beveridge has taken up all three.

Donna, 65, is a retired elementary school teacher diagnosed last year with early stage probable Alzheimer’s. She lives with her partner Betsey and their two cats, Shadow and Idgy, near the coast of Maine. Her three children and their families live close by.

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

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

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

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.

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.”

Chlamydia Pneumoniae and Alzheimer's

Summary: Infection with a common bacterium called Chlamydia pneumoniae may increase the risk of developing Alzheimer’s. The bacterium has already been linked to heart disease and hardening of the arteries. Work to investigate the role of viruses and bacteria such as Chlamydia pneumoniae in chronic diseases is in the early stages, but researchers hope it will help identify and treat the underlying causes of Alzheimer’s.

More study is needed to confirm the bacterium’s relationship with dementia, and rigorous clinical trials would be necessary before any treatments based on this research could be recommended.

I’ve written before about how viruses and bacteria can contribute to chronic diseases not previously linked to infections. It is now accepted that a type of bacteria contributes to ulcers, and that human papillomaviruses are the major cause of cervical cancer. A common bacterium called Chlamydia pneumoniae (also called Chlamydophila pneumoniae and C. pneumoniae) has been linked to atherosclerosis (hardening of the arteries) and other chronic diseases.

Dr. Brian Balin, a professor at the Philadelphia College of Osteopathic Medicine and Basic Science Director of the school’s Center for Chronic Disorders of Aging thinks that same bacterium may also contribute to many cases of Alzheimer’s. As the name indicates, the bacterium causes a type of pneumonia - it’s not the same as the sexually transmitted type of Chlamydia.

Although the link between C. pneumoniae and Alzheimer’s is not well-accepted, Dr. Balin has been researching the relationship for years. At a 1995 meeting he attended, talk turned to the possible link between the bacterium, hardening of the arteries and heart disease.

“I asked whether anyone had ever looked for the organism in brain tissue,” he remembers. “My background in neuropathology dealt with the blood brain barrier, and I had for some time believed that damage to the blood vessels in the brain could be involved in Alzheimer’s disease. My beliefs were not widely held….”

“Anyway, after asking the question, I performed a search of the literature and found that no one had ever looked in brain tissues for the presence of this infection.... So, I went to our -80 C freezers and pulled out frozen brain tissues from both AD [Alzheimer’s disease] and non-AD brains. I sent these samples in a coded or blinded fashion to Dr. Alan Hudson for analysis by polymerase chain reaction (PCR), which is a way of testing whether the DNA of the organism was in the tissue samples.” [Dr. Hudson is a Wayne State University School of Medicine professor whose lab focuses on Chlamydia research.]

It turned out that the AD tissue samples contained the DNA from the bacterium, while the non-AD tissues did not. The two researchers repeated the experiment with different samples, and got the same results.

“This then led to our expanded experiments to determine whether C. pneumoniae could be detected using a variety of methods,” says Dr. Balin. “All in all, we used six different techniques which gave consistent results. The first publication of our work was in 1998 in Medical Microbiology and Immunology.”

Chlamydia Pneumoniae - An Elusive Bacterium

All these different testing methods were necessary because Chlamydia pneumoniae is the Loch Ness Monster of the bacteria world – hard to categorize, and even harder to find.

“Because of the nature of this organism, one cannot take a ‘quick and dirty’ approach to this problem,” says Dr. Balin. The bacterium is hard to categorize because it acts more like a virus than a bacterium, growing inside cells and using the resources of the cell to reproduce. Even worse, he says, it keeps changing form. “C. pneumoniae has multiple developmental phases in its life cycle and expresses genes and proteins variably depending on things such as life cycle, environment, and tissue in which it is located.”

This may be why some labs report they have not found C pneumoniae in Alzheimer’s brains. But Dr. Balin thinks the extensive testing he and his colleagues have done is accurate. “There are a number of techniques used to detect C. pneumoniae in clinical samples… What we do, and which is not consistently done in other labs, is use multiple techniques with many different types of probes to detect the presence or not of C. pneumoniae in a clinical sample. We have used at least 15 different antibodies specific either to Chlamydia genus or Chlamydophila pneumoniae on our brain samples to determine if antigens from the bacterium can be detected in the tissues. In addition, multiple PCR primer sets have been used to detect different genetic sequences of C. pneumoniae. We also have used biochemical techniques, electron microscopy, and tissue culturing to demonstrate C. pneumoniae in brain samples. We believe the most thorough sampling is required to truly rule in or rule out presence of the organism in brain tissues.”

He received some confirmation of his findings this year, when scientists at the Wroclaw Medical University in Poland reported finding Chlamydia pneumoniae in the spinal fluid of 44 percent of the Alzheimer’s patients they tested, but only 11 percent of a control group. The Polish researchers suggested that testing for the bacterium in spinal fluid could be useful in the diagnosis of Alzheimer’s.

How Chlamydia Pneumoniae May Trigger Alzheimer’s

How could a type of pneumonia affect the brain? “My group has found that C. pneumoniae, once inhaled, infects white blood cells, in particular the monocytes that circulate throughout the blood stream,” Dr. Balin explains. “These cells can enter through the walls of the blood vessels and can carry the organism into different tissues, including the brain.”

“We also have evidence that the cells in our upper noses known as the olfactory neuroepithelial cells (those cells controlling our sense of smell) are infected by C. pneumoniae.” The olfactory neuroepithelial cells are close to the olfactory bulb region of the brain and to the hippocampus, where short term memory is formed. These areas of the brain are among the first to be affected by Alzheimer’s. This suggests there may be a link between infection with C. pneumoniae and the reported association between the loss of sense of smell and the onset of Alzheimer’s.

Finally, there is some tantalizing evidence that the bacterium may actually trigger the formation of the amyloid plaques characteristic of Alzheimer’s brains. When mice in Dr. Balin’s lab were infected with C. pneumoniae, they developed amyloid plaques in their brains. Adding to the evidence of the link between the bacterium and Alzheimer’s pathology, the bacterium was found near plaques and tangles in human Alzheimer’s brains studied in his lab.

C. Pneumoniae – Another Piece of the Dementia Puzzle?

Dr. Balin points out that the connection between C. pneumoniae and Alzheimer’s is consistent with other research on the disease. Some scientists think inflammation causes the brain damage seen in Alzheimer’s. “Quite possibly the inflammatory response due to a chronic persistent infection with C. pneumoniae and/or other infectants causes much of the cellular damage in the brain,” he says. “Also, genetic risk factors such as having the ApoE 4 variant which has been correlated with Alzheimer’s disease may actually increase one’s risk for being infected with C. pneumoniae and other infectants such as Herpes Simplex Virus 1. The interrelationship of ApoE with infectants may be how this variation confers greater risk for getting both infections and Alzheimer’s disease. Our data have shown that Alzheimer’s brains that express the ApoE4 variation actually have greater concentrations of C. pneumoniae than Alzheimer’s brains not expressing the variant.”

He thinks the connection between C. pneumoniae and hardening of the arteries may also be relevant to dementia. Of course, arteries are a type of blood vessel. Once white blood cells infected with C. pneumoniae reach the brain, Dr. Balin theorizes, they may damage the blood vessel walls there. This would contribute to vascular dementia and brain tissue damage.

But if exposure to Chlamydia pneumoniae is common, as indicated by the antibodies in many people’s blood, why don’t we all develop Alzheimer’s? “Exposure to an infectious agent does not necessarily translate into a specific disease,” says Dr. Balin. “There are many other factors, both genetic and environmental, that would dictate why some get a disease and others do not, even when you have a large percentage of the population exposed to the infectious agent. One example is exposure to the common cold viruses, which are very ubiquitous. Not everyone exposed gets a cold. …so, not everyone exposed to C. pneumoniae would develop Alzheimer’s, but the potential for the disease would be ever-present.”

Potential Treatments for Alzheimer’s and Dementia

Dr. Balin cautions against rushing to treat Alzheimer’s based on the possibility that C. pneumoniae could trigger the disease. “The dilemma that we face is that without current long-term effective treatments for AD, many people may want to try, even experimentally, other types of drug regimens based on the work that we and others are doing with infection,” he says. “Obviously, without clinical trials first, we cannot know for sure who would be most likely to benefit. We have to determine who is infected with which organism(s) and try to treat appropriately. This is why we really need a concerted effort to develop controlled clinical trials.”

He’s done some thinking about what types of therapies a clinical trial could test. “We know that Herpes Simplex Virus 1 may be involved in a significant number of AD cases and this may also have to be considered in a therapeutic regimen. All in all, I think that infection data (even at this point in time), suggests that using combination therapy of an anti-inflammatory, anti-chlamydial and an anti-viral for Herpes could be beneficial."

The “cocktail” he is proposing for trials includes anti-inflammatory medicines or NSAIDs (non-steroidal anti-inflammatory drugs such as aspirin and ibuprofen). Although some population studies have shown a link between NSAID use and decreased risk of Alzheimer’s, evidence from clinical trials using NSAIDs to slow progression of the disease is not very encouraging. If inflammation is caused by infection with C. pneumoniae, Dr. Balin says, it’s unlikely that it could be controlled in the long run by NSAIDs alone.

Antibiotics targeted to Chlamydia bacteria are also part of the proposed cocktail. At least one study has shown antibiotics may slow progression of mild to moderate Alzheimer’s, but more research is needed. “Our research suggests that treating individuals who have Mild Cognitive Impairment, and those who have newly diagnosed and/or existing Mild AD, with anti-chlamydial antibiotics may have a positive effect by either stopping a trigger for the disease or preventing disease onset in the case of MCI,” Dr. Balin says.

But antibiotics don’t always wipe out C. pneumoniae, and as with other infectious disease, there are worries that the bacterium will become resistant to treatment. These worries have scientists searching for alternative therapies, Dr. Balin says. “The use of more novel anti-infection compounds, and potentially the development of a vaccine for these infectants could result in combating dementia-causing organisms.”

Hopes For Finding And Treating The Causes Of Alzheimer’s

“I believe that we have uncovered a non-conventional infectious agent that likely is
increasing the risk for the development of Alzheimer’s,” Dr. Balin says. “We don’t yet have all the answers. However, there is hope because we are still discovering and studying how this actually works. Similar to how the discovery of a bacterium is the cause of gastric ulcers and some types of gastric cancers, we are hopeful that our findings result in expanded efforts by others to consider how infection may be causing many diseases in the nervous system not currently considered to be infectious. This understanding is vital to proceeding in a rational fashion to treat the problem based on the evidence. This will take us from simply trying to treat the symptoms of disease to actually treating the causes. This is why I have great hope that we will defeat this and other neurodegenerative diseases in our lifetimes.”

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.”

Cholesterol, Statins and Alzheimer's: Part 1 of 3

Summary: Cholesterol is the Anna Nicole Smith of the Alzheimer’s world – it’s always in the news, and its relationships are hard to understand. High cholesterol in mid-life may be a risk factor for developing dementia. Studies on whether cholesterol-lowering drugs called statins can reduce that risk have had mixed results, with more recent research finding no effect. As with the men claiming to be the father of Ms. Smith’s baby, further tests will determine the role cholesterol-lowering drugs will play.

Going through my father’s medical records, I found a 2004 notation from his first neurologist: The recent total cholesterol (on Mevacor) was only 139 (LDL 81). Therefore, the Mevacor will be decreased to 10 mg. daily beginning today.

Mevacor is a statin, prescribed to lower cholesterol levels. But as far as I know, Dad’s cholesterol was always low – why was he taking Mevacor?

In the last few years, headlines on the use of statins to prevent dementia have swung from wild optimism to flat-out skepticism, and it seems Dad was dragged along for the ride.

In early 2000, when Dad started calling himself “stupid,” Loyola University researchers announced their analysis of hospital records showed patients taking statin drugs had a lower prevalence of probable Alzheimer’s. A paper by Boston University scientists that same year showed that British patients taking statins seemed to have a reduced risk of developing dementia. Dad probably saw the headlines: “Cholesterol drug may prevent Alzheimer’s” and “Statins Take On the Brain: Cholesterol-lowering drugs may also treat or prevent Alzheimer's disease.”

By 2001, he was combing through newsletters from Mayo Clinic and Harvard Medical School looking for ways to improve his memory. That year, Finnish researchers at the University of Kuopio published an article in BMJ that seemed to confirm the Alzheimer’s/cholesterol link. In their study of 1449 Finns followed over 21 years, high cholesterol levels at midlife were a risk factor for Alzheimer’s disease later in life. Shortly after that, studies in several labs showed a relationship between cholesterol and beta amyloid plaques and suggested that, at least in a test tube, high cholesterol leads to increased beta amyloid production. Surely the newsletters Dad subscribed to carried stories about these studies.

In 2003 or 2004, his family doctor must have prescribed Mevacor, but none of us know why. Maybe both Dad and his doctor had read about these studies, and agreed to give a statin a try.

By early 2005, Dad wasn’t reading much at all. But when I called to say hi one day, he was exasperated by a headline he’d seen in the local paper. “Did you see that?” he asked. “Now they say those drugs don’t help your brain.” The story was about a study by Johns Hopkins University researchers. After following approximately 5000 people over a period of five years, they found “no association between statin use and subsequent onset of dementia or AD”. Later that year, University of Washington scientists said that their analysis of statin use and dementia prevalence among 2798 participants in the Cardiovascular Health Study showed the use of statins was not associated with decreased risk of dementia. They wrote that the results of their investigation and similar studies depended on how they looked at the data, and that more research is needed.

After these negative results were published, the excitement about using statins to prevent Alzheimer’s had died down. Dad had stopped taking Mevacor anyway, and had definitely developed dementia.

Although statins may not prevent Alzheimer’s, studies are underway to see if they can be used to treat the disease after onset. I’ll write more about that in my next post.

Dreaming About A Cure, Talking About Care: Part 4 of 4 - New Ideas for Care and Cure

Whether we view Alzheimer’s as a disease, or as part of aging, most of us know from personal experience that the way we deal with it is terribly inadequate. In the past three posts, I’ve written about the growing recognition that Alzheimer’s isn’t a single disease, and the controversy about whether we should spend our limited resources on trying to find a “cure.”

Maybe if we give up our fantasies of a single “cure” for Alzheimer’s, we can start talking about better ways to view and treat dementia. These discussions have already begun in labs, at conferences, on email lists, and in homes around the world. While preliminary, they provide us with a glimpse of how Alzheimer’s care might look in the future.

Dr. Peter Whitehouse’s work is an example. Earlier in his career, he focused on drug development. Now he’s more interested in prevention and in intervention studies aimed at improving quality of life for dementia sufferers.

“We need to re-evaluate what’s important,” he says. “Regardless of cure, care needs more attention. Trying to find a cure is part of caring, but there’s an imbalance. We have a great obligation to think clearly about the condition, then do things to improve it. We need to think about ethical considerations – for example, there are still children whose brains are being damaged by lead. Addressing this problem is important for future generations. And instead of focusing on degeneration, we should be focusing on renaissance and legacy.”

Dr. Whitehouse’s recent work includes research on using electronic aids for reminiscence therapies (LifeBook) and archiving individual stories of people’s experiences with disease (including dementia) and medical treatment (StoryBank). His main intervention studies will be at The Intergenerational School, a Cleveland public school serving learners of all ages. He founded the school with his wife Catherine. “The IG school represents one way of pulling it all together,” he says. “Purpose, a sense of community, remaining cognitively active, leaving a legacy, being engaged and valued - these things are much more important to quality of life.”

In labs and at conferences, other scientists are discussing new approaches to Alzheimer’s research, such as more accurate “sub-typing” for identifying different types of dementia, and focusing on investigating potential causes of dementia other than beta amyloid. I’ll write more about this in another post.

And within DASN, members are talking about how to improve care:

- “I think the 'person-centered' model is the ideal for both the care partner and the person with dementia. Each of us has different needs, so no care plan would suit even the majority of folks touched by this disease.” (Shirl Garnett, western Australia, diagnosed with early onset dementia at 59)

Shirl Garnett

- “The mind-body-spirit approaches developed by new age physicians to address those other diseases must be brought to bear on AD. Further, I believe that new era medicine - consciousness and healing - could inform the research being done in the AD research centers and private laboratories.” (Jay Smith, California, diagnosed with early onset Alzheimer’s)

- “Services in the form of support for caregivers and those of us with dementia can often be provided in part by volunteers. I am convinced that there are many more volunteers who are qualified and would contribute if given the opportunity.” (Charley Schneider, Missouri, diagnosed with early onset Alzheimer’s)

- “I think that the key to finding a better medication for treatment and possibly a cure lies in the minds (no pun intended)of those that ARE diagnosed in their 30's, 40's and 50's. If they were open to allowing us to be a part of research in clinical trials I personally think that this would speed up the process for their goal of a cure. So, so many of us work so diligently with great urgency to make this happen as we don’t have the time that the associations and researchers do to plan this all out as our time is running out. Why not focus on those under 50? They might be surprised how much money is saved in research if they would just broaden their horizons so to speak.” (Tracy Mobley, Missouri, diagnosed with early onset Alzheimer’s disease at the age of 38)

Tracy Mobley

- “What makes the best sense of all is empowering people with dementia to care for themselves as much as possible and for as long as possible. People with dementia absolutely can learn some things far into the disease. I truly believe that people with early dementia can be taught to better understand and manage their own disease and behaviors. I further believe that a society which allows people with dementia to stay involved in their chosen activities also prolongs life and emotional health.” (Carole Mulliken, Missouri, diagnosed with vascular dementia)

Dr. Whitehouse sees hope in this kind of open-minded discussion. “If we can think through Alzheimer’s in a deeper way, will have insights into how the brain works. Underneath Alzheimer’s is a re-thinking about what it means to be human, and science’s role in society.”

Dreaming About A Cure, Talking About Care: Part 3 of 4 - The Fantasy of "Cure"

When Dr. Peter Whitehouse of Case Western Reserve University says we should redirect Alzheimer’s funding to emphasize care over “cure,” the idea isn’t very popular (see previous two posts). But he’s not really suggesting we should stop funding research – it’s just that he doesn’t like how that research is presented to the public. “I’m not saying we don’t need bio research,” he explains. “But using the word “cure” is irresponsible.”

“I’m more of a psycholinguist than a physician, so I’m interested in words,” he continues. “In the discourse about Alzheimer’s, our field needs to be more honest. It’s unlikely we’ll fix the problem in the sense of a cure. Care is more complicated to appreciate than finding a drug that blocks pathways, and it involves ethical and cultural implications. It’s easy to say ‘give me half a billion dollars to find a cure,’ but asking for half a billon for better long term care is more difficult. But we keep saying ‘give us more money to find a cure.’ This is a fantasy – people are starting to realize the emperor has no clothes.”
Looking back, I think my dream of finding a cure for Dad really was a fantasy. I kept reading that we were making great progress towards a cure for Alzheimer’s, but the reality was that my father’s doctors were unsure why he had dementia, and unsure what to do about it.

This is part of the massive information disconnect surrounding Alzheimer’s and dementia, and a source of anger for many persons with dementia and their families. I think most of us dealing with dementia can understand the kind of complexity Dr. Whitehouse talks about. We will continue to support both research and care efforts even when the hype about a cure is replaced by careful discussion about how we should view and treat dementia.

“It’s our obligation to think through what “Alzheimer’s” is and how to address it,” Dr. Whitehouse says.

Diabetes and Alzheimer's

I was sorry to hear that Paula Martinac’s father died last month. As she writes in Dementia Blues, he had both diabetes and dementia. Gail Rae Hudson’s (The Mom and Me Journals) mom is a Type 2 diabetic, and has had what Gail refers to as “dementia-lite” since suffering a mini-stroke. “I think that her diabetes is definitely linked to her mental acuity,” Gail emailed me. “The better control we have of her blood glucose levels, the better her mental acuity.”

Bad for your memory?

These connections between insulin problems and dementia in real life are reflected in recent scientific theories and study results:

- Diabetes may increase the risk of Alzheimer’s

- Diet-induced insulin resistance [a condition in which the body fails to properly use insulin] increases beta amyloid production in mice, and is associated with increased memory problems and increased levels of plaque in the brains of these mice

- Alzheimer’s might be a “type 3 diabetes”

- Mutations in the IDE (insulin degrading enzyme) gene are associated with a higher risk of both diabetes and Alzheimer’s

- IDE degrades or decreases both insulin and beta amyloid [the protein thought to cause Alzheimer’s].

Diabetes and insulin resistance are clearly linked to dementia, but no one knows exactly how. Theories about the mechanism by which insulin problems may cause dementia include:

- Insulin affects glucose utilization in the brain [glucose provides the brain’s energy]

- Insulin modulates acetylcholine [a neurotransmitter involved in learning and memory] levels in the brain

- Insulin increases abnormal changes in tau, the protein that makes up the tangles found in neurons in Alzheimer’s brains

- Insulin makes cortisol [a stress hormone, chronically high levels of which are sometimes linked to cognitive impairment] more toxic to neurons

- Insulin increases inflammation in the brain, damaging cells and increasing production of beta-amyloid, which further increases inflammation

- Insulin problems may increase vascular disease, clogging blood vessels, and reducing blood flow to the brain

- Increased insulin uses more IDE, so less IDE is available to degrade the beta amyloid thought to cause Alzheimer’s.

Even before they can understand how insulin problems contribute to dementia, researchers are studying whether diabetes medicines can help treat or prevent Alzheimer’s and dementia. Scientists at the Veterans Affairs Puget Sound Health Care System and the University of Washington found that raising insulin levels in some patients [those without the APOE4 genetic mutation associated with Alzheimer’s] improved their memories. These researchers are also testing nasal insulin in people diagnosed with early Alzheimer’s or Mild Cognitive Impairment. In a small trial, “nasal insulin improved the ability to retain story details about 25 percent,” says Dr. Suzanne Craft, one of the researchers and Professor of Psychiatry and Behavioral Sciences at the University of Washington.

The idea of increasing insulin levels to improve memory seems counterintuitive, since high insulin levels may damage the brain. “In a healthy physiology, optimal levels of insulin that are secreted and cleared quickly are likely beneficial,” Dr. Craft explains. “But excessive or prolonged elevations are likely detrimental because of induction of insulin resistance and inflammation.” So we may need just the right level of insulin to keep our brains humming along.

Scientists are also studying drugs that increase sensitivity to insulin, instead of increasing insulin levels. “It’s too early to tell about the comparative benefits of the two approaches,” says Dr. Craft. Results of one study using this approach were disappointing. A twenty-four week trial of Rosaglitazone, a drug that increases sensitivity to insulin, in people diagnosed with mild to moderate Alzheimer’s disease showed no benefit over placebo. (Trial results did show that the drug may have helped participants who did not have the APOE gene mutation, but this needs further study.)

Even if it’s not clearly effective in treating Alzheimer’s, perhaps this approach will work to prevent mild memory problems from progressing to full-blown dementia. A preliminary study of Rosiglitazone in 30 people diagnosed with Mild Cognitive Impairment showed improvements in memory and attention. Researchers are now recruiting for a larger trial of the drug in people with Mild Cognitive Impairment. The study will measure the drug’s effects on attention and memory in 120 people 55 and older.

Whether or not diabetes drugs are useful in preventing or treating Alzheimer’s, this research shows how important it is to prevent insulin resistance and diabetes. “Our work strongly suggests that preventing insulin resistance by increasing physical activity, optimizing diet and preventing obesity will ameliorate the risk of Alzheimer’s disease, or at least delay onset,” Dr. Craft says.

Antipsychotic Medications and Alzheimer's

Throughout his life, my father laughed away any worries. He never locked doors; he trusted everyone. When lightening struck a transformer ten feet from where he stood, he brushed it off. Nothing kept him awake at night.

But when I visited my parents for Dad’s 73rd birthday last year, he was confused and seemed to be hallucinating. “Where are the others?” he asked over and over. “They were here a little while ago – I’m sure I saw them.” I had flown up by myself, and no one was with us in the house.

Later that week, he told Mom he couldn’t sleep because he thought the vibrating box fan in the doorway of the bedroom was going to attack him. He was upset, and it was hard for my mother to reassure him.

Symptoms like Dad’s are common in Alzheimer’s patients, and add to caregivers’ burdens. According to the U.S. National Institute for Mental Health (NIMH), antipsychotic drugs are widely used to treat psychiatric symptoms in people with Alzheimer’s. More than 27% of patients in American nursing homes receive these drugs, which were initially developed for schizophrenia. But, at least in the U.S., these drugs carry “black-box” warnings that they are not approved for the treatment of patients with dementia-related psychosis.

Results of a five year study of antipsychotic medicines in Alzheimer’s patients were published earlier this month in the New England Journal of Medicine. The “Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Alzheimer’s Disease” study tested three antipsychotic medications against a placebo in 421 Alzheimer’s patients living in their own homes, in family members’ homes, or in assisted living. The medications tested were:

- olanzapine (Zyprexa)
- quetiapine (Seroquel) and
- risperidone (Risperdal).

Input from caregivers was used to help with doctors’ assessments of any improvements or side effects. Although these drugs showed some benefit for some patients, the researchers concluded that “adverse effects offset advantages in the efficacy of atypical antipsychotic drugs for the treatment of psychosis, aggression, or agitation in patients with Alzheimer’s disease.”
Side effects seen in some patients included problems with coordination of movement, sedation, confusion and psychotic symptoms. Antipsychotic medicines have also been shown to increase the risk of developing diabetes and stroke.

Despite recent headlines about this research (“Little Benefit Seen in Antipsychotics Used in Alzheimer's,” etc.), it’s hard to say what the study results mean for each individual patient. Dr. Constantine Lyketsos, Chair of Psychiatry at Johns Hopkins Bayview and Vice Chair of Psychiatry at Johns Hopkins Medicine, co-authored the study. “Neither the CATIE study nor other studies suggest that these medicines shouldn’t be used,” he says. “If you look at the CATIE study, it’s not that the medicines weren’t effective, but the risk/benefit ratio has changed. For the sub-groups of trial participants for whom the medications weren’t discontinued because of side effects, they were more effective than placebo. If a patient’s symptoms are high-risk, then doctors can try antipsychotics with careful safety monitoring. If one of these drugs is well-tolerated, then I can tell you from clinical practice that it’s often effective.”

Constantine (Kostas) G. Lyketsos, M.D., MPH

“I think it would be unfortunate if everyone stopped prescribing any medication solely on the basis of one study,” agrees Dr. Ray Ownby, Professor of Psychiatry at the University of Miami Miller School of Medicine. “Contrary to what many people believe about the study results (and I'll agree that the presentation is confusing), I would not argue that it shows that antipsychotics don't work. It simply shows that antipsychotics aren't enormously effective and that they have lots of side effects. Physicians should prescribe what's appropriate for their individual patients while being aware of the risks and benefits of any given treatment.”

In a “Question and Answer” page on this study, the NIMH recommends caution in prescribing these drugs:

Although some patients may benefit greatly from these medications, the evidence from this study suggests these medications hold limited value for the majority of patients. These results further emphasize the challenge of managing behavioral problems in Alzheimer's patients. Prior to prescribing these medications, clinicians must ensure that agitation or aggression in their Alzheimer's patients are not related to medical, social, or environmental factors (e.g., fever from an infection, side effects from another medication) which might be mitigated without resorting to psychotropic medications.

In a future post, I’ll write about potential alternatives to these drugs, and efforts to develop antipsychotic medications with fewer side effects. But right now, there are no easy answers for doctors or for caregivers.

In the weeks after Dad’s birthday, things got better. Although he was still confused sometimes, he didn’t seem to be hallucinating, and wasn’t as agitated. His doctor thought maybe his symptoms were the result of heat exhaustion (he had mowed the lawn in the summer heat just before these incidents). I now wonder if he’d had a small hemorrhagic stroke that day. If my father had lived longer, he might have gone through more periods when he was anxious, agitated and confused. As the anniversary of his death approaches, we all miss him terribly. But I’m glad we didn’t have to agonize over whether antipsychotic medicines would help him or hurt him.

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.

Q & A With Dr. Tiia Ngandu: The Dementia Risk Score

Last week, I wrote about a dementia risk score developed by researchers at the Karolinska Institute in Sweden. To put the risk score in perspective, I checked in with Dr. Tiia Ngandu, co-author of the risk score article published in the September issue of Lancet Neurology. Here are her answers to my questions:

Tiia Ngandu, Ph.D.
Karolinska Institute (Sweden) and University of Kuopio (Finland)

Q: Some background information: my dad died of a hemorrhagic stroke last November, and his autopsy showed severe cerebral amyloid angiopathy (CAA) along with probable Alzheimer's disease. He had few of the risk factors I think were involved in calculating the "dementia risk score": his cholesterol was always low, he was not at all overweight, his blood pressure was low, he exercised and had 16 years of education. So, in my father's case, anyway, he would have had a low score, and I think would have been a "false negative" in your study.

A: First of all, I would like to say that the aim of our risk score was not to say definitely that someone will develop dementia or someone will not. That would not be possible, since we are dealing with a disease that is as complex and multifactorial as Alzheimer's disease. Those persons who had more risk factors had a higher risk of developing dementia in 20 years time, but even among those who had the worst risk score, only 35 % developed dementia - that is to say that with our score it is not possible to "label" persons into future demented and nondemented. We hope that the risk score will be more used to inform both physicians and patients about the risk factors behind dementia in a very practical way. We believe that the persons with most risk factors and highest risk score might benefit from both lifestyle and pharmaceutical interventions.

Q: Was a fairly homogeneous population used for the study? [I asked this because results from one population may not apply to another.]

A: All the participants are from Eastern Finland, and they were fairly homogeneous population.

Q: Did you differentiate at all among the various types of dementia? What cognitive or other tests were used to detect dementia?

A: We differentiated between different types of dementia. The majority of patients had AD. The Mini Mental State Examination (MMSE) was used as a screening test, and after screening the patient went through both clinical and neuropsychological examinations. Due to the use of MMSE at the screening, we may have missed persons with mild dementia, especially early vascular dementia.

Q: Were there risk factors considered that were not found to be predictive in this study? Smoking? Family history of dementia? Tooth loss? Genetic status?

A: Risk factors that were considered but not found predictive were midlife smoking and diastolic blood pressure. We did not have information on family history of dementia or tooth loss. ApoE4 was predictive in this study and it was included in a second risk score model. (It was left out from the first one because we wanted to include only parameters that are easily available in primary care settings)

Q: What other risk factors may be considered while you refine the scoring process?

A: Other risk factors that should be considered in the future risk scores are at least diabetes and family history of dementia: those factors have quite a lot of evidence behind them at the moment.

Q: I saw an abstract of a presentation by researchers at Kings College London at the recent Alzheimer's conference in Madrid that says that in the Honolulu Asia-Aging Study, "cholesterol levels in men with dementia, and in particular those with Alzheimer’s disease, had declined at least 15 years before the diagnosis and remained lower than men without dementia throughout that period." Do you think this is true in other populations? How might this affect the cholesterol component of your risk score?

A: Some studies have shown that the cholesterol levels (as well as blood pressure levels) decline in demented patients, and that this decline begins already before the diagnosis of dementia can be made. This decline is probably due to the disease process rather than the decline in cholesterol increasing the risk of dementia. In the Honolulu-Asia Aging Study this kind of decline was observed already 15 years before diagnosis. Also the research group from the Honolulu study thought that the decline might be due to early stages of dementia. I don't see that these findings are in any way contradictory to our findings that high cholesterol levels at midlife would increase the risk of dementia. One should keep in mind the trajectories of cholesterol change with aging and in relation to chronic diseases.

Q: The audience for my blog is mostly middle-aged people, many of whom are caregivers for dementia patients. On a practical level, is there anything we should learn from the dementia risk score other than a confirmation that cardiovascular health and education levels appear to be linked to dementia?

A: What I believe that a middle-aged person could learn from our risk score is that there are several things one can do in order to reduce the risk of dementia. Especially the cardiovascular risk factors can be modified with both lifestyles and medications. I think it is quite good news for those who worry that they might become demented and would like to do something to prevent or postpone it. Of course there are still many other and also unknown factors influencing the development of dementia, but we believe that this is a step in the right direction.

Stress, Depression and Alzheimer's, Part 1

For most of his life, my father was calm and happy. “No sweat,” he’d say when the furnace blew up or the car wouldn’t start. Even when his retail lumberyard burned down, or when his parents died, he seemed to take a Zen attitude towards life. But after he retired, I thought he was more pessimistic than usual. Was this somehow related to his later dementia?

I didn’t think much about mood, depression and dementia until I realized it was a topic of discussion on some of the caregiver blogs. In The Yellow Wallpaper, Deb Peterson writes about how her mother’s depression after the death of several family members seemed to mark the beginning of her dementia. Paula Martinac (Dementia Blues) reports both her parents were depressed before their declines into dementia. But many people with Alzheimer’s disease or dementia have no history of depression. Gail Rae Hudson (The Mom & Me Journals), who describes her mother’s condition as “dementia lite,” doesn’t think her mom has ever been depressed.

Was the change in Dad’s mood [I wouldn’t call it depression] a normal reaction to retirement? Or was it an understandable reaction to subtle signs of dementia the rest of us didn’t see? It makes sense that some dementia patients become melancholy when they realize they’re having memory problems.

But rather than dementia causing depression, it seems to be more of a two-way process. Several studies show a history of depression may increase your risk of developing dementia later in life:

• A large retrospective study at the University of Limburg in the Netherlands (published in 1996) and another at the University of Copenhagen in Denmark (2003) found associations between a history of depression and dementia
• When researchers at Rush Alzheimer's Disease Center in Chicago followed Catholic clergy aged 65+ for seven years, they concluded that each depressive symptom reported over the seven year period increased the risk of developing Alzheimer’s disease by an average of 19%, and increased average cognitive decline by 24%.
• Scientists at Boston University School of Medicine found a significant association between depression symptoms and Alzheimer’s in 1953 patients with Alzheimer’s disease and 2093 of their non-demented relatives. The association was most significant when depression symptoms first occurred within one year of the onset of Alzheimer’s, but there was still a modest association even when depression first happened more than 25 years before the onset of Alzheimer’s. [free registration required to view this article]

Other studies have not been as definitive. University of Ottawa researchers found a weak, but not statistically significant association between a history of depression and Alzheimer’s disease after following more than 4600 Canadians aged 65 and older over a five year period.

This year, a team of researchers from the University of Miami Miller School of Medicine and the Wien Center for Alzheimer’s Disease and Memory Disorders at Mt. Sinai Medical Center published the results of a systematic review and analysis of the research on this topic. Analyzing data from over 100,000 patients in 22 studies, the researchers concluded that a history of depression does seem to increase the risk of developing Alzheimer’s, although the absolute risk is still small. Their data also showed relatively long times between depressive episodes and the onset of Alzheimer’s, suggesting that depression may be an independent risk factor for developing Alzheimer’s rather than signaling the onset of the disease.

For dementia patients with a previous history of depression, it’s also likely their dementia will be more severe than that of patients with no such history. In a recent study, pathologists compared the brains of Alzheimer’s patients who had lifelong histories of depression to the brains of Alzheimer’s patients who hadn’t had depression. The pathologists found that the brains of patients with a history of depression had more of the plaques and tangles associated with Alzheimer’s disease than those of patients who hadn’t had depression. This increase in plaques and tangles seemed to correlate with the severity of memory loss.

If depression and Alzheimer’s are linked, then maybe there’s a common underlying cause. Several studies point to cortisol, a stress hormone, as the possible culprit. The thinking is that stress causes the body to release cortisol, and that chronic stress leads to the chronically high levels of cortisol sometimes associated with cognitive impairment and shrinkage of some areas of the brain.

The obvious question is whether lowering cortisol improves memory. I’ve always had trouble navigating, and this problem gets worse when I’m upset. Could I take something to lower my levels of this hormone before I drive an unfamiliar route? It turns out that for rats, lowering cortisol levels does improve their performance in mazes.

I was disappointed to find it’s not so simple for humans. In a small trial of seventeen people, a team headed by researchers from McGill University in Canada found that manipulating cortisol levels did have an effect on memory in some people, but that effect was dependent on historical cortisol levels in each participant or person. If the individual patient had had moderate cortisol levels for a period of five years, blocking cortisol levels actually decreased memory, and adding back cortisol reversed this problem. For patients with historically high cortisol levels and existing memory problems, blocking cortisol didn’t improve memory, although increasing cortisol levels made their memory problems worse. This could be because it’s the cumulative, long-term exposure to high levels of cortisol that hurt the brain, rather than the level at any one time. Some scientists think problems are caused by the malfunctioning of the receptors for cortisol, rather than the hormone itself.

So, the cortisol and stress connection is intriguing, but at least so far, hasn’t yielded the magic formula to fix dementia.

One of reasons it’s hard to untangle the relationship of depression and dementia or Alzheimer’s disease is that both diseases may have multiple underlying causes. “I think the evidence shows that there may be complex relationships among stress, cortisol (and other neuroendocrine substances), inflammatory markers, cardiovascular disease, and cognition,” says Dr. Ray Ownby, Professor of Psychiatry at the University of Miami Miller School of Medicine and the lead author of the scientific review of research on the topic. “Since cardiovascular disease may be related to Alzheimer's disease, it seems quite possible that stress, cortisol, inflammation, depression, and AD may all be related, but we don’t know how.”

Raymond L. Ownby, M.D., Ph.D., M.B.A.

But even if stress, cortisol and depression were only partially responsible for dementia, could they be considered “modifiable risk factors” for Alzheimer’s disease? I asked Dr. Ownby if treating depression could actually lessen a person’s chances of developing dementia.

“The possibility that treating depression might lower your risk for Alzheimer’s disease is intriguing,” he says, “but there simply isn't any evidence that I'm aware of on the subject, other than the possibility that antidepressants can lower levels of some chemicals that may be related to dementing illnesses.”

What about the idea that depression can masquerade as dementia? When I first started researching my father’s memory problems, several web sites mentioned “pseudo-dementia.” According to some of these sites, once you treat the depression, the dementia is reversed. But the diagnosis and prevalence of pseudo-dementia is now in question, and at least one study has shown that many people who seemed to have reversible dementia [their memory problems improved after their depression was treated] later developed [non-reversible] dementia.

Dad didn’t have a history of depression, and it’s pretty clear most of his dementia was related to cerebral amyloid angiopathy. But if he had lived long enough, depression might have been more of a problem. Treating any depression may have helped his dementia, at least for a while. I’ll talk more about that in my next post.

Dementia Paranoia and the Dementia Risk Score

When it was clear my father had dementia, I started to wonder about my own memory.  I've had trouble finding words in the last few years.  Just this week, I couldn't retrieve the word "charger" from my brain's database for two days.  The fact that I couldn't remember the word for a large decorative plate wasn't life-threatening, but it bothered me.  I'm starting to have problems navigating familiar streets, and appointments and must-do items seem to fall off my radar screen altogether.  Last night I left a carton of ice cream in the microwave instead of in the freezer.

I blame my memory problems on several factors:  lack of sleep, the stress of Dad's illness and death piled on top of other family crises, and trying to keep up with more people than any human was meant to know.

But I worry that these are the first signs of my cognitive decline.  Maybe next month I'll have trouble balancing my checkbook, and in December won't be able to match names to faces.  By spring, I could be in a nursing home.  Dementia paranoia is setting in.

Dementia paranoia changes how I see things.  Take the dinner we gave for a family member's 85th birthday the other night - a nice event by any standard.  But during the dinner, my fiance John triggered my problem with the word "charger" by calling the decorative plate a "racer."  I figured this was a sign he's also on the track to cognitive dysfunction.  While John was mumbling about "rac