More hereditary risk factors for Alzheimer's disease identified

Alzheimer’s disease is a hereditary condition. About 60% of the risk for the degenerative brain disease is thought to be genetic, based on the results of twin studies. The best known evidence of this is a gene called apolipoprotein E. People with a variant called APOE e4 are more likely to develop Alzheimer’s. But what accounts for the rest of the risk?

A study published in today’s edition of Archives of General Psychiatry helps fill in those gaps.

A team of Dutch researchers compared 206 middle-aged adults whose parents had late-onset Alzheimer’s to another group of 200 similarly aged adults with no parental history of the disease. They found that both groups had much in common, including levels of smoking, physical activity and intake of dietary fat. But there were significant differences in various measurements of blood pressure and inflammation.

For instance, the children of Alzheimer’s patients had higher systolic and diastolic blood pressure, and 40% of them had hypertension, compared with 29% of those in the control group. The Alzheimer’s offspring also had a lower ankle brachial index -- a comparison of resting blood pressure in the ankle and arm that is a sign of peripheral artery disease.

The researchers tested blood samples from both groups and found that the children of Alzheimer’s patients had significantly higher levels of several kinds of proinflammatory cytokines. Since these markers typically circulate at very low levels, the researchers said they are probably a consequence of the disease rather than a cause.

As expected, the APOE e4 variant was more common among the Alzheimer’s offspring (46.5%) than in the controls (21%). (Surprisingly, the researchers noted that APOE e4 carriers in both groups had nearly one less year of education compared with those who had other versions of the APOE gene.)

The study didn’t offer new clues about how these vascular effects and inflammatory markers may contribute to Alzheimer’s, but it did end with some hope for families dealing with the disease: If adult children of Alzheimer’s patients were screened for problems such as high blood pressure and treated when necessary, they might be able to prevent the disease altogether.

-- Karen Kaplan

Retired NFL players have high rate of brain damage

Retired National Football League players have five times the normal risk of developing Alzheimer's disease and other forms of dementia, according to a study prepared for the league and, apparently, leaked to the New York Times. The illness is presumably the result of repeated blows to the head suffered during games. According to a telephone survey of retired players and/or their caretakers, 6.1% of retired players over the age of 50 had such a diagnosis, compared with the widely published estimates of 1.2% in the population at large. For younger men, age 30 to 49, the diagnosis was 19 times more common: 1.9% in retired players compared with 0.1% in the population at large, according to the study conducted by the University of Michigan's Institute for Social Research. The study was distributed to league officials earlier this month, but has not been released publicly and not published in a journal.

The findings correlate well with previous studies. The league has largely ignored those earlier studies, however, saying it needed to perform its own. Now that it has, players are waiting to see what action it will take to minimize future risks.

-- Thomas H. Maugh II

Rodent of the week: Sleep loss linked to Alzheimer's

Chronic sleep loss may play a role in the progression of Alzheimer's disease, according to researchers using a mouse model.

Researchers found that mice that were chronically deprived of sleep had more plaques and developed them earlier compared with mice that slept normally. Plaques, a hallmark of Alzheimer's disease, are made up of amyloid beta protein. The study also showed that the protein orexin, which helps regulate sleep cycles, appears to be involved in the process.

The research team, led by Dr. David M. Holtzman of Barnes Jewish Hospital and Washington University in St. Louis, monitored levels of beta amyloid in mice that were genetically engineered to model Alzheimer's disease. Investigators found that the amount of brain amyloid beta rose and fell in association with sleep and wakefulness (with lower levels during sleep). They then used electroencephalograph  scans to show that mice who stayed awake longer had higher amyloid beta levels. Depriving mice of sleep caused a 25% increase in levels.

Finally, when the scientists injected orexin into the brains of mice, they stayed awake longer and amyloid beta levels increased.

The results suggest that sleep loss may play a role in development of Alzheimer's disease, which affects 39 million Americans, and that treatments to promote sleep may be helpful.

"Orexin or compounds it interacts with may become new drug targets for treatment of Alzheimer's disease," Holtzman said in a news release. "The results also suggest that we may need to prioritize treating sleep disorders not only for their many acute effects but also for potential long-term impacts on brain health."

The study was published Thursday in the journal Science Express.

-- Shari Roan

Photo: Advanced Cell Technology Inc.

Problems handling money can precede Alzheimer's

For people with mild signs of dementia, problems with managing money may be a clue that memory problems are developing into Alzheimer's disease, according to a study published today in the journal Neurology.

The study found that tasks people have performed for their entire adult lives, such as managing a checking account, often become too complicated in the early stages of Alzheimer's disease. The study involved 76 people with no memory problems and 87 older people with mild problems described as mild cognitive impairment. The participants were given a money management test at the beginning of the study and again one year later. The test included counting coins, making grocery purchases, understanding and using a checkbook, understanding and using a bank statement, preparing bills for mailing and detecting financial fraud situations.

After one year, 25 of the 87 people with mild cognitive impairment had developed Alzheimer's disease-type dementia. The people with no memory problems and those with mild cognitive impairment who did not develop dementia maintained the same test scores one year later. But the people who had developed dementia scored lower on the initial test and dropped by 9% on their scores for checkbook management skills one year later. These participants, for example, wrote out the check correctly but failed to calculate the balance after making the transaction.

Changes in money management skills are detectable, and caregivers and doctors should watch older people with mild cognitive impairment for signs of problems in this area, said the authors of the study, from the University of Alabama, Birmingham.

"Caregivers should consider overseeing a person's checking transactions, contacting the person's bank to find money issues such as bills being paid twice, or become cosigners on the checking account so that both signatures are required for checks written above a certain amount. Online banking and bill payment services are also good options," the lead author of the study, Daniel Marson, said in a news release.

The number of people with dementia is expected to reach 35 million worldwide next year, according to a report released today from Alzheimer's Disease International in London. The figures are higher than a 2005 estimate published in 2005 in the Lancet. But the new data better reflect dementia rates in Western Europe, South Asia and Latin America. According to the report, dementia prevalence will nearly double every 20 years, to 65.7 million in 2020.

-- Shari Roan

Photo credit: Justin Sullivan  /  Getty Images

 

New genes linked to Alzheimer's

European researchers have found three new genes linked to an above-normal risk of developing Alzheimer's disease, according to a report in the Washington Post. Cumulatively, the three genes contribute about 22% of the overall risk of developing the disorder, the researchers reported in the journal Nature Genetics.

The most important gene previously linked to Alzheimer's is a mutation in the gene coding for apolipoprotein E or APOE, which leads to the overproduction of amyloid protein in the brain, damaging nerve cells. The normal function of the new genes appears to be shepherding excess amyloid protein out of brain cells. When they malfunction, the amyloid builds up faster.

The discovery has little immediate practical benefit. It cannot be used to screen for an increased risk of the disorder and it most likely does not present any therapeutic targets. But every little bit learned about the disorder contributes to long-term efforts to develop new preventive measures and therapies. The urgency of the search is accentuated by the prediction that at least 120 million people worldwide will suffer from Alzheimer's by 2050. There are currently no effective treatments for it--only drugs that can delay its effects briefly.

-- Thomas H. Maugh II

Obesity linked to brain shrinkage, erectile dysfunction

The L.A. Times' science and health staff has recently been accused of an ongoing campaign against fat people. Commenting on a post Monday, reader Big Jim Slade predicted "tomorrow we'll have another fat assault on how breathing the same air as fat people is dangerous...Maybe we should waterboard them, eh?"

Don't shoot us, Big Jim: We're just the messengers!

But for those of you who share Big Jim's sense of persecution, let me say, I feel your pain. If you think it's hard reading our drumbeat of reporting on the health effects of obesity, imagine what it's like for, say, a significantly overweight health reporter to write this stuff on a daily basis. (Trust me, I'd rather be at the gym--though a controversial recent report suggests that won't help me lose any weight either.)

Which brings me to the latest crop of bad news on being obese--and there is just no way to sugarcoat this pair of studies, my friends: being fat makes your brain shrink and, if you are a man, your penis limp.

A new brain-imaging study by researchers at UCLA and the University of Pittsburgh finds that the brains of overweight and obese subjects were on average 4% and 8% smaller, respectively, than the brains of those who were at a healthy weight--evidence, according to UCLA neurology professor and study author Paul Thompson, of "severe brain degeneration."

For the obese--those with a BMI over 30--the news is particularly bad: the areas of significant observed shrinkage were the frontal temporal lobes, the seat of higher-order reasoning and judgment; the anterior cingulate gyrus, key to attention and decision-making as well; the hippocampus, where long-term memories are processed, and the basal ganglia, from which smooth movement is initiated.

Overweight people--those with a BMI over 25--also had shrinkage in the basal ganglia, as well as in the parietal lobe, where we integrate sensory input and position ourselves in space, and in the brain's white matter, which helps speed messages among regions of the brain that must work together for us to function properly.

After virtually weighing and measuring the brains of 94 subjects over age 70, the study authors concluded that the brains of the overweight appeared, on average, eight years older than those of subjects at healthy weight. Brains of the obese appeared 16 years older. While the subjects scanned in the study showed no outward signs of cognitive impairment at the time of the study, the study's authors predicted the premature aging and loss of brain volume they observed would put heavier subjects at greater risk of Alzheimer's disease and other degenerative brain diseases.

Why? Because a big, robust brain under attack by these diseases can often compensate for their ravages for some time--forestalling the onset of symptoms. But a shrunken brain is not so resilient. Memory loss, movement problems and cognitive deficits are far more likely to show up early for overweight and obese patients. This study is published online in the journal Human Brain Mapping.

The current issue of the "journalzine" Obesity and Weight Management--free online this month-- explores another, better-known fellow-traveler of obesity: erectile dysfunction. Erectile dysfunction is a common side effect of high blood pressure and atherosclerosis. Those conditions can lead to blockage of the major arteries that lead to the brain and the heart, causing stroke and heart attack, respectively. But they also can lead to "microvascular disease," including erectile dysfunction, say University of Colorado physician Adam Gilden Tsai and the University of Pittsburgh's Adam Sarwer.

Tsai and Sarwer present the case study of a 48-year-old man whose BMI is 32.6--considered "mildly obese," with erectile dysfunction that is not relieved by the use of tadalafil, the erectile dysfunction medication better known as Cialis.

There is, at least, some good news: A study expected to be published next month in the Lancet by the UCLA-Pitt researchers that observed brain shrinkage is expected to suggest that physical exercise can help spare even the obese some of the consequences of their excess weight. And, the patient with erectile dysfunction was medicated for his high blood pressure and, after dietary counseling, lost 4.6% of his body weight--just under 10 pounds. "The patient has been able to achieve adequate erections with the use of ED medication as needed," the authors report.

Now that's a happy ending.

-- Melissa Healy

For Alzheimer's patients, connection with caregiver might rival drugs

The goal of most Alzheimer's research is a drug that could stop the disease -- or prevent it or slow it or, frankly, do much at all. So researchers are furiously crafting new concoctions, retrying existing compounds in new ways and exploring new treatment targets all in their efforts to thwart the progressive, debilitating disease -- and yet their prize remains solidly out of reach for the immediate future. But what if simple, old-fashioned caregiving could slow the course of the disease? And what if it could do it just as well as some existing drugs?

It might.

New research indicates that a truly close relationship with a caregiver can give Alzheimer's patients an edge in retaining brain function over time. In a study of 167 pairs of caregivers and Alzheimer's patients, those patients who had rated their relationship with their caregiver as especially close kept more of their cognitive and functional abilities over the course of the study (up to four years).

The caregivers studied included spouses, adult children and adult children-in-law. Those patients cared for by close spouses fared the best, with changes similar to what would be expected if they'd been taking drugs known as acetylcholinesterase inhibitors (these drugs include Aricept, Exelon and Razadyne).

The study was funded by the National Institute on Aging and conducted by researchers at Johns Hopkins and Utah State University. It's to be published in the September issue of the Journals of Gerontology Series B: Psychological Sciences and Social Sciences. Here's the release.

And here are two recent Booster Shot posts from staff writer Shari Roan about medical attempts to thwart the disease: A puzzling finding for promising Alzheimer's drug... about dimebolin's effect on beta amyloid in the brain. And A new Alzheimer's treatment in an old remedy... about the possibility that intravenous immunoglobulin might help prevent or treat the disease.

For a broader look at the disease from a special Health section in November, all from staff writer Melissa Healy, there's: Memory loss: What's normal? What's not?; Early warning signs of Alzheimer's disease; The case for early diagnosis of Alzheimer's; and Bad health habits and lifestyle choices are among Alzheimer's causes.

Plus, here's an overview of current treatments from the Alzheimer's Assn.; a caregiver guide from the National Institute on Aging; a collection of resources and advice from Medline Plus, part of the National Library of Medicine; and a blog from Sherri, who's been there.   

She writes in a recent post: "When you provide long-term care for someone suffering from a debilitating illness like Alzheimer’s, the journey is not a sprint – it’s a cross country trek that most are not trained and prepared for."

-- Tami Dennis

Photo: Emotional intimacy seems crucial.

Credit: Los Angeles Times

A new Alzheimer's treatment in an old remedy?

Given the difficulty of finding medications to prevent and treat Alzheimer's disease, wouldn't it be terrific if a remedy were found among established therapies?

That is a possibility. According to a study published in the new issue of the journal Neurology, people who receive intravenous immunoglobulin (IVIg) treatments for conditions such as leukemia, anemia and other diseases seem to have lower rates of developing Alzheimer's disease. Intravenous immunoglobulin treatments contain healthy antibodies that are infused into the blood stream to boost a person's immune system.

The study compared 847 people who were given at least one treatment of intravenous immunoglobulin over four years and 84,700 similar people who were not given the treatment. The records were pulled from a database of 20 million people age 65 and older. Those who received the immunoglobulin had a 42% lower risk of developing Alzheimer's disease over four years compared to those who did not receive the drug.

"These findings do not constitute an endorsement of IVIg treatment for Alzheimer's disease," the researchers said. "A large-scale clinical trial is underway to determine whether IVIg could be an effective treatment for Alzheimer's."

Immunoglobulin may target the plaques in the brain found in Alzheimer's disease.

-- Shari Roan

Older people get a brain boost from exercise, but too much might be a bad thing

Most people hit the gym, bike path or track because of what it does for their bodies. But regular physical activity may have brain benefits as well.

Two studies recently presented at the Alzheimer's Assn.'s International Conference on Alzheimer's Disease in Vienna this week showed how exercise provides a boost to mental acuity. In one, researchers looked at physical activity and results from a cognition test in 3,075 men and women aged 50 to 79 who were part of the Health, Aging and Body Composition Study. Their levels of physical activity (determined by how many minutes they walked per week) and cognitive function were noted at the beginning of the study and at two, four and seven years. Those who didn't develop dementia and maintained or increased their levels of exercise had substantially lower rates of cognitive decline than those who were more sedentary, or saw their physical activity decline.

In another study, 90 women aged 60 to 63 were asked to report how much strenuous and moderate recreational activity they did from high school through menopause. The women were also given neuropsychological tests that measured memory and frontal lobe function.

Those who engaged in more moderate activity did better overall on brain function tests, and those who did more strenuous exercise throughout the years performed more poorly on the tests. Researchers noted that though long-term strenuous exercise has a protective effect for breast cancer, it could have harmful effects on cognition, although larger-scale studies are necessary to better understand the implications for recommending activity and lifestyle regimens.

-Jeannine Stein

Photo credit: Stephen Osman / Los Angeles Times

A puzzling finding for promising Alzheimer's drug

Many researchers believe that one way to treat symptoms of Alzheimer's disease is with drugs that reduce a substance called beta amyloid. This is a protein that is the main constituent of plaques found in the brains of people with the disease.

But in a surprising finding presented Wednesday at the Alzheimer's Assn. 2009 International Conference in Vienna, researchers discovered that a promising medication in phase-3 testing in the United States, called dimebolin or Dimebon, actually increases beta amyloid in the brain in animal models.

"This result is highly unexpected in what may prove to be a clinically beneficial Alzheimer's drug," Dr. Samuel Gandy, the lead author of the study, said in a news release. "We need more research to further clarify how dimebolin affects beta amyloid levels in the brain."

Previous studies show that Dimebon, which was used for years in Russia as an antihistamine, appears to help people suffering from mild to moderate Alzheimer's disease symptoms. In June, enrollment was completed for a six-month pivotal trial of the medication. The manufacturer, Medivation Inc., has announced it hopes to file a new drug application for Dimebon in 2011.

Researchers can't explain why Dimebon appears to be helpful even though it increases beta amyloid. It could be the drug's beneficial powers have nothing to do with amyloid. This theory would point to a new avenue of drug targets for treating Alzheimer's disease.

In other news from the Alzheimer's meeting:

A large study of people with mild cognitive impairment showed that the combination of cognitive tests and brain scans can be used to predict the development of Alzheimer's disease.

Researchers at UC Berkeley studied 85 people with mild cognitive impairment. Those with low scores on a memory recall test and low glucose metabolism in a particular brain region (measured by PET scan) had a 15-times greater risk of developing Alzheimer's disease within two years of the study compared with the other participants.

"By the time a patient is diagnosed with Alzheimer's disease, there is usually little one can do to stop or reverse the decline," Dr. William Jagust, the principal investigator of the study, said in a news release. "Researchers are trying to determine whether treating patients before severe symptoms appear will be more effective, and that requires better diagnostic tools than what is currently available."

Several studies have found that middle-age people who have moderate alcohol intake, such as a glass of wine a day, receive some long-term protection against cognitive decline and dementia in old age. A new study, the largest and longest to examine regular alcohol intake on dementia in seniors, has found that this protection also applies in old age. But there is one important exception: People who already have mild cognitive impairment might fare worse if they drink alcohol.

The study examined 3,069 people ages 75 and older about their drinking habits. The participants were examined and interviewed every six months for six years. The study showed that in people with no cognitive impairment at the start of the study, drinking eight to 14 alcoholic beverages a week resulted in a 27% reduction in the risk of developing dementia compared with people who did not drink at all. But for older adults with mild cognitive impairment, any consumption of alcohol was linked to faster rates of cognitive decline. People with mild cognitive impairment who were heavy drinkers were almost twice as likely to develop dementia compared with non-drinkers with mild cognitive impairment.

"Our results suggest that older adults who are normal cognitively and drink moderately do not need to change their drinking behavior," the lead author of the study, Dr. Kaycee Sink, said in a news release. "If you have mild cognitive impairment, however, it might benefit you to restrict your drinking and certainly not exceed one drink a day for women and two drinks a day for men."

-- Shari Roan

Photo: Steve Osman / Los Angeles Times