By LAURAN NEERGAARD, AP Medical Writer – Mon Aug 9, 2:24 pm ET

WASHINGTON – Doctors can’t tell if Leif Utoft Bollesen’s mild memory loss will remain an annoyance or worsen, but experimental
checks of the Minnesota man’s aging brain may offer clues.

About 1 million people a year begin a mental slide called mild cognitive impairment, or MCI, with forgetfulness that’s somewhere between healthy aging and Alzheimer’s disease. Now this gray zone is undergoing an evolution, with growing study of techniques to help predict which MCI patients may be on a path to later dementia — and who shouldn’t worry.

Many doctors aren’t waiting. A study published in the journal Neurology last week found 70 percent of neurologists say they prescribe Alzheimer’s medications to at least some of their MCI patients, hoping the drugs will slow their decline. That’s a startling number considering there’s no proof yet the drugs can do that even if doctors knew who’s most at risk.

Still, it’s becoming more and more clear that Alzheimer’s starts ravaging the brain at least a decade before memory problems appear. Thus stalling it may require treating the earliest symptoms, just as preventing a stroke begins with treating high blood pressure.

But to discover an early-stage therapy requires first discovering whose MCI really is pre-Alzheimer’s.

So when the National Institute on Aging and the nonprofit Alzheimer’s Association proposed new guidelines for diagnosing both full-blown Alzheimer’s dementia and that confusing MCI, they went an extra step. The draft also offers a roadmap for researchers testing new technology to help separate out the different types of MCI.

On the list: experimental PET scans that check for abnormal brain buildup of an Alzheimer’s-linked gunk called beta-amyloid. Bollesen, 78, is getting that and other brain scans at the Mayo Clinic in a large study hunting for patterns that predict progression.

The retired teacher gets embarrassed by his main MCI symptom — forgetting the names of longtime colleagues — but says he doesn’t worry about getting worse.

“They haven’t told me what I can expect in the future. … I’ll think about it when they bring it up,” says Bollesen, 78, of Rochester, Minn. If he does worsen, he figures the researchers “may have ideas of things I could be doing to delay it.”

Here’s the rub: Those technologies are becoming more available for use outside of strict research studies. Already, doctors at specialized medical centers can use MRIs to measure shrinkage of a brain region called the hippocampus. They can give spinal taps to look for that gooey amyloid in cerebrospinal fluid.

Soon, even the full-brain amyloid scans will be more available, says Dr. David Bennett, director of Rush University Medical Center’s Alzheimer’s program in Chicago.

Patients “want to know what’s going to happen to them,” says Bennett, who tries to redirect patients already demanding those test, or anti-Alzheimer’s medications, into clinical trials.

Scientists haven’t proven when a bad test result really means brewing disease, or even if you can believe a bad test result. Those spinal fluid measurements, for example, can vary as much as 30 percent from one sophisticated laboratory to another, says Dr. Marilyn Albert of Johns Hopkins University.

“The last thing in the world you want to do is tell someone they’re destined to have Alzheimer’s dementia when they’re not,” cautions Albert, who co-authored the draft guidelines and doesn’t want doctors jumping the gun.

And just harboring amyloid alone doesn’t mean pending dementia, as autopsy studies suggest a quarter of elderly people who die without memory problems may harbor the buildup, adds Mayo’s Dr. Ron Petersen, who helped to first define MCI.

“Would I like to have amyloid in the brain? No, not particularly but it doesn’t necessarily mean I’m going to become clinically demented in my lifetime,” Petersen says.

For now, diagnosing MCI requires a good medical history and standard memory tests. MCI is more than every so often losing your car keys or struggling for a word, but not serious enough to interfere with independent functioning. Worsening of episodic memory — recalling new information — is seen more than other types of memory loss in MCI that progresses to Alzheimer’s, say the draft guidelines, which will be finalized later this year.

Like so many with MCI, forgetting names sent Mac McNellis of Chicago to the doctor nine years ago. He feared the dementia his mother had suffered in her 90s, but he was relieved to learn he had MCI. McNellis enrolled in a study at Rush that scans his brain annually, and researchers advised mental and physical exercise.

Now 85, he plays golf and cards, and is a pro at Sudoku and intricate woodworking. Then last fall, he experienced a new MCI symptom — getting frustrated in unfamiliar places — and began an Alzheimer’s drug in hopes of slowing further decline.

“I just go with the flow,” McNellis says.

But his wife, Gerry, says learning about MCI early was a big help.

“Staying active was probably the most important thing,” says Gerry McNellis. “Fear of the unknown I think can really be detrimental. If you have an idea that there are some things that can be done within your own power, it’s really helpful.”
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EDITOR’S NOTE — Lauran Neergaard covers health and medical issues for The Associated Press in Washington.
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Online:
Alzheimer’s Association study info: http://www.alz.org/research/clinical_trials/find_clinical_trials_trialmatch.asp
Draft guidelines: http://www.alz.org/research/diagnostic_criteria/

SOURCE: http://news.yahoo.com

Alzheimer’s disease may be linked to an increased risk of anemia, new study findings suggest.

Australian researchers analyzed hemoglobin, iron and other blood-based measurements in 211 Alzheimer’s patients, 133 people with mild cognitive impairment (MCI) and 768 healthy people. They compared these measurements to tests of participants’ short- and long-term memory and cognitive abilities.

Compared to the healthy people, Alzheimer’s patients had significantly lower levels of hemoglobin, mean cell hemoglobin concentration, and packed cell volume, the investigators found. The Alzheimer’s patients also had a significantly higher erythrocyte sedimentation rate, a possible sign of anemia.

Participants with anemia were 2.56 times more likely to have Alzheimer’s disease, while those with Alzheimer’s were 2.61 times more likely to be anemic, the researchers noted in a news release from the Alzheimer’s Association.

“In our population, we found that people with Alzheimer’s disease were more likely to be anemic, and this was not explained by dietary iron deficiency. This suggests that hemoglobin production is deficient in Alzheimer’s patients,” Noel Faux, of the Mental Health Research Institute in Parkville, Australia, explained in the news release.

“Alzheimer’s had not previously been recognized as a risk factor for anemia, which is a common clinical problem for the elderly and can contribute to problems such as heart failure and renal failure. The cause of anemia in Alzheimer’s is still uncertain, but we speculate that Alzheimer’s is a disease that affects both brain and blood. We are currently investigating this intriguing possibility,” Faux added.

The study was slated to be presented Tuesday at the Alzheimer’s Association International Conference on Alzheimer’s Disease, in Honolulu.

More information

The U.S. National Heart, Lung, and Blood Institute has more about anemia.

SOURCE: www.everydayhealth.com

(CBS) If you needed another reason to brush and floss, maybe this will help.

Researchers at New York University have found that gum disease may increase the risk of cognitive dysfunction associated with Alzheimer’s disease.

This NYU study provides fresh evidence that gum inflammation is associated with inflammation in the brain.

The research team, led by Dr. Angela Kamer, assistant professor of periodontology & implant dentistry, studied 20 years of data from Denmark that support the hypothesis of a link between periodontal disease and Alzheimer’s.

Those with gum disease at age 70 were nine times more likely to test in the lower range of brain function tests compared to those with little or no periodontal inflammation.

Other health factors that tend to lower test scores, such as obesity, cigarette smoking, and tooth loss unrelated to gum inflammation, were factored in, but the strong association held true.

Kamer is working on a follow-up study, which will include a more ethnically diverse pool of people.

But why wait follow-up–go brush your teeth!

SOURCE: www.cbsnews.com

Toronto scientists test whether noodle-thin metal rods buried beneath the cortex can jolt memories and repair faulty nerve circuits

Carolyn Abraham

A team of Toronto scientists is pushing Alzheimer’s research in a radical new direction – testing whether electrodes implanted in patients’ brains can jolt their memories into good working order.

The procedure, known as Deep Brain Stimulation, aims to repair faulty nerve circuits with steady electrical pulses from two noodle-thin metal rods buried beneath the cortex. It is most often used to treat chronic pain, Parkinson’s disease and in research against intractable depression.

But at the University Health Network – after an intense 18-month ethics review – researchers have performed DBS as an experimental brain surgery on six men and women in the early stages of Alzheimer’s disease.

The small, world-first trial – published Wednesday in the Annals of Neurology – found DBS is a relatively safe procedure for people with Alzheimer’s, which affects about 500,000 Canadians. But no one knows yet if it will also prove to be an effective one. After a year of stimulation, two patients deteriorated, two showed no change, while two improved.

Exactly how or why electricity might bolster a brain struck with Alzheimer’s, however, is as mysterious as the disease itself – which after more than 100 years of study, still defies explanation. But the Toronto research team feels the phase-one results are promising enough to pursue a phase-two study, and now hopes to find funding to test DBS in another 50 early Alzheimer’s patients.

“This has to be pursued to find out if it is valuable or not,” said Dr. Andres Lozano, the neurosurgeon and senior scientist who led the study at Toronto Western Hospital. “It’s not more of the same, it’s a very bold, aggressive approach that seems reasonably safe.”

SOURCE: www.theglobeandmail.com

Scientists at the University of Lethbridge say they have successfully regrown adult brain cells in tests on mice, a breakthrough that could lead to treatment of neural diseases such as Alzheimer’s.

“We’re pretty excited by it,” said Dr. Robert Sutherland, who led the five-year project at the Canadian Centre for Behavioural Neuroscience.

“In just the same way as people have been able to regenerate pieces of skin that have been damaged, we’ve been able to do that in a part of the brain,” Sutherland told CBC News.

In the study, brain cells were destroyed in mice, which were then treated with a naturally occurring growth factor and behavioural and memory exercises.

According to Sutherland, the three-part treatment allowed the cells to regrow, and after six weeks of treatment, those rats fared just as well as those in a control group.

“We discovered the memory disorder [in the mice] was reversed,” Sutherland said. “It was gone. The memory was as good as normal.”

Dr. Simon Spanswick, one of the primary researchers involved in the project, said the implications of the cell regrowth research are vast.

“Things like Alzheimer’s disease, a number of memory diseases … dementia for example, Parkinson’s disease, what we’ve discovered will be part of a treatment process for these disorders,” he said.

Researchers couldn’t say when their research can start to be applied to humans. However, the Canadian Institute for Health Research has renewed funding for the research for another five years.

Read more: http://www.cbc.ca/health/story/2010/07/31/cgy-alzheimers-breakthrough.html

SOURCE: www.cbc.ca

Alzheimer patients have high accumulations of the beta-amyloid – appearing in the form of plaques – in their brain. The precursors of these plaques are thought to be the underlying cause of the nerve cell loss that leads to Alzheimer’s. Now scientists have identified an enzyme, alpha secretase, which cleaves the amyloid precursor protein (APP) without forming beta-amyloid.

The work, by researchers at the German Centre for Neurodegenerative Diseases (DZNE) and Ludwig Maximilian University of Munich (LMU), appears in EMBO Journal.

The research team has now been able to show that the enzyme ADAM10 alone is responsible for the specific cleavage. Dr. Stefan Lichtenthaler and his team developed highly specific antibodies that can identify the different cleavage products of the precursor protein in the brain cells of mice and in human cell cultures.

Using a special technique called RNA interference, the researchers managed to block each of the three genes that code for the three ADAM enzymes under suspicion. An analysis of the cleavage products revealed that the ADAM10 gene was the only one able to prevent the formation of beta-amyloids. They confirmed their results using mass spectrometry.

“In ADAM10 we have identified a target molecule that plays a central role in the development of the molecular processes in Alzheimer’s disease. We know that ADAM10 is less active in Alzheimer patients,” said Dr. Lichtenthaler. When ADAM10 is less active, the precursor protein is more likely to be cleaved in a way that promotes the formation of beta-amyloids.

“It is possible that less ADAM10 activity could increase susceptibility to Alzheimer’s disease. If that is the case, stimulating ADAM10 could be an important mechanism for therapy. But our antibodies also open up new possibilities for diagnosing and preventing the disease,” said Lichtenthaler.

The antibodies could be used to measure ADAM10 activity in spinal fluid and, by extension, identify persons who may have an increased risk of developing Alzheimer’s disease. A series of experiments to examine this possibility is already underway. (ANI)

SOURCE: http://sify.com

Over the past 20 years, scientists have learned that proteins called sirtuins play a vital role in longevity and stress response in organisms as diverse as humans, yeast and mice. A new paper from MIT biologists now reveals a surprising additional role for sirtuins: They appear to suppress the production of amyloid beta proteins, which form plaques in the brains of Alzheimer’s patients.

The finding, reported in the July 23 issue of Cell, suggests that targeting sirtuins could offer a promising new approach to treating Alzheimer’s, says Professor Leonard Guarente, leader of the research team.

Guarente and his colleagues showed that boosting the activity of a sirtuin called SIRT1 stifled the production of amyloid beta proteins and enhanced brain function in mice engineered to express Alzheimer’s symptoms. This marks the first time sirtuins have been linked to those proteins.
Several drug companies are now developing and testing compounds that enhance sirtuin activity. Guarente, who consults for one of those companies, Sirtris (a unit of GlaxoSmithKline), believes that sirtuin activators may eventually prove useful against Alzheimer’s, which affects up to one-third of people who reach age 80.

Protein clumping

Though amyloid plaques are a defining feature of Alzheimer’s disease, many researchers now believe that the symptoms are caused by smaller clumps of two or three amyloid beta (A-beta) fragments, not the larger plaques.

A-beta peptides form when proteins called amyloid precursor proteins (APPs) are broken into smaller pieces. However, APPs can also be cleaved at other sites, producing harmless protein fragments. APP’s normal function is unknown, but it has been established that people with a gene mutation that stimulates overproduction of APP are more likely to develop Alzheimer’s at an early age (before age 65).

Another mutation that stimulates early-onset Alzheimer’s (which accounts for 5 to 10 percent of cases) occurs in the gene for the enzyme that cleaves APP into A-beta peptides. Although those genes for early-onset Alzheimer’s have been identified, “with late-onset Alzheimer’s, we still don’t know why some people get it and other people don’t,” says Guarente.

Guarente, who first discovered the life-extending ability of sirtuins 20 years ago, started studying their role in Alzheimer’s after some recent studies showed that the gene that produces sirtuins, SIRT1, appears to protect mice from the effects of Alzheimer’s disease. When those studies came out, “I thought that the mice with extra SIRT1 probably had just as much A-beta, but that SIRT1 was protecting them against it,” Guarente recalls. “It turns out that they were actually making less A-beta peptide.”

In the Cell paper, Guarente and his colleagues showed that SIRT1 activates the production of an enzyme (alpha-secretase) that carves APPs into harmless fragments, preventing the formation of Alzheimer’s-associated amyloid peptides. Mice engineered to produce excess sirtuins had reduced peptide levels, while mice with SIRT1 knocked out showed elevated peptide levels.

Furthermore, learning and memory deficits in the Alzheimer’s mice were improved when SIRT1 was overproduced and worsened when the gene was deleted. The researchers also found that SIRT1 activates the so-called notch-signaling pathway via the elevated levels of alpha-secretase, which protects neurons and helps maintain brain function.

A new target for Alzheimer’s

The research, funded by the American Parkinson Disease Association, National Institutes of Health and the Paul F. Glenn Foundation, demonstrates that drugs that activate SIRT1 in the brain may be a promising approach to treating Alzheimer’s, says Guarente. Any such drug would have to be able to cross the blood-brain barrier, which prevents large molecules from diffusing into the brain.

Sirtris, a company co-founded by Guarente and then bought by GlaxoSmithKline, is now testing SIRT1 activators in a clinical trial for diabetes. Guarente believes that related drugs could have an impact on a range of neurodegenerative diseases, as well as diabetes and other diseases of aging.

However, any potential drug for Alzheimer’s would likely take several years to reach clinical trials, because of the need to find a drug that crosses the blood-brain barrier, says Guarente.

Rudolph Tanzi, professor of neurology at Harvard Medical School, says the new findings also suggest another approach: targeting one specific aspect of SIRT1’s activity. Tanzi’s lab recently found that mutations in the gene that produces alpha-secretase (ADAM10) are associated with late-onset Alzheimer’s disease.

“If this is how SIRT1 protects against Alzheimer’s — by turning on ADAM10 — you could try finding a drug that specifically addresses that mechanism,” instead of globally activating SIRT1, says Tanzi.
Provided by Massachusetts Institute of Technology (news : web)

SOURCE: www.physorg.com

By GAUTAM NAIK

Scientists have found a way to dramatically reduce the erosion of memory and learning ability in mice with a version of Alzheimer’s disease, potentially offering a new approach for tackling the illness in humans.

Mice with a model of Alzheimer’s disease that were genetically engineered to produce more sirtuin one retained both memory and learning ability as they aged; the loss of both are hallmarks of Alzheimer’s. Alzheimer’s mice without the extra sirtuin one capability, and those genetically engineered to produce no sirtuin one at all, showed steep declines in learning ability and memory as they aged.

Sometimes described as the “longevity gene,” SIRT1 has become the focus of intense research in recent years. Studies have shown that a highly calorie-restricted diet can turn on the gene and thereby increase longevity in everything from yeast to mice.

Similarly, a compound called resveratrol, found in red wine, also might switch on the gene, and tap the brakes on aging, at least in animals.

The connection between SIRT1 and Alzheimer’s is important because the illness has proved to be extremely hard to treat, even as its burden grows among the population. While lab-dish experiments have suggested a link between SIRT1 and Alzheimer’s, the new study establishes that link more definitively. It also suggests an alternative drug-based approach for treating the disease.

“This is the first demonstration that the SIRT1 pathway can mitigate Alzheimer’s,” said Leonard Guarente, a biologist at MIT and the lead author of the study, which appears in the journal Cell.

Dr. Guarente is a consultant for GlaxoSmithKline PLC, which is conducting early-stage research based on his findings. He sits on the advisory board of Sirtris, a GlaxoSmithKline company that is conducting sirtuin research on the diseases of aging.

The study was funded by an American Parkinson Disease Association fellowship and grants from the National Institutes of Health and the Paul F. Glenn Foundation, which backs research on the biology of aging.

Alzheimer’s is a neurodegenerative disorder affecting up to one-third of people who reach the age of 80. Patients suffer from memory loss and impaired cognition, which are believed to be linked to amyloid plaques. These plaques form when certain proteins get broken up into smaller fragments known as amyloid peptides.

But the proteins can also be broken into harmless fragments. The MIT researchers showed that sirtuin one breaks up the protein into such fragments, rather than the toxic ones associated with Alzheimer’s disease.

In one group of mice, the biologists introduced a second SIRT1 gene. These animals had lower amounts of toxic peptides in their brains than the mice with just one SIRT1 gene.

When put through lab tests as they aged, the mice with the second SIRT1 gene retained their memory and learning ability, while the other group showed a steep decline. The brains of the first group also revealed less inflammation and fewer plaques.

Still another group of mice, engineered without any SIRT1 at all, showed an earlier and steeper decline in memory and learning than the “normal” mice.

“SIRT1 is protecting the mice against memory loss,” Dr. Guarente concludes.

Scientists induced Alzheimer’s in mice by inserting in the animals two human genes associated with inheritable Alzheimer’s disease.

Translating the intriguing new findings into humans won’t be easy. Nobody knows whether mice are a good model for Alzheimer’s disease. And any future drug that can boost SIRT1 levels will need to reach a patient’s brain cells. That requires breaching the blood-brain barrier, not an easy hurdle to overcome, but one that Dr. Guarente says Glaxo is working on.

The Alzheimer’s Society, based in the U.K., said in a statement, “Much more research is now needed before we can find out if drugs that activate SIRT1 could be used to fight dementia.”

“The instant that GSK says they have a brain-permeable compound, I’ll try it in mice,” Dr. Guarente said.

Write to Gautam Naik at gautam.naik@wsj.com

SOURCE: online.wsj.com

A Cambridgeshire charity has funded research into Alzheimer’s disease, using fruit flies.

The Shelford-based Alzheimer’s Research Trust has given The University of Cambridge £30,000 to investigate the link between this combination.

The insects share many of the same genes as humans, and scientists hope knowledge of the flies’ ageing process will help them understand the disease.

The Trust says with an aging population research has never been more crucial.

Age and Alzheimer’s

Age is the biggest factor in Alzheimer’s with the risk doubling every five years after the age of 65. Alzheimer’s is the most common cause of dementia with 465,000 people suffering from it in the UK.

Dr Maria Giannakou is using fruit flies to understand Alzheimer’s disease

Dr Maria Giannakou is leading the research at The University of Cambridge. She says scientists are beginning to understand what is causing the disease.

They are looking into how ageing affects a protein called amyloid that builds up to form plaques in the brain causing brain cells to die.

Fruit flies

Fruit flies are commonly used in all sorts of laboratory research because their life cycle is so short, which means the ageing process can be tracked relatively quickly.

Dr Giannakou explained that a fruit fly has a lot of the same genes as humans, and similar brain processes, making them a good comparison for study purposes.

The protein amyloid which builds up causing Alzheimer’s

A cure in Cambridge

Dr Simon Ridley, head of research at The Alzheimer’s Research Trust said that £1.8m is being spent on various studies in Cambridge. The studies are looking at the causes, diagnosis, prevention, treatment and cure of the condition.

When this fruit fly project is complete, the trust will decide whether to continue along similar lines or send their research in a different direction.

He said: “We need to tackle this disease as soon as we can because it is likely to increase as our population ages. Really, there is an urgency to tackle this.”

‘Frighteningly rapid’

Kenny Fryde from Chesterton, in Cambridge, is looking after his mother who has Alzheimer’s.
Although only recently diagnosed, he said they saw symptoms years ago.

Kenny described how his mother would suffer memory lapses and was convinced she was living abroad.

He described her as “a highly intelligent professional woman” but her mental deterioration was “frighteningly rapid”.

He went on: “She’s disappearing bit by bit.”

SOURCE: news.bbc.co.uk

Marilyn Maldonado is not quite sure why she is at the Memory Enhancement Center in the seaside town of Oakhurst, N.J.

“What are we waiting for?” she asks. About 10 minutes later, she asks again. Then she asks again.

She is waiting to enter a new type of Alzheimer’s drug study that will, in the boldest effort yet, test the leading hypothesis about how to slow or stop this terrifying brain disease.

The disease is defined by freckles of barnacle-like piles of a protein fragment, amyloid beta, in the brain. So, the current thinking goes, if you block amyloid formation or get rid of amyloid accumulations — plaque — and if you start treatment before the disease is well under way, you might have a chance to alter its course.

On Tuesday, that plan got a new push. The National Institute on Aging and the Alzheimer’s Association proposed new guidelines for diagnosis to find signs of Alzheimer’s in people who do not yet have severe symptoms, or even any symptoms at all.

The guidelines are needed for the new approach to Alzheimer’s drug development. Just about every pharmaceutical company and many biotechnology companies have experimental drugs to block amyloid — there are more than 100 in the pipeline. And the companies would like to show that if they give their drugs early, they can slow or stop the disease.

That is the ultimate goal for the drug in the study Mrs. Maldonado wants to enter, sponsored by Bristol-Myers Squibb. The company is, for the first time, testing such a drug in patients who, on evaluation with memory tests and new brain scans and tests for amyloid in cerebrospinal fluid, seem to be in a very early stage of Alzheimer’s. The idea is to attack the disease when there may still be time to stop the worst brain cell death.

But there is a problem. The Food and Drug Administration says it needs to know not just that plaque was reduced or even that it disappeared, but that those who took a drug ended up with better memory and better ability to think and reason as compared with those who did not take the drug.

Alzheimer’s, though, progresses so slowly that showing that a drug, started early, affects symptoms can take far longer than companies can afford to wait.

There is reason not to accept other forms of proof, like scans or cerebrospinal fluid that show changes in amyloid in the brain, the F.D.A. says. The agency has approved drugs for diseases, including sudden death from heart arrhythmias, on the basis of tests that showed symptoms, like heart rhythms, improved. Then it turned out the drugs did not affect the course of the disease and, in the case of the heart drugs, actually hastened death.

So the Alzheimer’s field is poised at an agonizing point — ready to move forward with new methods of diagnosis and drugs that might modify the course of the disease, but without proof that blocking amyloid actually makes a difference.

In the meantime. Bristol-Myers is trying a two-pronged strategy to gain faster approval. It is starting treatment early, but not so early that patients are a decade or more away from Alzheimer’s. And as it looks for effects on symptoms like memory and reasoning, the company will be tracking what happens to amyloid in the brain, hoping to show symptoms improve or no longer worsen as plaque formation slows or stops.

It is a gamble for the company, because even people with fairly mild symptoms may have too much brain damage to be helped. But it is a strategy that makes sense, said Dr. Dennis J. Selkoe, a Harvard researcher who is not affiliated with the study.

“In my view, the sweet spot for amyloid-lowering trials is mild Alzheimer’s disease,” Dr. Selkoe said. “As soon as one of those trials shows benefit, everyone will move to prevention trials,” he said. “They will begin treating before there are symptoms.”

Mrs. Maldonado may be one of the pioneers.

The Amyloid Hypothesis

Considering how important a medical problem Alzheimer’s is — afflicting 5.3 million Americans, the seventh-leading cause of death, and devastating and bankrupting families — it took a surprisingly long time to be recognized as a disease at all. And it took longer still to reach any kind of agreement on its cause.

Dr. Paul Aisen, an Alzheimer’s expert at the University of California, San Diego, remembers well the old days, in the late 1970s. He was in medical school, studying to be a geriatrician. There was no discussion of Alzheimer’s disease.

Ever since it was described by Dr. Alois Alzheimer in 1906 as a “peculiar” disease in a 51-year-old woman, doctors had considered it an oddity, a rare illness of middle, not old, age. Old people who lost their memory and ability to reason and care for themselves were said to be “senile.” That word did not refer to any specific disease like Alzheimer’s. Senility, Dr. Aisen said, was “what might happen when you got old.” And “there was nothing you could do about it.”

Then, in 1976, doctors’ eyes were opened by an editorial in Archives of Neurology by Dr. Robert Katzman, a neurologist. Alzheimer’s, he wrote, is not rare — it is common. It can arise in old age. And it is a leading cause of death and, Dr. Katzman said, a disease whose origin could be determined and whose course might be stopped.

Neurologists took note. But it was 20 years before there were any drugs for Alzheimer’s, and the four approved so far treat only symptoms, modestly and temporarily improving memory, for example, and do not affect the relentless brain cell death.

In the meantime, researchers came upon an exciting target for a drug. They discovered two enzymes that snip pieces from a large protein protruding from brain cells. The result is toxic fragments of a substance known as amyloid beta peptides. Those shards accumulate as plaques on the brain. One way to prevent plaques might be to block one of those crucial enzymes.

Just about every drug company got to work.

They had long suspected amyloid beta was a key player in the genesis of Alzheimer’s, but until they found the enzymes researchers had no way to block it. Amyloid beta itself might be injuring nerve cells or the plaques, made of accumulations of amyloid beta, could be the culprits. But whichever was true, three lines of evidence pointed to amyloid beta: rare gene mutations that lead to its overproduction cause Alzheimer’s in middle age. Down syndrome also causes overproduction of amyloid beta, and people with Down always get Alzheimer’s. And when scientists put the rare mutated genes that cause Alzheimer’s into mice, the mice developed plaques and memory problems.

The logic was not airtight. Scientists note that older people with typical Alzheimer’s often have something else wrong in their brain — damage from mini-strokes, for example. Perhaps some of these other conditions set off waves of cell death independent of amyloid beta.

But over the years, researchers say, what has become known as the amyloid hypothesis — the notion that overproduction or reduced clearance of amyloid beta is a cause of the disease and blocking amyloid beta could stop it — dominated their thinking.

“Ninety percent of us in the field believe it is correct,” Dr. Aisen said.

An Antibody Approach

Testing of the amyloid hypothesis began a few years ago with two experimental anti-amyloid drugs, homotaurine and tarenflurbil.

Patients who took them did not improve.

But, some researchers asked, was that a fair test? The first drug was not very potent, and little of the second reached the brain. And it was not clear whether either was really affecting amyloid because there were no direct measurements of plaques or amyloid beta protein.

The results, said Dr. Samuel E. Gandy, a professor of Alzheimer’s disease research at Mount Sinai School of Medicine, were “uninterpretable.”

Then there was the vaccine approach — immunize against amyloid beta and let the immune system clear plaque. It worked in mice and so, to great excitement, researchers tested it in patients. But a preliminary study was abruptly halted when 18 of 300 patients developed a brain inflammation. Two immunized patients who later died after reaching “severe end-stage dementia” had almost no plaque in their brains on autopsy — the vaccine had apparently cleared plaques but not noticeably affected their disease.

But that is not proof a vaccine would not work, said Dr. Selkoe, a founder of the company that did the study and a consultant to it. Two patients hardly constitutes a full analysis of the trial data, he says.

Now, the company, Elan, and its collaborators are trying a different tack. Instead of using a vaccine, they made an antibody to amyloid beta, a drug called bapineuzumab.

Some initial results were published in March. A new type of scan that can show plaques found the drug was removing them. But so far it is unclear whether patients are improving.

Johnson & Johnson, which partnered with Elan and its collaborator, Pfizer, says it will continue the study.

That makes sense, said Dr. Gandy, who is not part of the study.

“We have no idea how long we might need to treat,” he said.

Tough Road to Consensus

Dr. Russell Katz, director of the F.D.A.’s division of neurology products, is in a quandary about Alzheimer’s drugs. What, he must decide, should be the criteria for showing that a drug works?

The agency is not ready to do that, Dr. Katz said.

“You only care if down the road the patient gets better,” Dr. Katz said. “What we are concerned about is approving a drug based on a lab test and being wrong about what happens to the patient clinically.”

With Alzheimer’s, Dr. Katz said, “the great fear is that maybe amyloid has nothing to do with the disease.” If that were the case, and the agency approved a drug that blocked amyloid formation, millions of healthy people could end up taking something useless or even dangerous. And because it takes so long for Alzheimer’s to develop, it could be decades, if ever, before anyone knew the drug did not work.

“It is a conundrum,” Dr. Katz said. “We all hope to get to the point in our understanding of the disease process where everyone in the field says: ‘Look. We know it now. Amyloid causes Alzheimer’s, and we have drugs that decrease amyloid.’ But we are not there yet.”

Bristol-Myers Squibb, though, is betting amyloid beta is the culprit. And it is betting it can show an effect in people who are in the early stages of Alzheimer’s.

Still, Dr. Aisen is concerned that even those patients, people like Mrs. Maldonado, might be beyond help. Treatment may have to start much earlier. So he is planning a large federal study to test amyloid-blocking drugs in people over 70 with normal memories but evidence of some amyloid accumulation. His criteria for success will not be the F.D.A.’s current one. Instead, he will ask whether the drugs slow the brain atrophy that is characteristic of Alzheimer’s and prevent amyloid from accumulating in subjects’ brains.

“If you think Bristol-Myers Squibb is going out on a limb, this is going farther,” Dr. Aisen said. If blocking amyloid beta and slowing brain atrophy are not accepted as sufficient evidence that a drug works, a study with normal 70-year-olds could end up taking 10 to 15 years to show an effect on the actual symptoms of Alzheimer’s.

After her scan that recent day, Mrs. Maldonado was entered in the Bristol-Myers study.

She is 82, a former school bus driver living in nearby Jackson with a diagnosis of mild memory impairment. She came with her son-in-law to the Memory Center that day, in black slacks and a flowered blouse, wearing a gold bracelet and gold rings. Her short white hair was fluffy, freshly washed. And she had a way about her, a joking demeanor, intended to disguise her forgetfulness.

Her brain, the scan showed, was riddled with plaque.

Dr. Joel Ross, who runs the Memory Center, told her the results.

“We found you are producing a sticky material called plaque,” he told her.

“Yeah,” she said.

“It’s coating some of your brain.”

“Yeah,” she said again.

“If you stay this way there will be a lot of it.”

“Yeah.”

“So we’re going to give you a drug that may clear it up.”

“Yeah.”

SOURCE: www.nytimes.com