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On the frontier of Alzheimer's research

Imaging pioneer—Dr. Michael Weiner, who has been conducting research at the San Francisco VA Medical Center since 1980, heads the Alzheimer's Disease Neuroimaging Initiative. (Photo by Ed Caballero)
Imaging pioneer—Dr. Michael Weiner, who has been conducting research at the San Francisco VA Medical Center since 1980, heads the Alzheimer's Disease Neuroimaging Initiative. (Photo by Ed Caballero)

One day, people may talk about their levels of "amyloid"—a protein that gradually accumulates in the brain of those with Alzheimer's disease—the same way they talk about their cholesterol levels and blood pressure. They may use their amyloid score together with other measures—say, their trends over time on computer-based cognitive exercises—to predict their Alzheimer's risk, just as cardiovascular tests warn of impending heart disease.

That's the prediction of neuroscientist Michael Weiner, MD, of VA and the University of California, San Francisco.

Weiner leads the nationwide Alzheimer's Disease Neuroimaging Initiative, started in 2004 and recently renewed until 2015. The study, funded mainly by the National Institute on Aging and involving some 60 clinical sites across the U.S. and Canada, has pushed the field of early diagnosis of Alzheimer's light years ahead of where it was just a decade ago.

Weiner presented the latest findings from the initiative at the 11th International Conference on Alzheimer's and Parkinson's Disease earlier in March.

A new way of thinking about Alzheimer's

According to Weiner, who recently won the Potamkin Prize from the American Academy of Neurology for his groundbreaking work, ADNI has changed the way people think about Alzheimer's disease.

Inside the brain—MRI scans are just one measure researchers are using to gain a glimpse of brain changes that signal Alzheimer's disease in its earliest stages. (Photo by Roy Kaltschmidt)
Inside the brain—MRI scans are just one measure researchers are using to gain a glimpse of brain changes that signal Alzheimer's disease in its earliest stages. (Photo by Roy Kaltschmidt)

"The ability to detect amyloid in the brain, either with imaging or lumbar punctures [which detect the protein in cerebrospinal fluid], is the big news in the early diagnosis of Alzheimer's in the last decade," notes Weiner.

The brain-imaging pioneer says people used to equate Alzheimer's with dementia—memory loss and confused thinking. Now, they associate the disease more with amyloid on the brain—regardless of whether the specific symptoms of dementia have set in yet.

"Brain amyloid and Alzheimer's disease are essentially equivalent," asserts Weiner.

In fact, dementia can result from any number of other health problems—strokes, tumors, other neurodegenerative diseases. It is amyloid buildup that distinguishes Alzheimer's from other dementia-causing conditions.

"For many years we've known there was a continuum from a healthy brain, to mild memory problems, to mild cognitive impairment, and finally to dementia," says Weiner. "But now, because we can detect brain amyloid, we can call it dementia due to Alzheimer's, or mild cognitive impairment due to Alzheimer's."

He notes there is also an early stage known as pre-clinical Alzheimer's—"people with totally normal brain function who show no signs of damage but who have amyloid in their brain."

On the flip side, ADNI has driven home the point that not everyone with a diagnosis of Alzheimer's actually has the disease. Weiner: "If you don't have amyloid in the brain, you don't have Alzheimer's. In ADNI, 20 percent of people who had received a diagnosis of Alzheimer's don't have any amyloid in the brain, and therefore don't really have the disease. It turns out their dementia was from other causes."

Amyloid—does it always mean Alzheimer's?

Amyloid—more precisely, beta amyloid—has always been one of the biological hallmarks of Alzheimer's disease. It's the sticky protein that clumps up and forms hard plaques between neurons in the brain of those affected by the mind-robbing ailment. Beta amyloid is the pathological form of the protein. It starts out, further upstream in the biochemical pathway, as Alzheimer's precursor protein (APP).

The problem was, amyloid clumps could be seen only after a patient died and underwent an autopsy. The brain tissue was sliced and viewed under a microscope. It was in 1906, at a meeting of German psychiatrists, that Alois Alzheimer first described the findings from one such autopsy, done on a woman who had been a patient in the mental hospital where he had worked.

The physician described thick tangled fibers inside the brain's nerve cells. These are caused by the protein known as tau (rhymes with cow), which undergoes a chemical process known as phosphorylation to become the pathological form that invades neurons.

Alzheimer then noted the "storage of a peculiar material in the cortex," which formed together into plaques between the cells. This was amyloid.

For nearly a century after the German physician's discovery, the only way to definitely diagnose Alzheimer's was autopsy.

That began to change in 2004, with the discovery of a compound called Pittsburgh B. The chemical is injected into a vein and travels through the bloodstream to the brain. There it binds to amyloid deposits and can be imaged with a type of brain scan called positron emission tomography (PET).

Enter ADNI. It became the largest amyloid imaging project in the world. The study also brought into the mainstream other means of detecting amyloid—namely lumbar punctures, formerly known as spinal taps.

"It turns out that measuring cerebrospinal fluid with a lumbar puncture gives you information that is almost equal to that obtained through amyloid imaging, at a much lower cost," says Weiner.

The various tests refined through ADNI are now commonplace—if not de rigueur—in Alzheimer's clinical trials. Researchers worldwide have a standardized way to measure drugs' impact on amyloid formation.

Lumbar punctures also detect tau and phosphylated tau. This adds further clues about the progression of Alzheimer's. "We've learned that people who have elevated tau and phospho-tau in their cerebrospinal fluid progress more rapidly toward Alzheimer's," explains Weiner.

The precise relationships among the three proteins, and what it all means for early Alzheimer's detection, is still being worked out by ADNI investigators. But one of the most pressing questions for now concerns amyloid.

It turns out that 30 percent of normal, healthy people have amyloid in the brain. In other words, they have pre-clinical Alzheimer's. "It's a very early form of Alzheimer's disease that is not producing any symptoms," says Weiner.

ADNI investigators know that these people are at much greater risk for cognitive decline and eventual dementia than people who have no amyloid whatsoever. But here's the rub: Not everyone with amyloid in the brain gets dementia. Some people won't get it simply because they won't live long enough. (Age itself is the biggest risk factor for Alzheimer's. Of those who live past 85, nearly half develop the disease.) Others live long enough but seem to be protected against the ravages of brain deterioration. What ADNI investigators don't know is what keeps these amyloid-positive people from developing Alzheimer's.

"That's something we need to work on—we need to explore exactly what factors are protecting them," says Weiner.

Who will be tested?
PET scans are expensive—up to three or four thousand dollars, in some cases. Health care systems—including VA's—won't be able to give one to every patient who wants one. Other types of brain scans now being explored for Alzheimer's diagnosis aren't much better in terms of cost. Lumbar punctures may be a cheaper, more practical option for early detection of Alzheimer's, but still the question remains: As these tests go mainstream, should everyone over a certain age—say, 50—get tested to find out his Alzheimer's risk? Is that really necessary, or advisable?

The question will take on a whole new dimension when effective treatments become available. Right now, doctors don't have much to offer patients with Alzheimer's, other than keeping them as comfortable as possible. Some symptoms can be managed to an extent with medication or other therapies, but nothing halts the disease's terrible course.

So, until effective Alzheimer's drugs emerge, will the average person want to know years ahead of time whether he or she is at high risk for Alzheimer's? If a PET scan and other tests can tell them—say, with 80 percent surety—that they will develop the disease within 15 years, is that information going to help them? Should doctors offer early diagnosis of Alzheimer's if there is still no good treatment on the horizon—something that can instill at least some hope in patients and their loved ones?

And what if Alzheimer's diagnostic tests become as quick, cheap, and painless as a finger prick? Scientists are working on blood tests that detect abnormal amyloid or tau levels, or related biomarkers, without the need for a brain scan or lumbar puncture. This would further change the landscape. "It would be a dream, and lots of people are pursuing it," notes Weiner. ADNI provides blood samples to qualified researchers who request them, after approval by a committee.

Some experts say early warning could help with family planning, or perhaps spur patients to buy long-term-care insurance.

The medical literature abounds with articles on this question. Professional groups have wrestled with it and issued guidelines, but the issue is hard to pin down because the science on the ground has been steadily advancing.

The popular press has explored the dilemma as well. A wave of stories came out last year when the Food and Drug Administration's approved florbetapir (sold as Amyvid), a later-generation version of the original Pittsburgh B compound used in PET scans. Now, the scans are easier to do and more reliable, albeit more costly because of the new imaging agent.

A 2010 New York Times article was headlined "Tests Detect Alzheimer's Risks, But Should Patients Be Told?" A 2012 Wall Street Journal piece put it more bluntly: "The Curse of a Diagnosis: Is Early Detection Useful if a Disease Has No Cure?"

There are few neat answers.

Weiner boils it down to simple terms: "If people don't want to know, they simply won't pursue going to the doctor and getting the test."

Ellen Fox, MD, VA's chief ethics officer, says that "if and when science progresses to the point where these tests are more reliable" and they come into routine care, the department will watch closely to ensure they are used only as clinically indicated. It will be important, per standards of care, she says, that physicians "inform patients about their condition to the extent it is known, acknowledging the uncertainly in diagnosis and practice." She says VA would need to develop practice guidelines that address ethical issues such as false positives from testing—telling people they are at high risk for Alzheimer's when it's actually not the case—and the psychological effects the results might have.

One patient, quoted in the Wall Street Journal, said her diagnosis of early-stage Alzheimer's at age 56 felt "like a bomb has gone off in my life." Her husband said allowing his wife to be tested "was the biggest mistake of my life."

As the tests come further along, a middle ground might be testing only those with strong pre-existing risk factors, such as a family history of Alzheimer's, especially on the maternal side, or a past head injury. Other candidates might be those who, based on a preliminary DNA test, are found to have the gene variant APO e4, known to raise Alzheimer's risk.

Is a cure on the horizon?

Talking about Alzheimer's, Weiner is both a realist and an optimist. He knows better than most what a diseased brain looks like—the shrunken, shriveled cortex, the widened fluid-filled grooves. But he also brims with hope. He seems to have little doubt that scientists are on the verge of a breakthrough in treating Alzheimer's.

Even he admits recent clinical trials have been disappointing. Some treatments that seemed promising turned out to have nasty side effects. "There have been some failed trials, but it wasn't clear they had the right drugs, or that patients were treated early enough," says Weiner.

He has faith they'll get it right soon. He talks enthusiastically about a number of potential treatments. Some use the body's own immune system to get rid of amyloid. Others block the enzyme that rips apart Alzheimer's precursor protein to form beta amyloid. These compounds are similar to the protease inhibitors used in HIV treatment, "so there's a lot of experience in the development of these drugs," notes Weiner. He says at least two pharmaceutical companies have viable products in early clinical trials. "They look very promising. They are lowering amyloid in cerebral spinal fluid. And so far we haven't heard about side effects from them."

Another theory: Rogue proteins such as beta amyloid and p-tau jump from neuron to neuron, spreading like an infectious disease. Block the signals that trigger the cell-to-cell transmission, and you slow the disease.

Even as these experimental treatments are being tested, scientists still don't know for sure that amyloid causes Alzheimer's, notwithstanding its role in diagnosis. It could be "just along for the ride," says Weiner—a biological byproduct of a disease process triggered by other causes. There's strong genetic evidence that amyloid is indeed the culprit in early-onset forms of the disease—which strike people as young as 45 or 50—but experts still debate whether amyloid is a cause or merely a sign of the disease when it affects older people.

Some clinical trials in Europe are taking a wider approach—not only medication, but various lifestyle changes, from brain exercises, brisk walks, and gym workouts to more olive oil and omega 3s in the diet. It's all good, acknowledges Weiner, but he points out there's still a lack of hard evidence on whether these lifestyle measures can actually prevent or slow Alzheimer's.

He thinks blocking amyloid should still be the number-one treatment goal. When scientists do hit on an approach to stop the brain ailment in its tracks, the field of early diagnosis will explode, says the seasoned Alzheimer's researcher.

"As soon as there's an effective treatment," says Weiner, "it's going to be a huge game changer."

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