Science Watch

Muddled thoughts, skewed reasoning, precious memories snuffed out forever — a diagnosis of Alzheimer’s disease is devastating for both patients and their families. With as many as 5.1 million Americans suffering from the disease, according to the National Institute on Aging (NIA), the race is on to find better ways to diagnose and treat this debilitating disorder.

In April, the NIA updated its diagnostic guidelines for Alzheimer’s disease for the first time in nearly 30 years. Up to now, Alzheimer’s disease has been a diagnosis of exclusion: If a patient exhibits behavioral symptoms but causes for other types of cognitive impairment have been ruled out, he or she is labeled with Alzheimer’s. The pathological features of the disease — proteins in the brain known as amyloid plaques and neurofibrillary tangles — are invisible to traditional neuroimaging techniques and can only be confirmed at autopsy.

Now, that may be changing. The updated NIA guidelines address the emerging use of methods to detect biological markers of Alzheimer’s disease, including new brain scan techniques and tests of cerebrospinal fluid.

Researchers are also aiming to identify behavioral symptoms earlier, at the stage of mild cognitive impairment, or MCI, which is often a precursor to dementia. Symptoms of MCI include forgetfulness, trouble with multitasking and difficulty solving problems. MCI doesn’t significantly interfere with activities of daily living, “but it may make those activities more effortful or challenging for you,” explains Glenn Smith, PhD, a clinical neuropsychologist at the Mayo Clinic.

In the past 10 years or so, clinicians have gotten more skilled at recognizing signs of MCI, and many clinical trials are now enrolling such patients before they develop full-blown dementia. In fact, MCI is a fairly good predictor of who will develop Alzheimer’s disease, researchers say.

In a given year, Smith says, about 15 percent of people with a new MCI diagnosis will progress to dementia. “By about eight years out, roughly 80 percent of people will have progressed,” he says.

Looking at biomarkers and spinal fluid

But the link between MCI and Alzheimer’s isn’t absolute. Most people with MCI will go on to have Alzheimer’s disease, Smith says, but others may develop different types of dementia — or none at all. “Some people meet the criteria for MCI and don’t [progress] at all,” says Peter Lichtenberg, PhD, a clinical psychologist and director of the Institute of Gerontology and of the Merrill Palmer Skillman Institute for Child and Family Development at Wayne State University. And, he adds, “some people have MCI and get better.”

While MCI is diagnosed earlier than Alzheimer’s, it might not be early enough. “It turns out that even at that stage, the disease has probably already been going on for 10 years,” says Reisa Sperling, MD, a neurologist at Harvard Medical School and director of the Center for Alzheimer’s Research and Treatment at Brigham and Women’s Hospital. So far, drugs designed to slow the progression of Alzheimer’s have been disappointing. That could be because patients are starting the drugs too late, she says. To push diagnosis back even further, researchers have set their sights on biomarkers for the disease. One promising approach that’s receiving a lot of attention lately is positron emission tomography (PET) imaging (Journal of the American Medical Association, Vol. 305, No. 3). The technique employs a dye that stains amyloid plaques in the brain, making them visible on PET scans. In January, a Food and Drug Administration advisory committee recommended that the agency approve the use of a dye developed for this purpose.

Another approach being developed involves testing for the presence of certain proteins in the cerebrospinal fluid. In a study published last summer in the Archives of Neurology (Vol. 67, No. 8), researchers reported that three proteins — beta-amyloid protein 1-42, total tau protein and phosphorylated tau — were identified in 90 percent of subjects with Alzheimer’s disease, but in just 39 percent of a control group.

The new NIA guidelines specify that testing for Alzheimer’s biomarkers should only be used in clinical trials until more is known. And even experts who are excited about these approaches caution that both PET imaging and cerebrospinal fluid testing still have significant limitations. In the Archives of Neurology study, for example, nearly 40 percent of patients without dementia tested positive for the protein biomarkers. It’s not clear whether they’re at risk of developing Alzheimer’s disease down the road, or whether some people can live long, healthy lives with elevated levels of these proteins in their bodies.

The PET-imaging technique has similar weaknesses. Amyloid plaques are a defining feature of Alzheimer’s disease — virtually everyone with the ailment has these plaques in their brains. However, many people have amyloid buildup and never show any signs of cognitive impairment. “Some people can walk around with a head full of amyloid for a long time and not develop clear dementia,” Sperling says.

For that reason she expects that in the short term, biomarker testing will be most effective in confirming diagnoses in people with other Alzheimer’s risk factors, such as MCI. “A predictive use of these biomarkers is a bigger hurdle,” she says.

“What we’re worried about as a society is not necessarily whether people have amyloid in their brain, it’s whether people have a dementia syndrome that’s impairing their ability to function,” adds Adam Brickman, PhD, a neuropsychologist at the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain at Columbia University College of Physicians and Surgeons and a member of the APA Committee on Aging (CONA). To that end, he adds, biomarker identification is “a huge advance in the field, but how it translates is still a big question mark.”

‘Not the whole story’

Biomarker testing for very early diagnosis of Alzheimer’s may not be ready for primetime, but research in this area is pushing the whole field forward, according to Brickman. “I think there’s been this field-wide sigh of recognition that amyloid is important but it’s not the whole story,” he says.

In fact, scientists still aren’t entirely sure whether the amyloid plaques cause Alzheimer’s disease, or are merely side effects of the condition. Researchers are now searching for other biological and environmental factors that may underlie the disease. Some people appear to have a “cognitive reserve,” Sperling says, and function normally even though their brains show signs of Alzheimer’s pathology. Much of her research is devoted to understanding this cognitive reserve. “Is amyloid necessary but not sufficient [to develop Alzheimer’s disease]? Are there genetic factors? What makes somebody resilient?” she asks.

Smith, at the Mayo Clinic, agrees that physical markers alone will never be able to capture a person’s mental resilience. “Those biomarkers will be good in the same way neuropsychological markers are good, but there will always be some slop in the system,” he says. For that reason, neuropsychology will always play an important role in diagnosing dementia. “You need a comprehensive approach to have the highest degree of accuracy, especially as we move back into these preclinical areas,” he says.

Yet critics caution that the psychological element shouldn’t be overlooked in the recent hype over biomarkers. For the time being, Brickman says, “psychologists are really the best-equipped to identify some of these cognitive changes that are due to the disease.”

Psychologists are also critical as patients and their loved ones grapple with a dementia diagnosis. “It’s great to go for the cure and the earliest detection,” says Wayne State’s Lichtenberg, “but I think that in all the excitement of investigating biomarkers, the field is not demonstrating its full commitment to caring for the people and the families that are experiencing this disease.”

Indeed, without effective pharmacological treatments yet, coping techniques are key. Smith encourages patients to get in the habit of keeping calendars and journals, and using reminder systems for medications — practices that will aid them as their dementia symptoms progress. “While we may not be able to change the underlying course of brain changes, we can teach compensation strategies to help maintain a person’s functional independence for as long as possible,” he says.

Ultimately, many researchers believe, the biggest gains in Alzheimer’s will come not in treatment, but in prevention. Epidemiological studies continue to uncover the importance of lifestyle factors such as diet and exercise to brain health. Increasing evidence suggests that maintaining vascular well-being is probably “hugely important” for protecting against Alzheimer’s disease, Brickman says.

In the past several decades, the fields of cancer and cardiovascular disease have moved toward a preventive approach. Many Alzheimer’s experts believe their field is poised for a similar shift. But it will be an uphill battle. “This is a massively enormous public health problem,” Brickman notes, “and it’s getting bigger.”

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