The pre-Alzheimer's brain

In his search for ways to prevent Alzheimer's disease, Rhode Island Hospital neuropsychologist Peter J. Snyder, PhD, didn't want to rely solely on the memory and learning tasks that have been used for more than 50 years to detect cognitive impairment. Instead, Snyder was on the hunt for a fresh, scientifically sound approach that identifies the early stages of the underlying disease process.

Snyder found what he was looking for in the pattern separation task, developed by neuropsychologist Craig E.L. Stark, PhD, of the University of California at Irvine. The task assesses how well study participants can tell whether either of a pair of pictures they previously saw on a computer was moved, even slightly. The test measures the ability to store and retrieve memories — processes that involve a subregion of the hippocampus — and may help to detect brain changes that occur very early in the Alzheimer's disease process.

"I think it has great potential" to uncover how the disease process unfolds, says Snyder, also a neurology professor at Brown University.

His colleagues in the international Dominantly Inherited Alzheimer's Network (DIAN), which is funded by the National Institute on Aging and directed by John C. Morris, MD, of the Washington University School of Medicine in St. Louis, will use the test in a new clinical trial launched to evaluate three drugs for preventing Alzheimer's.

Stark is just one of many psychologists who are assuming broader roles in Alzheimer's research, as the focus shifts from finding treatment for symptoms to stopping the disease process before symptoms begin. In fact, neuropsychologists have been critical in the design and performance of several pivotal trials, says DIAN principal investigator Randall Bateman, MD, also of the Washington University School of Medicine.

New and different techniques

Using several effective methods to find early signs of Alzheimer's disease is important, says Glenn Smith, PhD, a clinical neuropsychologist working on early detection of Alzheimer's at the Mayo Clinic in Minnesota, and a member of the APA's Committee on Aging. "The more ways you measure something, the more accurately it's measured," he says.

He points to data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), a large-scale study launched in 2003 to find biomarkers, including behaviors in standardized tasks, that are most effective in detecting early signs of Alzheimer's. Funded by the federal government, the pharmaceutical industry and several private foundations, the study's principal investigator is Michael W. Weiner, MD, of the Veterans Affairs Medical Center at the University of California, San Francisco.

A recent ADNI data analysis led by Bruno Jedynak, PhD, of Johns Hopkins University showed a somewhat surprising result: The Rey Auditory Verbal Learning Test, a memory task commonly used in clinical practice, indicated abnormalities earlier in the course of neurodegenerative disease than six other biomarkers, including the well-publicized amyloid-beta seen on positron-emission tomography (PET) scanning and tau proteins found in cerebrospinal fluid.

Role of vascular changes

Amyloid plaques and neurofibrillary tangles have been considered Alzheimer's defining features, but some researchers are probing whether changes in the brain's blood vessels play a role in the disease process. In his lab at Columbia University, neuropsychologist Adam Brickman, PhD, and colleagues are using MRI to examine vascular abnormalities in the brain that might be harbingers of Alzheimer's disease.

Brickman says vascular changes in the brain — measured with neuroimaging — may predict which healthy adults will develop Alzheimer's and the severity of their symptoms when they do. His lab uses MRI scanning to measure various structural brain changes, including white matter hyperintensities — distributed bright patches seen on one type of MRI scan that Brickman says are signs of damage to small blood vessels.

His lab also studies amyloid formation related to white matter hyperintensities, strokes and microbleeds, which are tiny specks of blood that have seeped from leaky vessels in the brain. "These three types of pathology in the brain seem to occur with higher prevalence among people with Alzheimer's, and they also seem to predict the types of symptoms we see in Alzheimer's disease," Brickman says.

Clarifying the relationship between Alzheimer's and vascular disease in the brain — whether they occur independently of each other, or they interact, or if one causes the other — could lead to some basic, low-tech prevention strategies, says Brickman.

"We know how to prevent vascular disease a lot better than we know how to prevent plaques and tangles," he notes. "It's with lifestyle factors, medication, hypertension control and exercise."

Long-standing public health campaigns that have emphasized stroke and heart disease prevention by not smoking, eating a healthy diet and exercising "are making a great deal of sense for Alzheimer's disease as well," says Smith.

Changes in blood flow patterns in the brain also may be early indicators of Alzheimer's disease, says neuroscientist Lori Beason-Held, PhD. Her work with colleagues at the National Institute on Aging has followed 121 participants in the Baltimore Longitudinal Study on Aging, which began in 1994. Annual PET scans and neuropsychological exams showed that 22 participants developed cognitive impairment, on average about 11 years into the study.

People who developed impairments had increased blood flow in the frontal lobe in areas critical for memory and attention. They had decreased blood flow in the parietal lobe, also an important area for memory and attention, and in the temporal lobe in key areas for visual memory. These changes not only occurred before symptoms of decline appeared, but they took place in brain regions where amyloid and tau proteins accumulate the earliest, Beason-Held notes.

For now, the findings are statistically significant only at the population level, not in individuals. "But if we can take what we know from large studies and develop screening techniques we can use in a single person, that's the ultimate goal of the early markers," Beason-Held says.

Intriguing ideas, but no magic bullet

In another intriguing approach, Snyder suggests that the pharmaceutical benzodiazepine lorazepam could help identify preclinical Alzheimer's disease. With Cynthia Stonnington, MD, of the Mayo Clinic, Snyder studied the effect that a single dose of 2 mg of lorazepam had on 36 cognitively healthy older adults, half of whom carried the apolipoprotein E4 allele (a gene mutation that increases the risk of Alzheimer's) and half of whom weren't carriers. All participants had the expected reactions to the drug — sleepiness and slowed motor function. But two-and-a-half hours later, those with the E4 allele had significant problems on cognitive tests compared with the noncarriers (Journal of Clinical Psychiatry, 2009).

"A small dose unmasks a latent [cognitive] deficit in otherwise healthy carriers," says Snyder.

Bringing neuroimaging into the mix could reveal whether these people have the added risk of amyloid in the brain. "Pairing the best cognitive probe with a pharmacological stressor, I think that's what we need to identify presymptomatic patients," Snyder adds.

Even though research is making rapid progress, psychologists including Snyder don't see a cure emerging anytime soon. "There's not going to be a single magic bullet," he says. "This isn't a disease, but a syndrome with multiple etiologies."

Researchers now realize that the development of Alzheimer's probably is more complex than amyloid building up in the brain. Imaging studies in recent years have shown that about 30 percent of healthy adults who never develop Alzheimer's have fairly substantial plaque accumulations, Brickman notes. A less common occurrence is people who have the classic symptoms of Alzheimer's disease but no amyloid in the brain, he adds. "So that just raises the question of what really causes cognitive impairment," he adds.

Especially in older individuals, amyloid accumulations in the brain may co-occur with other pathologies — for example, Lewy body dementia, a condition with abnormal protein clumps in the brain, or cerebrovascular disease, says neuropsychologist Mark Bondi, PhD, a professor of psychiatry at the University of California, San Diego, and director of the Neuropsychological Assessment Unit at the VA San Diego Healthcare System.

Even if a cure isn't within sight, Snyder envisions the development of therapies to slow disease progression. "If we can slow the progression by just five years, we can cut the cost of Alzheimer's to society by 2050 by almost 50 percent," he adds. "It's an attainable goal."

Rebecca Voelker is a writer in Chicago.