Research Seeks Ways to Treat Alzheimer’s Long Before Symptoms Emerge, Scientists Say

The emerging ability to detect changes in the brain linked to Alzheimer’s disease gives scientists the prospect of developing preventive measures for the devastating disorder, a leading specialist on the disease told a recent gathering at AAAS.

Dr. Reisa A. Sperling, director of the Center for Alzheimer’s Research and Treatment at the Harvard Medical School, said there has been some “very exciting research” recently which suggests that the preclinical process of Alzheimer’s typically is underway for 10 or even 20 years before detectable symptoms.

The ability to identify the start of the disease years before symptoms appear, Sperling said, “provides an incredible opportunity” for early intervention to delay or prevent the onset of dementia.

While the prevention goal remains a formidable challenge, the hope is that physicians may someday treat Alzheimer’s—the most common form of dementia among the elderly —at the preclinical stage, just as they do when they prescribe preventive measures for other common afflictions such as diabetes, heart disease, and osteoporosis.

Dr. Reisa A. Sperling

Dr. Reisa A. Sperling

Sperling spoke at a 13 June panel discussion on “The Aging Brain,” co-sponsored by AAAS and The Dana Foundation. It was the first in a series of co-sponsored events on “Neuroscience and Society.”

Through autopsy studies on Alzheimer’s patients, researchers have known since the 1980s that certain brain abnormalities are associated with the disease, including clumps of proteins called amyloid plaques and fiber bundles (called neurofibrillary tangles) that form in nerve cells.

During the past decade, scientists also have used brain imaging methods such as positron emission tomography (PET) to identify early hints of Alzheimer’s in living individuals with no outward symptoms of the disease. Such research suggests that about one-third of persons over age 65 have some amyloid plaque in their brains. Researchers also have identified several biomarkers—proteins circulating in the spinal fluid—that seem to be associated with the development of the disease.

An ability to detect preclinical evidence of Alzheimer’s disease in living individuals using biomarkers and neuroimaging could allow researchers to track a patient’s response to early intervention efforts, Sperling said. By targeting the disease in its earliest stages, scientists would try to intervene before irreversible brain damage or mental decline occurs. Even mild cognitive impairment, an intermediate stage on the way to Alzheimer’s, may already by too late for intervention.

In addition to memory loss, Alzheimer’s symptoms often include language difficulties and trouble with routine activities of living such as driving and shopping. Currently, there are a handful of approved drugs for treating the condition, but while the drugs can temporarily delay the disease’s progression, none are curative.

Efforts so far to curb the disease after the onset of dementia, when irreversible brain cell loss is underway, have been unavailing. According to Sperling, there have been 10 clinical trial failures during the past decade involving drugs aimed at treating or preventing the disease at the dementia stage. New results from several clinical trials aimed at reducing brain degeneration in Alzheimer’s patients with mild to moderate dementia are expected this fall, Sperling said.

While she holds out hope that one or more of those drug trials will give a “signal of efficacy,” Sperling said interventions prior to the onset of dementia may have a better chance of affecting the clinical outcome of the disease.

Several such efforts are in the planning stages, including a three-year trial with older individuals without symptoms who have amyloid plaques in their brains. The trial, co-led by Sperling and Paul Aisen of the University of California, San Diego, will use an anti-amyloid agent to test whether reducing the burden of plaques in the brain delays or slows the rate of cognitive decline.

Dr. Richard J. Hodes

Dr. Richard J. Hodes

With an “unlimited supply of baby boomers turning 65,” as Sperling noted, there is more urgency than ever to treat or prevent Alzheimer’s and other forms of dementia. Dr. Richard J. Hodes, director of the National Institute on Aging (NIA), said the number of Alzheimer’s patients in the United States, now estimated at from 2.7 million to 5.3 million, may triple by 2050 unless preventive measures are found.

Hodes said it makes sense to pursue earlier interventions. He noted successes in sharply reducing the projected rate of chronic disability in the elderly from 1982 to 2005. “Disability was not inevitable,” he said, and there is no reason to believe that Alzheimer’s is immutable.

If the goal is to begin treatment before symptoms of dementia appear, early identification of even mild cognitive impairment is essential. NIA, other federal agencies, and various stakeholders currently are assessing 140 different screening tools for cognitive impairment, with the aim of recommending one or more for use during annual Medicare wellness checkups, Hodes said. (Such testing is required by the Affordable Care Act, which was upheld 28 June by the Supreme Court.)

Any screening instrument must be brief (less than five minutes to administer), free, and with sufficient power and specificity, Hodes said. Such screening could allow physicians to pick up early signs of cognitive troubles, just as they now screen for high blood pressure or high cholesterol. But there remain questions about the value of such information in the absence of a verified intervention to slow or prevent dementia.

While Alzheimer’s remains one of the most feared outcomes of aging, researchers have been learning much about the changes in mental function, in the absence of disease, that occur as we age.

Marilyn S. Albert

Marilyn S. Albert

“There is some degree of change that is normal, and that we anticipate would occur even in the best of circumstances, and that’s different from people who are developing a progressive illness,” said Marilyn S. Albert, director of the Alzheimer’s Disease Research Center at The Johns Hopkins University in Baltimore.

Normal age-related memory loss may have some features in common with Alzheimer’s. But as a pamphlet from the Dana Alliance for Brain Initiatives and AARP notes, there are differences between typical age-related changes (missing a monthly bill payment, sometimes forgetting which word to use) and the more serious causes for concern (inability to manage a budget, difficulty having a conversation).

As Alzheimer’s patients progress along a trajectory from mild cognitive impairment to dementia, Albert said, they start to experience substantial problems with memory, constantly repeat conversations day to day, have trouble understanding complicated explanations, and can’t be depended upon to handle emergencies in their lives.

Even in the absence of disease, Albert said, research studies over many decades have made clear that by the time we reach middle age, we all start to experience significant changes in our ability to learn and retain new information. But in a series of very large population studies over the past two decades, researchers also have repeatedly found four factors that can help us remain mentally sharp as we age:

Physical activity: In randomized, controlled clinical trials involving people who are physically active versus a control group, Albert said, there is clear evidence that exercise can have a beneficial impact. In one study in which elderly subjects engaged in aerobic exercise for six months, the researchers found increased activation of sites in the brain associated with memory formation. Another study with 120 older adults found that aerobic exercise training increased the size of the anterior hippocampus, leading to improvements in spatial memory. Physical activity stimulates brain function “in some ways that we don’t totally understand,” Albert said.

Mental activity: Daily activities that are mentally stimulating—such as doing crossword puzzles, playing board games, reading books and attending lectures—can help preserve mental function. Albert described a randomized controlled clinical trial involving about 3000 elderly persons in which researchers tested the value of training exercises to help improve or maintain memory, reasoning abilities, and mental speed. Two years after the training, Albert said, gains in mental speed and reasoning ability persisted. There also appeared to be benefits for reasoning skills even five years after the training exercises.

Social engagement: Staying socially active and engaging with friends and family is an important predictor of cognitive resilience. Albert noted an ongoing effort in Baltimore, called the Experience Corps, which sends older adults into local elementary schools as volunteer tutors. The program provides social activity for the seniors, and also increases their physical and mental activity. A controlled study is now underway to assess the outcomes of the program, including a sub-study on the brain health of about 100 of the participants.

Vascular health: Those with conditions, such as stroke, that can damage blood vessels and restrict blood flow to the brain, may be at increased risk of developing cognitive problems know as vascular dementia. Risk factors for heart disease such as high blood pressure, high cholesterol, diabetes, and smoking have been implicated, Albert said, and the mechanisms at work may include disruption in the blood brain barrier, inflammation of brain tissues and stress as the brain is deprived of vital oxygen. Because vascular dementia is closely tied to diseases of the heart and blood vessels, many experts consider it the most potentially treatable form of dementia.

Statistics suggest that the benefits of physical activity, mental activity, social engagement, and reduced vascular risk are additive, Albert said. If you are doing well on two or more of the factors, she said, you are much more likely to maintain mental function as you age. She noted that genetics also plays a role in mental resilience as we age.

And genetics offers researchers avenues to follow as they seek to better understand the onset of Alzheimer’s. Sperling noted that the converging evidence on the preclinical stage of Alzheimer’s comes from studies of individuals and families with a genetic risk for the disease as well as from those who develop it primarily as a part of the aging process.

The role of genes in the more usual late-onset form of the disease is complex. People who inherit a variant of a gene called ApoE have an increased risk of developing Alzheimer’s and about 40% of all those with the late-onset form of the disease carry the mutation. If someone has two variants of the gene, their risk of getting the disease by age 85 increases to 95%. A third variant of the ApoE gene appears to be protective against the disease, however.

For early-onset forms of Alzheimer’s, which appear in people age 30 to 60, single-gene mutations can virtually guarantee that a person will come down with the disease. Sperling noted that one of the planned prevention trials, part of a collaborative effort called the Alzheimer’s Prevention Initiative, will be carried out among cognitively healthy individuals in Colombia who carry a mutation of gene called PS-1. They are destined to develop Alzheimer’s symptoms by about age 45.

In the trial, about 300 people from a large extended family with the gene will receive an anti-amyloid antibody treatment called crenezumab. The trial also will involve a smaller number of individuals in the United States. If the trial is successful, it could open the door to tests of the anti-amyloid agent in larger segments of the population.

Links

Watch a video of the panel discussion on “The Aging Brain,” co-sponsored by The Dana Foundation and AAAS.

Learn more about the AAAS Scientific Responsibility, Human Rights and Law Program.

Learn more about The Dana Foundation.