Title:Slowly Breaking Ground in Alzheimer’s

Like the disease itself, the study of Alzheimer’s takes time and patience. Georgetown researchers walk the long road to uncover the mysteries of memory and cognition in the aging brain.

Medical researchers have found the keys to cure many maladies that cause sickness and suffering, but Alzheimer’s disease has for decades remained a stubbornly resistant foe.

The Food and Drug Administration last approved a drug to treat the disease nearly two decades ago, and all four of the currently approved drugs provide, at best, a modest improvement in symptoms for a while. Family members feel helpless as they struggle to provide care for their loved one, who seems to fade into the persona of a familiar-looking stranger.

Meanwhile, the number of Americans living with Alzheimer’s continues to grow, and now approaches six million. With no way to prevent it and no cure in sight, it is the sixth leading cause of death.

These troubling statistics haven’t deterred researchers at Georgetown University Medical Center, several of whom are engaged in ground- breaking research on different aspects of this complex disease.

Alzheimer’s is the most common cause of dementia. It is characterized by abnormal levels of beta-amyloid proteins and accumulations of neurofibrillary tangles in the brain that disrupt how nerve cells communicate and result in a loss of neurons. These changes gradually affect people’s ability to think and reason and remember. Eventually, they can no longer perform daily tasks or live independent lives.

Aging is the most common known risk factor for Alzheimer’s disease. After age 65, the number of people with Alzheimer’s doubles every five years. By the time someone is 85, the likelihood of having Alzheimer’s “is almost a coin flip,” says G. William Rebeck, professor of neuroscience at Georgetown, who heads the university’s Laboratory of Aging and Neurodegeneration.

Family history and genetics can also increase the odds that someone will develop Alzheimer’s disease. The APOE gene is associated with significantly higher risk; if someone has one copy of the APOE4 variant of the gene, their risk of developing the disease is pushed forward by five to seven years, Rebeck says.

Cancer Treatment and Cognition

The APOE4 gene figures prominently in the work of some Georgetown researchers. Jeanne Mandelblatt, a professor of oncology at Georgetown’s Lombardi Comprehensive Cancer Center, is investigating the interaction between cancer and cancer therapy and cognition in older breast cancer patients, including those with the APOE4 allele.

Mandelblatt was curious about older women with breast cancer, a little studied group whose aging brains, she theorized, might be more vulnerable to cognitive decline after cancer and its treatment.

Mandelblatt didn’t set out to study Alzheimer’s. She spent much of the past 30 years conducting research on the intersection of cancer and aging, with an early focus on breast and cervical cancer screening. Mandelblatt’s research helped pave the way for Medicare to cover Pap smears to screen for cervical cancer, the first preventive benefit that the program covered. She continued to advocate for health care for older women at risk for or with cancer.

Mandelblatt’s research demonstrated that older women with breast cancer wanted similar treatment options as those offered to younger women, including aggressive therapy regimens. Her work led to an interest in the long-term cognitive effects of chemotherapy and hormonal treatments, the foggy thinking now referred to as “cancer-related cognitive impairment.” She was curious about older women with breast cancer, a little studied group whose aging brains, she theorized, might be more vulnerable to cognitive decline after cancer and its treatments.

What she and her colleagues learned, in a large study of older women with breast cancer aged 60 to 98, was that most women did not suffer long-term cognitive ill effects after chemotherapy or hormonal treatment. But there was one conspicuous exception: a small group that had the APOE4 genetic variant. Two years after completing chemotherapy, with or without hormonal treatment, women with one or two copies of the APOE4 gene had significantly lower cognitive scores related to attention, processing speed and executive function than those with other APOE genotypes.

(About 25% of people in the United States have at least one copy of the APOE4 gene, whereas roughly 65% have only the APOE3 genetic variant, which doesn’t affect the risk of developing Alzheimer’s. Approximately 10% of people have the APOE2 gene, which actually reduces a person’s risk of developing Alzheimer’s disease.)

How to explain what was happening in these women? Cancer and cancer treatments probably don’t themselves cause Alzheimer’s disease. “Is what we’re seeing an unmasking of neurodegenerative disease in women who were already on a course of developing dementia?” Mandelblatt wondered. “Or are they suffering cognitive declines as a result of cancer and treatment for the cancer, which may have accelerated their aging process?”

The Role of Genetics

Mandelblatt approached Rebeck, who works with animal models, to discuss collaborating on this research. Rebeck, a well-known expert on the link between APOE and Alzheimer’s, uses mouse models to try to understand why inheriting different forms of the APOE gene affects people’s risk of developing Alzheimer’s so markedly.

Rebeck and his colleagues in the lab set out to see if they could replicate the results in mice that Mandelblatt had observed in people. In a recently published study, Rebeck, Mandelblatt, and Georgetown colleagues reported that, like their human counterparts, mice with human APOE4 genes showed markedly impaired learning after receiving a common chemotherapy drug compared to APOE3 mice that were given the same drug. After treatment, APOE4 mice that were placed in a maze had much more difficulty locating the escape hole, compared with APOE3 mice that received the same treatment.

The results pave the way for researchers to explore the interaction at the genetic and molecular level between the APOE genotype and other chemotherapy drugs in mice. These experiments aren’t feasible to conduct in humans, but they could help researchers glean information about the potential effectiveness of different drugs in individual patients.

Ultimately, the research could provide clues to preventing Alzheimer’s disease altogether, says Rebeck.

“Could I treat the APOE4 mice with something before they were given chemotherapy that would prevent the cognitive impairment in the first place?” he wonders.

Rebeck didn’t plan on a career in Alzheimer’s research. After receiving a bachelor’s degree in chemistry and then a PhD in toxicology from Harvard University, he got a Fulbright fellowship and took a post-doctoral position at a lab in Germany that specialized in Alzheimer’s disease. It was the early 1990s, and not much was known about it.

“Since I started out kicking around in different areas, I think I always imagined I would kick around more, but I never did. This stayed interesting and productive,” he says. Rebeck has been at Georgetown since 2003.

Rebeck, who also has a master of fine arts in writing, occasionally explores science from a completely different perspective: he writes plays. His subjects have ranged from a play about the life of Dr. Alois Alzheimer, a German neurologist whose research led to the identification of Alzheimer’s disease, to a 10-minute dialogue between a pair of placebo control lab mice who are dealing with existential angst.

Trials of the Long Road

Another key locus for studying the impact of Alzheimer’s disease and other types of dementia at Georgetown is the university’s Memory Disorders Program, which provides clinical care for patients with Alzheimer’s disease and recruits patients for and oversees their participation in several national and international clinical trials to test drugs to prevent or treat the disease. Last year, the program celebrated its 20th year.

Though he acknowledges that progress in key measures to combat the disease has been disappointing, program director R. Scott Turner remains optimistic.

“We’ve been persistent, and I think we are going to develop new treatments eventually,” he says. He points to incremental advances over the past several years that have greatly enhanced researchers’ ability to understand the disease and identify predictive biomarkers decades before the disease appears. For example, PET neuroimaging scans that can detect beta-amyloid plaques in the brain can now be performed on living patients, opening the door to treatment in the disease’s early stages.

Turner is also optimistic about the prospect of new drugs in development, particularly Biogen’s immunotherapy drug, aducanumab, which harnesses the body’s own defenses to fight disease and which has shown promise in slowing cognitive decline in patients with early-stage Alzheimer’s.

“It looks like we may have arrived at a whole new way to treat the disease with monoclonal antibodies,” Turner says. “It’s a crack in the door.”

Gresenz has explored how the disease plays out in people’s financial lives, particularly in the years immediately before diagnosis when neither they nor their families may realize that their financial decision-making and judgment may be impaired.

The drug testing process has been a rollercoaster, however. Georgetown was one of the sites in a multi-center phase 3 clinical trial of the drug. But that trial and another identical one were halted last spring when the drug failed a key test. After conducting a new analysis of a larger dataset from the trials, Biogen determined that the drug is effective at the highest dose and has submitted it for approval to the Food and Drug Administration.

Turner points to other significant studies led by Georgetown, including successful phase 2 trials of resveratrol and nilotinib, both of which also take aim at amyloid plaques in the brain. Neuroscientist Charbel Moussa uncovered the new use for the repurposed cancer drug nilotinib, and along with Turner, recently completed a study in people with Alzheimer’s disease. Results are expected soon.

The Memory Disorders Program is also involved in clinical trials of experimental drugs that could prevent Alzheimer’s disease. Results of those trials are expected in the next two to three years, according to Turner.

A neuroscientist, Turner has spent his career researching Alzheimer’s disease, first conducting animal research and then transitioning to human clinical research. He took over the Memory Disorders Program in 2008.

One of the biggest challenges the Memory Disorders Program faces is finding enough people to participate in the clinical trials that are crucial to testing drugs that are in the pipeline, Turner says. Some of that stems from a failure to diagnose the disease in the first place.

“One issue is that the medical community doesn’t like to bring up the topic of dementia,” he says. “It may never be discussed with patients, and even if they do develop cognitive problems, there’s a reluctance to bring up Alzheimer’s.”

Clues from the Bottom Line

Where her colleagues focus on understanding the biology and genetics of Alzheimer’s disease at the cellular level, Carole Roan Gresenz’s research examines Alzheimer’s from a behavioral perspective. The health economist has explored how the disease plays out in people’s financial lives, particularly in the years immediately before diagnosis when neither they nor their families may realize that their financial decision-making and judgment may be impaired.

Living in the Present

An avid reader and traveler, Rochelle Jaffe founded Washington, DC’s renowned Travel Books & Language Center in 1984, as well as libraries in Sierra Leone and in her Maryland retirement community in memory of her beloved daughter, Eve. “I’m a senior now, living with memory loss. But it doesn’t scare me. It’s a new experience, and I live one day at a time,” she says. Jaffe recommends a few favorite books from her collection on aging:

• Redeeming Dementia: Spirituality, Theology and Science by Dorothy Linthicum and Janice Hicks
• Dancing with Elephants: Mindfulness Training for Those Living With Dementia, Chronic Illness or an Aging Brain by Jarem Sawatsky
• Caring for a Person with Alzheimer’s Disease by National Institute on Aging and National Institutes of Health
• The Gift of Years: Growing Older Gracefully by Joan Chittister
• The 36-Hour Day: A Family Guide to Caring for People Who Have Alzheimer Disease, Other Dementias, and Memory Loss by Nancy Mace and Peter Rabins

Gresenz and colleagues merged Medicare claims data with data from a large, longitudinal survey of Americans over age 50 that asks them about their financial assets and liabilities, among other things.

The researchers found that in the two to three years before people received an Alzheimer’s diagnosis, they and their families faced a heightened risk of experiencing a reduction in their net worth, especially in liquid assets like savings and checking accounts.

As their cognitive abilities falter in the early stages of Alzheimer’s disease, people may lose the ability to handle routine financial tasks like balancing their checkbook and paying bills on time. They may also make inexplicable purchases as their memories fail, like a woman who bought the same pair of blue jeans over and over, says Gresenz, the interim dean for Georgetown University’s School of Nursing & Health Studies.

The problems can be compounded because in the early stages of the disease, many families don’t yet realize that their parent or spouse is sick and needs help with these tasks.

“One of the things that is so significant is that these expenses are happening right around the time of diagnosis, just when people are going to need to spend money on their care,” says Gresenz.

Gresenz is beginning work on a related study that will link Medicare claims data with credit card data to get a more granular picture of people’s spending in the early stages of the disease.

Inspired by Family

The issue resonates personally with Gresenz, whose mother developed dementia similar to Alzheimer’s several years ago, in her late 70s. Years before her diagnosis, her mother, who’d been widowed decades earlier and had capably managed her own financial affairs for years, inexplicably hired an unlicensed, uninsured contractor to put a new roof on her house. It ended poorly, and the financial repercussions were significant.

“Looking back, it might have been a canary in the coal mine,” says Gresenz. “In the early stages of the disease, people’s family members don’t have a strong signal that there’s a problem. They’re not aware of the deficits that are occurring.”

As the number of people with Alzheimer’s grows, many people have personal and painful experiences with loved ones who have the disease. Alzheimer’s researchers are no exception.

Like Gresenz, over the last 10 to 15 years Turner’s mother’s Alzheimer’s disease has slowly progressed.

“It’s been hard to watch,” he says. Knowing that in addition to age, family history is one of the strongest risk factors for developing the disease, Turner decided to find out if he had the APOE4 genetic variant that significantly raises the risk for developing Alzheimer’s. He swabbed his cheek and sent
a sample of saliva to a consumer genetic testing company. Happily, he learned that he does not.

The increasing ease with which people can learn their APOE status with at-home tests makes the quest to find answers all the more urgent for some researchers.

“What we’re witnessing now is that people are learning their APOE genotype, and there’s nothing they can do about their risk of these really serious conditions,” says Rebeck.

Not yet, anyway. But the search for solutions continues.

“A lot of people run the other way when they hear about or see Alzheimer’s,” says Turner. “But one of the largest unmet needs in all of medicine is the treatment or prevention for Alzheimer’s.”

Stay tuned.