Within the next 30 years, the number of Americans living with Alzheimers Disease will likely grow by an estimated 240 percent. By the end of that 30-year mark, the disease and other dementias will cost the United States nearly $1.1 trillion. In seniors, it kills more patients than breast cancer and prostate cancer combined. Every 65 seconds, a person in the U.S. develops Alzheimers, according to the Alzheimers Association. But how has research into this disease changed over the years, how has the University shaped this research and where is it leading to now?

Over the past ten years, there have been significant advances made in the understanding of and approach to a disease that currently has no cure. This past September, the University received the largest federal grant in its history to research care for Alzheimers disease as part of this effort.

Alzheimers disease, or what may be more accurately referred to as a syndrome because its cause is unknown, is a form of dementia a mental condition characterized by issues in cognitive functioning and difficulties with daily activities.

Early treatments for Alzheimers Disease

There are at least two distinctions of AD: clinical and pathological. Clinical syndrome AD specifically refers to individuals with symptoms of dementia. In contrast, pathological Alzheimers refers to the phenomena of amyloid plaques and tau neurofibrillary tangles in the brain, both characterized by buildups of their respective proteins. Traditionally, pathological AD is identified post-mortem, or after death; but over the past ten years, two newer techniques that can identify pathological AD in living people have been created: PET scans and lumbar punctures. In recent years, researchers have begun exploring a third and more accessible test a blood screen.

More recently, people have also associated mutations in three specific genes as predictors of AD. But in an article published this year in Nature, Assistant Professor of Opthalmology Joseph Arboleda-Velasquez at Harvard Medical School and his group showed that there may be a mutation that can delay the progression of AD.

Over the years, the way people have thought about the underlying pathology of AD has evolved. In the 1990s, people believed that it was caused by a deficiency in neurotransmission how nerves communicate in the brain. Then, researchers began thinking that it was amyloid plaques that caused the disease, and that these plaques would build up for years before an individual was finally diagnosed. In a clinical trial known as the A4 study, coordinated at the University of Southern California, researchers tested an anti-amyloid therapy, but it failed clinically. Scientists have theorized that perhaps this failure was caused because the patients were treated too late to counteract the disease.

The last decade in research at Brown and the greater University community

Brian Ott, professor of neurology at the University and director of the Alzheimers Disease and Memory Disorders Center, managed a clinical site used for the testing of Tacran, the first drug to clinically succeed for Alzheimers treatment. Tacran targeted the deficiencies in neurotransmission, one of the early hypothesized causes of AD. All of a sudden, people saw Alzheimers as something that was treatable, Ott said. Unfortunately, Tacran has since been found to be toxic to the liver.

Ott also conducted clinical trials for Memantine, which is the last Alzheimers drug to have been approved by the FDA in the last 16 years. Memantine blocks NMDA, a receptor found in nerve cells. While Memantine appears to be safe for human use, it only targets explicit symptoms of dementia and does not actually prevent the diseases progression. Memantine is one of only two types of currently approved treatments.

Earlier this year, Ott and his team collaborated with the lab run by William Heindel, professor of cognitive, linguistic and psychological sciences at the University, in a large, controlled clinical trial. Their research showed that transcranial magnetic stimulation, which uses magnetic fields to stimulate neurons and is often used to treat depression, could potentially also treat dementia.

Currently, TMS is approved for the treatment of Alzheimers disease in various countries in Europe and Asia but not the U.S., Ott said.

In 2013, University researchers began clinical trials for the drug Aducanumab at the Rhode Island and Butler Hospitals in coordination with biotechnology company Biogen. Named the EMERGE clinical trials, these tests administered high doses of anti-amyloid treatment, similar to the A4 trials. Aducanumab is being submitted to the FDA in 2020 for approval for what may be the first disease-modifying Alzheimers treatment since 2003. But scientists remain wary, given that only one of their two clinical trials showed success.

Recent advances in improving Alzheimers care

Stephen Salloway, professor of neurology and psychiatry and human behavior at Alpert Medical School and director and establisher of the Memory and Aging program at Butler Hospital, has conducted more than 100 clinical trials on AD and related disorders. The cost of care for Alzheimers is already greater than that of cancer and heart diseases, taking to account formal and informal costs, Salloway said.

About four years ago, Salloways program became the first to perform an infusion using an antibody that targeted beta amyloid to try to prevent AD. Unfortunately, the clinical trial was not successful, but it does have implications for future research.

At the community level, Salloway and his program are organizing prevention swab parties all around the state. These swab parties allow people to swab their cheeks; the research team can then use genetic tests to identify Alzheimers risk genes. If someone tests positive for any of the risk genes, they become eligible to participate in research studies.

In 2011, Ott received a grant from the National Institutes of Health to start the Rhode Island Alzheimers Prevention Registry. Families can sign up for these registries, and they are sent monthly newsletters and announcements for recruitment to prevention-related studies. Butler Hospital also has a prevention registry run by Salloway that allows people to sign up for studies and receive updates on current research. These registries are important venues to reach out to the public, Salloway said.

More recently, the Carney Institute of Brain Science has made it a greater priority for the University to study diseases like Alzheimers. With increased funding, the Institute has been able to recruit more faculty, including Yu-Wen Alvin Huang, assistant professor of molecular biology, cell biology and biochemistry. Huang came from a Stanford Nobel Laureate lab and is developing a chip brain model to study AD signaling pathways. This year, the University also opened the Institute for Translational Neuroscience, which aims for scientists who work in clinical and lab settings to work together on brain disease-oriented research.

Largest federal grant in University history

This past September, the University was awarded a $53 million grant for Alzheimers research, which will be co-led by Vincent Mor, professor of health services, policy and practice. Mor conducts his public health research in nursing homes where 70 percent of his research population has dementia. Over the past ten years, he has seen dementia research generally move from observational work to more intervention-based studies.

In an early project, Mor examined whether there was a relationship between the amount of money spent to fund nursing homes and the self-reported experiences of their residents. The study showed that more money correlated to a decrease in self-reported negative experiences.

In an ongoing project, Mor has been studying music and memory in an effort to create personalized music for people with advanced stages of Alzheimers. He hopes these programs can be implemented in nursing home settings to reduce treating patients with antipsychotic drugs. As a public health professional, Mor explains that just as public health focuses on the population, we focus on the population of people with dementia. When we have that information, we can identify things that work for the (entire) population, not just a handful of subjects.

The $53 million grant will fund projects across the country like the one completed by Mor and his team in nursing homes.

The notion that you can take existing, large administrative data collected by providers and turn it into a data system to test outcomes in a large population base is being used more in the field, Mor said.

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