Novel study at Brown shows how late-life health traces back to what happened in the womb

Researchers examined how children were developing by recording their growth, height, weight, perceptual and motor skills, neurological behavior, and medical conditions, recorded observations and data at birth; at four, eight and twelve months; and at ages 3, 4 and 7 years.

In the 1980s, when the children entered their 20s, the research shifted into a different phase as Buka and other investigators at Brown and Harvard University followed up with the now-adult participants in Providence and Boston, expanding their focus to consider conditions that affect people in young adulthood, middle age and later. The researchers also extended the study to include the next generation.

Information collected from the same families is the best way to learn the causes of disease and conditions that develop across the lifespan, Buka said. During follow-up visits, researchers assess participants' physical activity, memory and cardiovascular measures, focusing on the brain, heart and general well-being. In keeping with technological advancements, the team is now able to use cutting-edge tools to analyze DNA, RNA, proteins and metabolites.

Buka, who leads the Brown research team, has been joined by Jill Goldstein, a clinical neuroscientist and professor at Harvard Medical School and the Department of Psychiatry at Massachusetts General Hospital. The team has been able to sustain participation with more than 4,000 cohort members, some at multiple times at different ages, and Buka estimates that the team has conducted around 5,000 assessments. They continue to reach out to study participants to add even more information to their database.

"Studies are usually conducted when people have already developed Alzheimer's disease and other disorders of aging," said Goldstein, a principal investigator of the New England Family Study. "We have the advantage of being able to continuously follow a large group of people prior to illness and perform advanced tests to identify red flags, patterns and other signs. That's practically unheard of. The data from the New England Family Study is an absolute gold mine."

Research with real-world benefits

Ongoing New England Family Study projects by researchers at Brown and Harvard include studies of how mood and anxiety, memory, information processing and brain function change with age; an investigation into early causes and preventive measures for breast cancer and other types of cancer; and efforts to understand how early-life factors may contribute to the risk of adult heart disease, its co-occurrence with depression and Alzheimer's disease, and how this differs by sex.

Study participants not only have the opportunity to learn about their physiology and brain function, but also, in some cases, receive personalized recommendations for how to reduce their risks.

As part of one proposed study, participants will be screened for biomarker and brain changes, or clues in blood or other fluids, that can indicate the potential onset of Alzheimer's disease or dementia even before a person is experiencing symptoms.

"This study is uniquely poised to help us answer some important questions about the development of Alzheimer's and dementia," said Dr. Ted Huey, the associate director of Brown's Center for Alzheimer's Disease Research and director of the Memory and Aging Program at Butler Hospital. "We know there are disparities in incidence and prevalence of Alzheimer's and dementia. This study allows us the opportunity to investigate the biological basis of these disparities, as well as the impact of social determinants of health. It's remarkable."

Participants will be able to learn about their risk for Alzheimer's and dementia and about resources available to help them manage their condition, Huey said, including the option to enroll in one of the many clinical trials at Butler.

Another study led by Buka and Brown physician-scientist Dr. Charles Eaton, which is funded by a federal grant and involves 1,500 participants, is exploring the mechanisms that may cause premature, low-weight babies to be at risk for heart disease in middle age.

"The theory is that a fetus that is not adequately nourished in the womb, for whatever reason, may react physiologically by limiting development of certain systems, including its cardiovascular system," Buka said.

The results of the study may influence proactive medical treatment for high-risk, growth-restricted babies, Buka said, to help prevent the development of heart disease later in life.

Goldstein is leading New England Family Study projects that include prenatal immune and stress antecedents of sex differences in the risk for depression and heart disease; discoveries that have led to the development of a novel neuromodulation treatment targeted to the brain circuitry that regulates mood, anxiety and cardiac tone through the vagus nerve; a clinical algorithm for identifying women who are at risk of developing Alzheimer's disease; and tools to identify immunological red flags for major depression that may provide clues to why women and men respond differently to antidepressants.

"The study participants are directly contributing to the development of new diagnostic tools and therapies on conditions ranging from depression to the risk for Alzheimer's disease," Goldstein said.

Participants have described many benefits of being a part of the long-running New England Family Study. From a practical perspective, the brain scans, heart monitoring and laboratory results have detected unknown health problems leading to improved diagnosis and treatment. Access to records from early childhood have helped participants document long-term disorders such as depression, ADHD or learning disabilities. And results of assessments in mid-adulthood have been used to track changes in cognitive abilities and brain and cardiovascular function to help understand risk factors for Alzheimer's disease and potentially other disorders of aging.

Some members are motivated to continue to participate out of respect for their parents, or respect for the scientific process. One participant recently spoke about his experience at a data conference at Brown.

"I had faint memories of participating even as a young boy," said Jason, who shared only his first name. "When I was contacted again [by the researchers] in the 90s, I jumped at the opportunity. At the time, I didn't know the impact the study was having globally, but I knew that what they were discovering was of serious value."

Buka confirmed that Jason's sentiments echo those he's heard from many participants.

"They know they're special," Buka said. "People have told us that participating in the study gives their life special meaning; that they feel like they're making a contribution to society, to the world. We want them to know: They really are unique, and we're so grateful."