More than six million Americans over age 65 live with Alzheimer’s dementia, according to the Alzheimer’s Association. That number is expected to double by 2050. “We’ve made so many advances in longevity, in keeping aging bodies alive,” says Scarlett Barker PhD ’21, a neuroscientist at Denali Therapeutics in San Francisco. “But in too many cases the mind just declines.”
Barker believes the findings of her research at MIT can improve future outcomes. Born and raised in Miami, Barker studied psychology with a concentration in neuroscience as an undergraduate at Princeton. “I was always interested in human behavior and the brain,” she says. “I got more interested in dementia during college when my godfather’s mind began to fail. His decline was so rapid. It was shocking to see him lose his personality from month to month, to change from a person who was constantly making jokes to a person who didn’t recognize the people around him.”
At MIT, Barker studied cognitive resilience against Alzheimer’s. Researchers had already observed that a small percentage of people whose brains showed advanced physical degeneration somehow did not decline into dementia. Under the tutelage of Professor Li-Huei Tsai, director of The Picower Institute for Learning and Memory and a founder of MIT’s Aging Brain Initiative, Barker and her colleagues studied sections of human and mouse brains. In both, they discovered a molecular mechanism that seems to preserve cognitive function even in brains with significant neurodegeneration.
“Li-Huei was one of the main reasons I came to MIT,” says Barker, who spent two years working as a lab technician at Washington University in St. Louis between college and graduate school. “But it wasn’t only because of her research in dementia. I was drawn to her research in epigenetics. I wanted to study how the environment and our behavior could change our neurobiology.”
Epigenetics is the study of gene expression—the mechanisms that determine which of our approximately 20,000 genes are chosen for expression in individual cells. In brain cells, gene selection determines which proteins those brain cells will produce, and at what rate. The brain uses these proteins to build connections called synapses, which channel the electrical impulses that are our thoughts and memories. Epigenetic changes in the brain can have significant impact on synapses, and therefore on cognition.
For her thesis, Barker and her colleagues examined two human datasets comprising more than 1,000 people. They discovered a link between MEF2—a transcription factor linked to the production of synaptic proteins in the brain—and cognitive health later in life. Transcription factors are proteins involved in converting DNA to RNA. They play a key role in the epigenome. Barker and her team observed that when MEF2 was present in sufficient volume, cognitive functions remained intact, even in the presence of major neuropathology.
Having established that MEF2 seemed to protect the brain from cognitive decline, the group then wanted to see whether it could induce brain cells to express more of the factor. Barker observed laboratory mice living in varied environments, ranging from solitary to very stimulating and exciting. They found that the mice with exciting, or “enriched,” lifestyles had higher levels of MEF2 in their brains. This suggests that humans might be able to ward off dementia by staying mentally and emotionally active. Even humans with a genetic disposition for dementia.
“That’s one of the cool things about epigenetics,” says Barker. “It enables you to override the genetic hand you’re dealt. And there are policy implications as well. How can we reach people who don’t have the ability to change their lifestyles? Like kids who by no fault of their own are born into environments that are not enriching or stimulating.”
At Denali Therapeutics, Barker works on a drug delivery system that can transport therapeutics through the blood-brain barrier, including therapeutics for dementia. It’s an ambitious goal. “It would be a dream to see this through to completion,” says Barker, “to help create something that can benefit people. And that dream started at MIT. Being at MIT made me feel the opposite of helpless. Like I could make a major contribution to the world. That anything was possible and no idea was too crazy or too big.”
Photo (top): MIT News, iStockphoto.