Remarkably, Doug Whitney, 75, has escaped genetic destiny. Like many members of his family, Whitney inherited a rare genetic mutation that all but guarantees he would develop early-onset Alzheimer’s disease. But Whitney, whose relatives first showed symptoms of cognitive decline in their early 50s, remains mentally sharp with no signs of the devastating disease, and a new study by researchers at Washington University School of Medicine in St. Louis helps explain why.
Their findings, published Feb. 10 in Nature Medicine, point to potential therapeutic avenues to explore to help protect against the development of Alzheimer’s.
Combing through data on Whitney’s genes, and information gleaned from his brain scans and other biological features, the researchers identified changes in genes and proteins suggestive of resisting neurodegeneration. They also observed a near absence of the buildup in the brain of the key Alzheimer’s protein — tau — that is associated with the onset of disease symptoms such as cognitive decline.
“These extensive studies indicate a remarkable resistance to tau pathology and neurodegeneration,” said Randall J. Bateman, MD, the Charles F. and Joanne Knight Distinguished Professor of Neurology at WashU Medicine and co-senior author of the study.
Whitney, who lives near Seattle, was first identified as an exceptional case in 2011, when he arrived at WashU Medicine to enroll in a groundbreaking Alzheimer’s study: the Dominantly Inherited Alzheimer Network (DIAN) study. The international network focuses on families with inherited forms of Alzheimer’s disease that lead to cognitive decline at an early age, typically in a person’s 30s, 40s or 50s, and is led by WashU Medicine clinicians and researchers in the Charles F. and Joanne Knight Alzheimer Disease Research Center.
“When he came to WashU Medicine for the first time, together with his cousin, he was already 10 years past the age of onset for his family,” said Jorge Llibre-Guerra, MD, an assistant professor of neurology and co-first author of the study. Whitney’s family members with the same genetic variant typically showed signs of the onset of Alzheimer’s around 50 years of age. Because Whitney showed no sign of cognitive decline, WashU Medicine clinicians and researchers initially assumed that he was not a carrier of the genetic variant in the presenilin 2 (PSEN2) gene that had led to early-onset Alzheimer’s for every other member of his family who had inherited the genetic mutation.
“It came as a big surprise to learn that he was actually a mutation carrier,” said Llibre-Guerra. “At that point, he earned the title of the DIAN escapee, because he actually was able to escape the expected course of the disease.”
Whitney is one of three known escapees — more formally called “exceptional resilience mutation carriers” — in the world. The inherited form of Alzheimer’s that they have avoided accounts for fewer than 1% of all cases worldwide, and researchers expect that identifying successful treatments for this rare form of Alzheimer’s will inform prevention and treatment efforts for more common forms of the disease that develop later in life. So, identifying a case so rare and relatively early in a person’s life was an incredible opportunity for the WashU Medicine team: some unknown factor in Whitney’s body or in his genes was preventing the PSEN2 mutation from fully taking hold.