Posted with permission from STAT

ELLIJAY, Ga. - Louise Lowman Lee remembers stories about her great-grandmother being put in a fenced area in the backyard, so she could wander safely. She watched her mother patiently care for her grandmother, who lost her reason, inhibitions, and ability to care for herself. Then Alzheimer's disease gradually eroded the brain of her devoted mother, too.

But when Lee and two of her sisters brought their mother, Mildred Chastain Lowman, to Emory University in Atlanta in 2006, they weren't thinking about the family tree. They were just looking for the best possible treatment.

Dr. Allan Levey asked them to come into a conference room with a genetic counselor and other members of his team. "We've been waiting for you," he said.

"We were sort of stunned," recalled Sherry Dunn, another sister. "We were looking at each other like, 'What are they talking about?'"

Levey explained that he had seen other Chastains in his clinic over the years and had begun studying their pattern of Alzheimer's inheritance. Genetic studies are stronger if they include multiple branches of a family tree, and here was Lowman, a distant cousin. She even looked uncannily like another Chastain patient Levey had treated.

The Lowman sisters immediately agreed to give blood samples and take baseline cognitive tests. Their personal struggle took on a greater purpose. Emory researchers "needed us just as much as we needed them," said the youngest sister, Holly Phillips.

Researchers have since determined that there exists in the extended Chastain family an astonishing rate of Alzheimer's: The disease strikes 44 percent of family members with an affected parent. No other large family has been found with such a high likelihood of inheriting the typical, late-onset type of Alzheimer's. The rate suggests some family members carry a previously unknown gene so powerful that it can cause disease in someone who receives a copy from just one parent.

Despite sparse funding for their work, Emory scientists say they have made progress in their quest to identify this new Alzheimer's gene, which could provide clues about the disease's causes, and possible treatments.

"If you want to really be able to find a new gene with certainty, nothing is better than having one large family of dozens or hundreds of family members that you can study," said Rudolph Tanzi, a Harvard University neurogeneticist who co-discovered genes that cause a less-common, early-onset form of Alzheimer's. "It's very hard to get a family like that."

Lowman's last days were heartbreaking but also bittersweet, a descent back into childhood softened by the constant, reassuring presence of her daughters.

They drove her around dirt roads in Ellijay, a mountain town in north Georgia, as she fretted about "getting home" to her mama and daddy, who had passed away years before. Eventually, she calmed down and accepted the trip back to her real home. They spoke to the young girl Lowman imagined she saw at the foot of her bed and promised to take good care of her. If she became upset about taking a shower, they climbed in with her.

Lowman died in 2008 at the age of 78. Every one of her five siblings who lived into late adulthood had Alzheimer's disease. So did her mother and grandmother. On another branch of the family, her grandmother's brother had Alzheimer's. All nine of his children who lived to late adulthood either were diagnosed with Alzheimer's or had undiagnosed dementia. And yet there are sub-branches of the family with no Alzheimer's, as if a genetic mutation is absent.

That plague on the family tree stirs dread among the next generation of Chastains - but it also has inspired Lowman's daughters to rally their relatives to participate in Emory's research.

"We were told in our lifetime we might not have the answer or a cure," said Dunn, who is 58. "But we're thinking about our children and grandchildren."

The Chastain family's DNA gives scientists perhaps their best shot at finding the genetic origins of late-onset Alzheimer's, a goal that has eluded them for decades.

Researchers have found gene mutations strongly linked to early-onset Alzheimer's, in part by studying a large Colombian family with hundreds of affected individuals; its symptoms start when people are in their 40s and 50s. But no such gene has been found for the disease that strikes after age 65 - which accounts for more than 90 percent of cases.

A gene called APOE-e4 modestly increases the risk of late-onset Alzheimer's in some people, but it isn't enough by itself to cause disease. Instead, the risk seems to come from a complicated combination of gene variants, or mutations.

"If we can identify a new gene, it could have profound impact on understanding the disease," said Levey, a neurologist and director of Emory's Alzheimer's Disease Research Center. Genetic sequencing of the Chastains has identified some promising targets, but has not yet produced a pivotal result, he said.

The Chastains did not know, at first, that they were any different from thousands of other families with a history of Alzheimer's, but most have embraced the study. Emory University now has blood or saliva samples from about 250 relatives in different branches. Eleven of the Chastains donated their brains for autopsy after they died, and others have undergone spinal taps, MRIs, and cognitive tests.

"This family to this day remains amazingly engaged and interested in participating in research," Levey said. "They understand the implications of the disease for their family. They're afraid, understandably. And they're brave and courageous and they want to make a difference."

Levey's study of the Chastain family dates back 17 years, to when Betty Chastain Bagwell walked into his office in Atlanta.

Her descent began, as it usually does, with small mishaps. She couldn't remember where she put her keys or her purse. She got confused in grocery aisles she had navigated many times before. She accidentally pulled her car into her neighbor's driveway instead of her own.

One day, while Bagwell's son was fixing her clothes dryer, she picked up a shirt to put it on a hanger. She fumbled with it, but couldn't maneuver the sleeves around the ends. "She looked at me with this look of a certain knowing and sadness and said, 'I've done this a million times, but for the life of me, I can't remember how this goes,'" her son recalled. (He asked not to be named because of the stigma that still surrounds Alzheimer's disease.)

Bagwell's diagnosis confirmed what her three children already knew. On a drizzly spring day in 2000, they brought Bagwell to see Levey, hoping the neurologist could offer something to forestall the decline. Chastain was a familiar name. Levey had consulted with other family members and even performed some of their brain autopsies, the ultimate confirmation of Alzheimer's.

But when he asked the routine question about family history, the answer startled him. Betty Bagwell's sister and brother had Alzheimer's. Her father was one of 12 siblings. Three had died as children, but of the remaining nine, all had a diagnosis of Alzheimer's or some undiagnosed form of dementia.

"If you had only two or three or four or five children, I wouldn't even think about making any conclusions [about heredity]," said Levey. That can happen by chance, just as it's possible to flip a coin and land on heads several times in a row.

But nine times? "It could happen randomly, but [the probability] is so small that it made me think it's very likely there's a genetic cause in this family," he said.

Bagwell's son called family members and confirmed that his great-aunts and great-uncles all had Alzheimer's, "senility," or dementia in their older age, even if they died of a different cause. When Betty Bagwell died in 2005 at age 76, her family donated her brain to Emory, and Levey was able to see the telltale amyloid plaques and tau protein tangles that are the defining characteristics of the disease.

Levey consulted with Stephen Warren, a renowned Emory geneticist who played a pivotal role in the discovery of the gene for fragile X syndrome. Warren agreed that the family history indicated a "very strong genetic cause," possibly a single gene. Emory hosted a Chastain family reunion and asked for blood donations.

The hunt was on.

It turned out that the Chastain family had one enormous advantage for a geneticist trying to track the course of a disease through generations. Few families know as much about their "pedigree" as the Chastains.

Genealogists have penned volumes on the family, including "Chastain Kith and Kin," which spans 280 years and 402 pages. An online genealogy site contains more than 18,000 names. The Pierre Chastain Family Association has about 320 dues-paying members in 40 states.

They all share a single forbearer: Pierre Chastain, a physician and Huguenot who came to Virginia with his family in 1700 to escape religious persecution in France. His wife and two of his five children died in the first harsh winter, but he quickly remarried and had five more children.

Genealogists have traced the family's path through early American history. A great-grandson, born at the start of the American Revolution, settled on land in the north Georgia mountains that had just been wrested from the Cherokee Nation. He had 21 children; among his descendants were Mildred Chastain Lowman and Betty Bagwell. Another branch settled in South Carolina and later moved into the same mountain valley, along the Cartecay River in Ellijay.

The Lowman sisters didn't know the Bagwells; they were three generations removed. They didn't know about Pierre Chastain's many descendants. But when they heard from Levey that their kinship might hold the key to a cure, they got to work.

They called their cousins and people they hadn't even known were kin. They invited Emory researchers to the poolside reunion of Mildred Lowman's branch of the family. Virginia Rutledge, a younger cousin who owns a testing lab, offered "Chastain Days." Family members lined up to give blood at the clinic, where a paper scroll displaying the family tree stretches around the lobby and down a hallway. Rutledge and another cousin who is a phlebotomist attended national Chastain family reunions to take blood.

"The more branches get involved in it, the better the chance of finding that common gene," Dunn said.

Neurogeneticist Dr. Thomas Wingo, who began his work as a fellow with the Emory Alzheimer's Disease Research Center in 2008, recently selected seven Chastain family members with Alzheimer's from different branches and began sequencing their genomes. He was looking for genetic changes, or variants, that they share but are rare or not found in the general population. Emory has blood samples from unaffected, unrelated people to use as controls.

He immediately found some promising candidates, but sequencing technology can produce false positives. When he repeated his work, some of those differences turned out to be errors. Still, the results of the whole genome sequencing gave him a guide as he looked at samples from about 250 family members, focusing on chunks of the DNA where variants are more likely to reside.

He has tested about 2,000 variants. Four are "significant"- which means they may be associated with Alzheimer's disease. More testing will confirm or refute the finding.

"There's enough power in this pedigree to find two or three variants in genes that are likely damaging in some way - that are causal or have a high effect in this family," Wingo said, adding, "I would settle for one."

Most of the work at Emory is being done with money from private donations and a career development award Wingo received from the Veterans Affairs Office of Research and Development, rather than through a large federal grant. Levey said he wanted to show progress in the gene search before applying for a large grant.

In the years after Betty Bagwell arrived, Levey focused on gathering samples, sorting out the family relationships in the vast "pedigree," and verifying that the family didn't carry one of the three known genes, which have been linked to early-onset disease.

Financial constraints, along with the complexities of analyzing millions of sites on the genome, shaped Wingo's sequencing strategy. But as the cost of sequencing declined and computing power surged, Wingo has expanded the scope and pace of his work.

Harvard's Tanzi, director of the Genetics and Aging Research Unit at Massachusetts General Hospital in Boston, worked with the Emory team early in the Chastain research. He said he hopes to begin a new collaboration that relies on the greater power of whole genome sequencing. His interest is more than just scientific: One of his neighbors and closest friends is a Chastain.

Ernie Chastain, 68, figures Alzheimer's isn't just about a gene; life choices must make a difference. So Chastain, a nephew of Betty Bagwell, rarely eats red meat, exercises at least three or four times a week, and takes a baby aspirin every morning and evening to counteract inflammation, which is a feature of Alzheimer's. "You've got to fight the aging process as much as you can and hope for the best," he said.

When he sips red wine on the deck of his Massachusetts beach home, Chastain often shares the bottle with Tanzi. They bonded over their mutual love of music - especially jazz, Aerosmith, and the Beatles - but by coincidence, they discovered they share a resolve to conquer Alzheimer's.

"I think we're at the brink of getting the answer whether there's a new gene in that family or not," Tanzi said.

Louise Lowman Lee, 62, knows that her sisters are watching her for any signs that she's slipping. They agreed to keep an eye on each other, and after years of caring for their mother, they know what it will be like. Repeating questions that have just been answered. Constantly losing things, or putting them in unexpected places. Memory lapses, covered up by excuses. A faraway gaze.

Being the oldest living sister (Daisy Greer died of lymphoma in 2016) makes Lee feel the most vulnerable. But she carries on, placing faith in God and science; after all, when her father died of lung cancer at age 70, he was sharp as a tack.

"If I gave in to the fear, I would sit around and think there's something wrong with me," she said. "I think I'm not going to get it. I think my sisters and brothers aren't going to get it."

Soon it will be time for Lee and her sisters to take annual cognitive tests as part of a large, long-term registry at Emory that is unrelated to the Chastain study. The test typically begins with some words to remember and instructions to draw a clock. Then the tasks become more stressful. Listen to a story and repeat it back. Repeat a series of complex numbers. Now repeat them backwards.

"I know I don't remember numbers backwards as well as I used to," said Lee.

Aging causes mild changes in memory recall. But if those tests show early signs of decline, she wants to begin on medication that slows the progress of Alzheimer's. Meanwhile, she keeps active, mentally and physically. And she hopes the genetic studies will bear fruit - soon.

"If I thought it would stop it or if it would give everybody else a chance, they could have my brain right now. I'm serious - if it would mean nobody else in the family had to have it," said Lee. "I just so much don't want anybody else to have it."