Hannah Mackay knew something was wrong with her father when he wandered into his granddaughter's room, waking the 2-year-old for the second time that night. “He wasn't understanding what was going on and couldn't answer me when I asked why he'd done that,” recalls Mackay, 37, a police officer in West Sussex, England. “He had this look of what I can only describe as utter confusion.”

The changes in her father were gradual at first and different each time, says Mackay. Her father, an engineer and longtime do-it-yourselfer, was in his late fifties when he began struggling with everyday tasks like driving, using tools, and assembling toys for his grandchildren. He made financial decisions that were out of character, and he became less empathetic. “We thought maybe it was his job or that he was going through a stressful time, but the changes got to a point where it became obvious that something more was wrong.”

The family embarked on a yearlong investigative journey that included a slew of doctors' visits, neurologic exams, and medical assessments. In 2017, a genetic test finally provided some answers: Mackay's father had a mutation in the GRN gene, which gives instructions for making a protein called progranulin. The mutation is found in about 10 percent of people with a condition called frontotemporal dementia (FTD).

For Wanda Smith, her mother's diagnosis was not as definitive; in fact, it was plain wrong. “This was the 1980s, so when we brought my mother to see a neurologist, we received the same response that most people seeking a diagnosis for memory problems received at the time: ‘She must have Alzheimer's disease,’” says Smith, now 64, who lives in San Diego with her husband.

Smith describes her mother as “a gentle woman with a backbone of steel.” Widowed in her thirties, she raised four children and worked in the billing department of a community hospital for 12 years. She was detail oriented and quick with numbers, but in her early fifties she began forgetting things. It all came to a head one Thanksgiving. “We had just finished our big meal, had cleaned up, and the whole family was sitting in the living room watching football, when my mother walked in very upset that she wasn't getting any help with cooking,” remembers Smith. “She had no memory of the meal, the cooking, the relatives who came by to visit, nothing—she had forgotten the whole day.”

Eventually her speech started to decline. Her language became scrambled, and she would point to something and be unable to find a word for it. At age 52, Smith's mother was diagnosed with what her doctors thought was Alzheimer's disease. Researchers had yet to dive into genetic testing for neurologic symptoms—the missing link, it turns out, for Smith's family.

Her mother died at age 58 in 1988. In 2006, Smith finally got the truth. Researchers were able to do a genetic test on a saved sample of her mother's blood and found the progranulin gene mutation. In the 15 years since that discovery, Smith has been advocating for patients and families coping with the disease.

FTD is a rare neurodegenerative disorder that causes significant nerve cell loss in the brain's frontal and temporal lobes. Although it affects only about 15 to 22 people per 100,000 worldwide, it accounts for up to 10 percent of all dementia cases.

How It Differs

FTD is unlike the more common types of dementia, which are associated with memory and problem-solving difficulties (such as Alzheimer's disease), or movement difficulties, sleep disorders, and hallucinations (such as Lewy body dementia). Instead, FTD primarily affects personality, behavior, and the ability to communicate. It also affects judgment, decision making, and risk assessment. People with the disease may make rash financial decisions or ignore the feelings of family members or loved ones, says Bradford Dickerson, MD, FAAN, director of the frontotemporal disorders unit at Massachusetts General Hospital in Boston.

It also occurs at a relatively young age. “The disorder peaks [in frequency] at age 65 and becomes less common in older populations, as opposed to Alzheimer's disease, which gets more common as people age,” says Thomas M. Wisniewski, MD, director of the Alzheimer's Disease Research Center and professor of neurology, pathology, and psychiatry at the New York University Grossman School of Medicine.

FTD advances more quickly than Alzheimer's and the prognosis tends to be worse. The mean survival rate of patients with FTD is between three and seven years after symptoms appear. “Clinical symptoms can be quite varied, and diagnosis is often delayed for a number of years,” explains Dr. Wisniewski. “Patients are often misdiagnosed because symptoms such as speech impairment can mimic those of a stroke. The disorder also can mimic psychiatric disorders like schizophrenia, bipolar disorder, and depression.”

In three years, Mackay's father went from being helpful and reliable to nonverbal and unable to care for himself—a devastating decline that her family is still coping with. “Suddenly my father—a happy, capable person—started to struggle to make a cup of tea,” says Mackay. “It has changed our lives. We've gone through a grieving process even though our dad is still alive.

“FTD is all-consuming and just as devastating for caregivers and family members as it is for the person who has the condition,” adds Mackay, who recently made the difficult decision to move her father into a nursing facility. “We wanted to provide the best, most concentrated care for him going forward,” she says.

Smith was the primary caregiver for her mother, who eventually moved in with her. While Smith's two children were learning to speak, her mother was losing her ability to communicate and care for herself. At one point “I had three in diapers—my toddler, my infant, and my mother,” says Smith.

Genetic Component

The two main types of FTD are behavioral variant frontotemporal dementia (bvFTD), which affects personality and behavior, and primary progressive aphasia (PPA), which affects the ability to speak and comprehend speech as well as executive functions such as self-control, problem solving, and time management. Mackay's father has bvFTD; Smith's mother had PPA.

“Neuroimaging with a PET scan can look at the metabolism of different parts of the brain, which is helpful in differentiating between the two types and ultimately making an accurate diagnosis,” says Dr. Wisniewski.

About one in five cases of FTD is inherited. Most genetic cases are caused by a mutation in the C9orf72 gene, the tau (MAPT) gene, or the GRN gene, although “genetic abnormalities can be in any of some 20 genes that are linked to the presentation,” says Dr. Wisniewski.

In cases of an autosomal dominant gene—meaning that a single disease-associated mutated gene causes FTD—“there's a 50 percent chance of passing that gene down to each one of your children,” says Erik Roberson, MD, PhD, director of the Alzheimer's Disease Center and the Center for Neurodegeneration and Experimental Therapeutics at the University of Alabama at Birmingham. “So genetics play an important role, and it's certainly something to talk to doctors about, especially if there is a family history.”

Once Mackay learned of her father's genetic mutation, she connected the dots and realized that her paternal grandfather—who died in his mid-fifties—likely had FTD, although it was diagnosed as Alzheimer's disease at the time. Knowing that FTD runs in her family, Mackay had to choose whether to get tested to find out if she was destined for the same challenges as her father and grandfather or live her life without knowing.

“It probably took me 10 months to decide,” says Mackay. “I weighed all sorts of different things: How does this affect me, my children, the people around me, and planning for the future? Will I be treated differently? Will my family and I be able to cope if I have the gene?”

In the end, uncertainty seemed worse to Mackay. “I needed to know what I was facing in order to take action against it,” she says. In December 2018, she found out she carries the gene mutation that will likely lead to FTD. It also means her daughters, ages 5 and 7, have a 50 percent risk of developing FTD. “I remember crying a lot at the appointment,” recalls Mackay. “Not because I was sad—I was crying with relief that that part of the process was over. I now had the result and could do something with it.”

Taking Action

The next year, Mackay began helping the United Kingdom–based Alzheimer's Society with fundraising and research efforts. She has addressed various conferences, universities, and research institutes around the country to raise money and awareness. She's even traveled to Washington, DC, to speak about her experience. She also maintains a blog, where she's written about her decision to get tested, told stories about her father, provided updates on her fundraising campaigns, and shared details about her own progress. “By writing about it and sharing my experiences,” says Mackay, “I've been able to help support people who are facing their own FTD decisions and journeys with their relatives.”

Remaining hopeful is key, says McKay, who believes her advocacy work is a good example for her daughters. “I want my kids to see that you can turn a negative into a positive,” she says. “From a very young age, dementia has been a part of their lives. And whether they have FTD or not, it's going to be a part of their lives going forward. My friends, family, and employers have been amazing and so supportive, as has my community.”

Smith too was compelled to become an advocate after discovering her family's genetic predisposition. She co-leads a support group through Alzheimer's San Diego, working to spread awareness about the importance of genetic testing and the benefit of knowing what you're up against and how best to treat it. “The hardest part is dealing with the unknown, so I encourage families to get their genetic testing done. If there's a hereditary basis, that's significant for future generations to know,” she says.

“Once the initial shock of the diagnosis is over, families should behave as facilitators,” says Smith. “If your relative doesn't remember something, provide the answer. Most importantly, never shame them with harsh words or make a big deal out of the hundredth time they repeat the same comment. Be attentive, but let many of the shortcomings slide. And find time to laugh.”

Both Mackay and Smith say it's important for people with FTD to engage in enjoyable and stimulating activities. It can be as simple as listening to music or sitting in the garden watching birds. Following a daily routine also can help patients and caregivers as long as there's room for flexibility, since FTD can be unpredictable.

“To help my mother find purpose, I would encourage her to play with her grandkids,” says Smith. “Sometimes that was just sitting in the rocking chair with my toddler, which meant the world to her and me.”

Currently no treatments approved by the US Food and Drug Administration exist for FTD. Some antidepressants and selective serotonin reuptake inhibitors can help with symptoms such as depression, irritability, or agitation, since FTD is linked to serotonin and dopamine deficits in the brain. “In patients who have more severe behavioral problems, antipsychotics also can provide some benefit, although they do have side effects,” adds Dr. Roberson.

The Road Ahead

Clinical research into disease-modifying therapies—medications that target the underlying disease process—is just starting, says Dr. Roberson. “Each type of FTD is going to have a different specific disease-modifying therapy, which is why an accurate diagnosis is so critical,” he says. “For example, the GRN mutation indicates a loss of progranulin, so strategies such as increasing progranulin expression through gene therapy are being explored.”

Scientists have deepened their understanding of the disease, says Dr. Roberson. “For a long time, FTD was the neglected stepchild of dementia research and was poorly understood. But we're making great strides in finding specific ways to treat the disease.”

For FTD patients with aphasia (loss of language abilities) or other communication problems, speech therapy can be helpful. That wasn't available for Smith's mother in the 1980s, but Smith encourages families to get involved in research organizations that are testing new treatments.

She also suggests caregivers seek out ideas and solutions from other families who have been in similar situations. “Manage FTD or it will manage you,” she says. “Be empowered with as much information and as many resources as possible, because drowning in caregiving is not a healthy way to live and you'll eventually burn out.”

Mackay is optimistic that new treatments will be available if her children need them. “I believe we will have the scientific knowledge and capability to beat this terrible disease,” she says. “I've made sure my daughters are supported financially and emotionally for the future, but the biggest thing I try to do is to seize moments—to create joyful memories here and now. To make sure that whenever my time comes, our family and friends have those moments to look back on.”

Clinical Trials for Frontotemporal Dementia

Research into the causes of frontotemporal dementia (FTD) and possible targets for treatment is in high gear. A small study published in Neurology in February found that areas of brain damage known as white matter hyperintensities and associated with vascular problems and Alzheimer's disease are also visible in FTD. In fact, the number of white matter hyperintensities was higher in people with FTD than in people with Alzheimer's disease, and elevated levels correlated with more severe disease. Researchers hope further study will help determine the underlying molecular cause of the white matter hyperintensities.

Scientists at Denali Therapeutics have developed DNL593, a recombinant progranulin protein that can cross the blood-brain barrier and enter cells to treat patients whose FTD is related to a deficiency in progranulin, though it is not yet being tested in clinical trials. Here is a sampling of ongoing trials.

ALLFTD Study

• What: Researchers are collecting cognitive and behavioral assessment data from patients and sharing them with the scientific community to prepare for treatment trials targeting most varieties of FTD.
• Where: 19 sites across North America
• Contact: Email info@allftd.org.
• Website: allftd.org

PROCLAIM Study

• What: Subjects are needed to test an investigational drug, PR006, for treating the underlying cause of FTD at the genetic level. A neurosurgeon or radiologist injects PR006 one time into the cerebrospinal fluid at the base of the skull.
• Where: Florida
• Contact: Call Jessica Garaycoa at Prevail Therapeutics at 689-216-3100, or email her at Jessica.Garaycoa@ppdi.com.
• Web page: prevailtherapeutics.com

IONIS-MAPTRx, or BIIB080

• What: A phase 2 study is testing the safety and efficacy of an investigational gene therapy for some forms of FTD. Scientists inject the drug, which is designed to selectively reduce production of tau protein in the brain, through lumbar puncture.
• Where: Canada, UK, Germany, the Netherlands, Finland, Sweden
• Contact: Call 760-931-9200.
• Web page: ionispharma.com

AL001

• What: A phase 2 trial is recruiting patients with FTD caused by a granulin C9orf72 mutation to evaluate the safety and tolerability of the monoclonal antibody AL001, a synthetic protein that mimics human antibodies in the immune system and was designed to increase levels of progranulin in the brain.
• Where: Worldwide
• Contact: Call 833-346-3383.
• Web page: alector.com

Resources for Frontotemporal Dementia

• Association for Frontotemporal Degeneration: theaftd.org; 866-507-7222
• Alzheimer's Association: alz.org; 800-272-3900
• FTD Disorders Registry: ftdregistry.org; 888-840-9980
• National Institute of Neurological Disorders and Stroke: ninds.nih.gov; 800-352-9424
• National Organization for Rare Disorders: rarediseases.org; 800-999-6673