When Mike McGuff was in college at Baylor University in Waco, TX, he made a point of calling his mom, Elizabeth, at least once a week. By his senior year, their conversations began to feel a bit "off." Always known for her wit, vibrancy, and confidence, Elizabeth was now increasingly passive and unsure of herself. In the span of six months, she also had been let go from her longtime job as a fourth-grade teacher because she couldn't keep up.

"I didn't know what was going on," says McGuff. "Mom thought she was depressed and started seeing a therapist." The mystery of his mother's rapid mental decline was finally solved in September 1999, about a year after McGuff first started noticing changes in her behavior. At just 53 years old, Elizabeth was diagnosed with young-onset Alzheimer's disease. "I was in total shock. She was so young. I could never imagine someone getting Alzheimer's at 53. In fact, I don't think I even knew such a thing was possible." She died from complications related to the disease five years later.

Alzheimer's is not just a disease of old age. About 200,000 of the 5.7 million people with the disease have the young-onset form, meaning they were diagnosed before age 65, according to the Alzheimer's Association. Many people are in their forties and fifties with dependent children and booming careers when the disease strikes. As it does with age-related Alzheimer's disease, the young-onset form also impacts memory, thinking, behavior, and, in later stages, daily activities and functions.

The Role of Genetics

Young-onset Alzheimer's disease has a strong genetic component. So far, researchers have linked the condition to mutations in one of three genes: APP, PSEN1, or PSEN2, which account for about 10 percent of all young-onset cases. When any of these genes is altered, the brain produces large amounts of amyloid beta peptide, a toxic protein fragment that clumps together to form amyloid plaques, a key marker of the disease, says Richard Sherva, PhD, research assistant professor at Boston University School of Medicine. These clusters bind themselves to receptors on nerve cells, triggering a process that erodes their synapses with other nerve cells, says Dr. Sherva.

For nearly 20 years, John M. Ringman, MD, MS, FAAN, professor of neurology at the Keck School of Medicine at the University of Southern California, has studied families who carry the A431E or Jalisco gene mutation and develop Alzheimer's disease in their forties. His research, including an article in the April 2013 issue of Continuum: Lifelong Learning in Neurology, led him to conclude that this strand likely began with a single ancestor who lived in Jalisco hundreds of years ago.

Studying families with at least three individuals in two or more generations who develop symptoms between the ages of 30 and 60 led to significant progress in understanding the genetic roots of the disease and the cause and effect of the disease overall. "These genes are inherited in a dominant way, which means you only need one mutated copy of the gene," explains Dr. Sherva. "If you have the mutation, you are virtually assured of getting the disease."

Generations of Disease

Former pastor and registered nurse Renee Perkins, 61, is more than familiar with the genetic component of the disease. She was diagnosed seven years ago when she recognized what looked like a familial genetic predisposition for the disease. She recalls her grandmother's odd behavior on a camping trip when she was in high school, "She was doing strange things like repeatedly asking me if I wanted coffee when I didn't drink coffee and never had," recalls Perkins. "Then she poured coffee into a saucer instead of a cup." More than 20 years after her grandmother's diagnosis, Perkins' mother was also diagnosed. In the interim, Perkins discovered that her great-grandmother had died in her fifties and that her death had been attributed to tuberculosis (TB) that had spread to her brain. She is convinced her great-grandmother had Alzheimer's, not TB.

Given her family's history, Perkins knew she was vulnerable, and when she began experiencing memory problems around 2011 at age 54 she was greatly concerned. "I had just finished seminary and was starting at my first church when I noticed that I was getting forgetful, missing meetings, and just struggling to keep up with my schedule," she recalls. "My stepfather kept saying I should get genetically tested because of my mother and my grandmother. So, I scheduled a meeting with the Indiana Alzheimer's Disease Center. I underwent CT and cognitive testing, and a year later they basically told me to get my ducks in a row and make plans for long-term care."

As a former nurse, Perkins is acutely aware that she may have passed on the gene mutation to her three sons, giving them even odds for being the next generation to be diagnosed. "My younger son has been tested, and he is not a gene carrier. Thank God for that," she says. "One down and two to go. Let it stop with me!" If her two other sons haven't inherited the gene, the disease won't be handed down to successive generations.

Crushing Diagnosis

While at work in 2012, Rod Blough, 59, of Dublin, OH, collapsed on the floor of a manufacturing facility and sustained a concussion. His primary care physician referred him to a neurologist. When the same thing happened five months later, the hard-charging human resources executive saw another neurologist who ordered an MRI and an electroencephalogram to check for neurologic causes.

"After the accidents, my memory, which had been a real strength, was not the same," says Blough. "I also had trouble processing information."

Attributing these problems to his recent concussions, Blough developed strategies to compensate. "I'm very good at planning, organizing, and taking notes. So, I started to rely heavily on those skills to compensate for the losses I had in other areas. I was able to perform at a significantly high enough level that I was promoted just six months before I left the workforce."

Blough's career ended with a severe bicycle crash two years after his first collapse. "I don't know if I just ran off the road or was forced off, but I hit a utility pole and sustained my third traumatic brain injury in the span of two years." Results of a subsequent PET scan and lumbar puncture were consistent with the early stages of Alzheimer's disease. Based on those results as well as a series of tests to evaluate impaired cognitive skills, changes in personality or behaviors, and the degree of memory and thinking impairment, doctors diagnosed Blough with young-onset Alzheimer's disease in December 2017. He was surprised because he had no family history of young-onset Alzheimer's.

Blough's doctors don't know if the concussions exacerbated his dementia or if early dementia contributed to his accidents. A genetic test revealed that he doesn't carry the gene, so it's difficult to say why he developed early-onset Alzheimer's.

New Tests Help Diagnose Earlier

Getting an accurate diagnosis of Alzheimer's disease can be a long, frustrating experience, says Heather Snyder, PhD, senior director of medical & scientific operations at the Alzheimer's Association. It may be in part, she says, because doctors may attribute initial symptoms of Alzheimer's disease in younger people to stress, depression, mental illness, or, as in Blough's case, prior injuries.

Recent advances in imaging and a greater understanding of the complexities of the disease has made it easier for physicians to provide a definitive diagnosis, says Randall Bateman, MD, Charles F. and Joanne Knight Distinguished Professor of Neurology at Washington University School of Medicine in St. Louis. "Twenty years ago, we used to teach medical students that you couldn't fully diagnose Alzheimer's until someone died and you looked at the brain," he says. "Today, we have PET scans, cerebrospinal fluid tests, and now blood tests that can identify Alzheimer's pathology while people are alive."

The earlier the diagnosis comes, the better, says Steven T. DeKosky, MD, FAAN, deputy director of the McKnight Brain Institute of the University of Florida in Gainesville. It allows patients and families to assess treatment and prepare for the future. It also allows patients to make decisions about end-of-life protocols while still cognitively intact and consider enrolling in clinical trials, Dr. DeKosky says.

A Deeper Understanding

Researchers believe that many genes that affect the risk of Alzheimer's disease are yet to be discovered and that identifying others will prove vital in the development of new ways to treat, or even prevent, the disease. That is why much of current research focuses on understanding what's happening to the brain, says Dr. DeKosky.

Part of this research has to do with the amyloid beta peptide. The race is on to develop a drug that would block this abnormal buildup because amyloid begins to amass in the brain up to 20 years before symptoms appear, says Dr. Bateman. In addition to their understanding of amyloid buildup, researchers now know that the neurofibrillary tangles found inside the brain's cells consist primarily of the tau protein. In a healthy brain, tau plays an important role in supporting normal brain cell function. In the brains of people with Alzheimer's, tau forms abnormal clusters that cause the microtubule structures—hollow protein tubes that aid in cell activity—to collapse, Dr. Bateman explains. This occurs at about the same time symptoms appear. The objective is to find a way to stop the abnormal clustering of tau or remove it from the brain altogether.

"We define the disease by the presence of amyloid and tau protein in the brain, along with the loss of synapses and cognitive function," says Dr. DeKosky. "So, if it's defined by the presence of those things, it is pretty logical that those are still major targets for us to go after [in research]."

While recent news has been filled with stories about setbacks and the lack of progress made in finding a cure or even effective treatment for Alzheimer's disease, researchers like Drs. Bateman and Sherva see many reasons to be hopeful. For example, they say, the newfound ability to track the path of the disease in the brain during life has been extremely valuable in research and clinical trials. By following the pathology of the neurofibrillary tangles that correlate with symptoms, researchers can monitor brain changes and design clinical trials focused on preventing memory loss.

Studying Disease Progression

Dr. Bateman is the principal investigator of the Dominantly Inherited Alzheimer Network (DIAN) observational study which currently has 531 participants. Established by a grant from the National Institutes of Health in 2008, researchers from around the world evaluate asymptomatic gene carriers who are destined to develop Alzheimer's disease to determine the sequence of changes in the brain. This allows them to define the disease's natural history and establish reliable biomarkers such as amyloid and tau proteins detectable in spinal fluid and tracers such as plaques that are visible on PET scans. By contributing their findings to a central research database and tissue repository, the hope is that this broad collaboration will result in therapeutic options to detect and treat Alzheimer's disease at its earliest stages—or prevent it altogether.

"We've learned quite a bit from the families with any of the genetic mutations," says Dr. Bateman. "We now know that patients develop the amyloid plaques about 15 to 20 years before they develop symptoms and about five to 10 years before the brain begins to shrink and have trouble using energy." The longitudinal data have also revealed that a subtle decline in cognition begins as early as 15 years before a person's expected year of onset, making earlier therapeutic intervention possible.

In 2012, Dr. Bateman launched the DIAN trial unit (DIAN TU) study, the first prevention trial for at-risk families with dominantly inherited AD. Moving beyond observation to intervention, the trial focuses on immunotherapies such as solanezumab and gantenerumab that could potentially change the course of the disease. Dr. Bateman and colleagues expect to report their first findings by the end of 2019.

The Longitudinal Early-onset Alzheimer's Disease Study (LEADS) is a two-year observational trial designed to look at the progression of the disease in people such as Blough who have young-onset Alzheimer's disease not caused by dominantly inherited genetic mutations. Enrollment began in July and researchers hope to recruit 500 patients and establish a nationwide network of sites to collect clinical and biomarker data that will help identify additional risk factors for Alzheimer's, including susceptibility genes. For more information, visit nia.nih.gov.

Researchers are also taking broader measures to combat the disease, Dr. Snyder says. "In the last five years, we've seen an expansion in the number of approaches in the clinical trials, such as exploring combination therapies," she says. "For example, we're working with University of California, Davis, on testing a multi-component lifestyle interventional approach, including physical activity, nutrition, diet, and managing cardiovascular risk factors to determine the impact on cognition after two years."

Living with Young-Onset Alzheimer's

While doctors and scientists push ahead in their effort to understand more about young-onset Alzheimer's and how to better treat it, those already diagnosed must learn to manage the condition's day-to-day impact.

Ever an optimist, Blough volunteers as an advisor for the Alzheimer's Association and chronicles the disease's silver lining in his blog, "Sunny Side of Alzheimer's." These days, he puts as much energy into checking things off his bucket list as he once put into his executive job. "I recently bought a boat and a two-seater convertible sports car," he says. "Now, I spend much of my time fishing on Lake Erie with my dad."

Perkins also insists on looking on the bright side. "Even though I know my destiny, I feel fortunate that I've come this far and been able to see my eight grandkids born and growing up," she says. She worries about how she will explain what's happening to her to her grandkids in the coming years. "I would like to convey that it is not the end of the world, that people with Alzheimer's are still people, and that they still need to be shown love and respect." Perkins, who is enrolled in the DIAN study at Indiana University, encourages her sons to participate. So far, they have not.

McGuff, an Alzheimer's Association ambassador for the Texas 7th Congressional District, meets with his representative to push for more funding for research and care for those with the disease. He doesn't know if he will get early-onset Alzheimer's and has no plans to be genetically tested. However, many of the decisions he makes assume he will follow his mother's medical path. He works from home, which allows him to spend more time with his two sons. "I'm 41, and my mom was 53 when she was diagnosed," says McGuff. "If I get it like she did, my kids won't really know me. This way they will remember me."

6 Ways to Be Proactive After a Diagnosis of Young-onset Alzheimer's

1. Consider genetic testing. Genetic tests can be used to confirm the presence of mutant genes linked to young-onset Alzheimer's and predict who will develop the disease in the future, says Martin Rhys Farlow, MD, FAAN, professor emeritus of neurology at Indiana University School of Medicine. Before undergoing such tests, he recommends talking with a genetic counselor to thoroughly evaluate how knowing this information will impact your life.
2. Participate in a clinical trial. "The road to better care and treatment of Alzheimer's runs through clinical trials, but recruitment is a persistent problem for Alzheimer's researchers," says Steven T. DeKosky, MD, FAAN, deputy director of the McKnight Brain Institute of the University of Florida in Gainesville. Ask your doctor about ongoing studies in your area. It's a great way to help, says Dr. DeKosky, and possibly be on the cutting edge of care.
3. Keep your friends close. A 2017 study published in the Journal of Biomedical Science analyzing the correlation between loneliness and the risk of developing Alzheimer's disease found that people who were lonely had a higher risk of the disease than those who were not lonely. Making close friends and staying in contact with family members offer a protective effect against the ravages of Alzheimer's disease.
4. Make good health a priority. A study published in the March 14, 2018, issue of Neurology found evidence linking cardiovascular and brain health, including the risk for Alzheimer's disease. So, one of the best things you can do for your brain is take good care of your heart, says Heather Snyder, PhD, senior director of medical & scientific operations at the Alzheimer's Association. Exercise and follow a healthy diet to reduce your risk of cardiovascular and other diseases.
5. Stay mentally engaged. In 2017, the Journal of the American Geriatrics Society reported that brain-stimulating activities such as researching your genealogy, taking a class on a new topic, and using a computer are associated with a reduced risk of Alzheimer's. As with physical exercise, which can slow muscle deterioration, exercising your brain is thought to build reserves of healthy brain cells and connections between them, according to the study.
6. Join support groups specifically for young-onset. A diagnosis of young-onset Alzheimer's disease is rare, and it's easy to feel alone. By joining a support group, you can share your concerns and feelings with others who are going through the same experience. Find an in-person or online group through the Alzheimer's Association, which offers sessions led by both professionals and peers.