“A lot of people who have dementia do not have Alzheimer’s disease.” That is a statement that guides researchers at the University of Kentucky’s Sanders-Brown Center on Aging as they aim to better define other causes of dementia.

“Dementia is a big umbrella term and is a symptom of things that go wrong,” said David Fardo, Ph.D., professor and acting chair of the Department of Biostatistics in UK’s College of Public Health. “If we call something 'Alzheimer’s disease' that is not, then we are misguided.”

Fardo and Pete Nelson, M.D., Ph.D., professor and director of the neuropathology division of the Department of Pathology and Laboratory Medicine in UK’s College of Medicine, are co-investigators on a project focusing on how genetic factors contribute to dementia. The work was recently awarded funding from the National Institute on Aging that will total more than $1.7 million. 

Nelson uses the analogy of pneumonia versus asthma to explain why it's important to make the distinction between what is believed to be Alzheimer's disease and what may mimic it.

“They are two different diseases that can have similar symptoms — namely difficulty breathing. Despite the similar symptoms, they have quite different causes. Diagnosing each underlying disease is important because giving the wrong therapy (treating for asthma if the patient has pneumonia) may actually harm the patient,” said Nelson. “The same thing is true for dementia: different underlying pathologies may be at work. How can we characterize disease mechanisms or find effective therapies when we’re looking at a mixed bag of diseases caused by different mechanisms?”

Back in 2019, Nelson and large group of international experts, working together, named a new form of dementia now known as limbic-predominant age-related TDP-43 encephalopathy (LATE). Fardo and Nelson are working through this project to understand the genetic influences of how and why the protein misfolds occur in LATE, causing dementia.

“We are hoping to better define the pathology in order to localize the genetic risk and be able to learn about the biological mechanisms that drive it,” said Fardo.

Through their previous work with LATE, researchers know that symptoms of LATE mimic Alzheimer’s disease by causing memory loss and problems with thinking and reasoning in old age. But it has been found the LATE-affected brain looks different from the Alzheimer’s brain, and the therapies that may work for one probably would not work for the other.

Nelson says that focusing research on genetics will hopefully allow for better insight into the prognosis for the patient. He says looking at the genetics will also help get a better look at potential therapy targets for Alzheimer’s disease and then also for non-Alzheimer’s disease.

“We now have therapies that work for about 35% of Alzheimer’s disease. This work with non-Alzheimer’s disease dementia is key to figuring out who and why these drugs work for that percentage of patients,” said Nelson.

Eventually, if this work leads them where they expect it will, Nelson says they will be able to make personalized medicine in the field of dementia a reality.

“One day, we would love to see a cheek swab that then tells you a personalized prognosis and potential treatments,” said Nelson. Researchers believe they will be able to figure out the right therapy for a patient based on the genetics obtained through the swab.

This work is complimentary to Alzheimer’s disease research, and experts believe moving toward not calling all dementias Alzheimer’s disease is a big step forward toward finding a cure. The University of Kentucky is uniquely positioned to take on this type of work and Sanders-Brown continues to be a leader in dementia-related research.

“Dr. Nelson has led international efforts to appreciate and understand LATE, and we have worked collaboratively here between neuropathology, biostatistics and statistical genetics to make great progress in this area,” said Fardo. His team has been among the first in the world to study the genetics of LATE.

The close collaboration between Fardo, a biostatistician, and Nelson, a neuropathologist, helps make this very complicated work a bit easier to understand and analyze.

Nelson can diagnose which brain pathologies a person who suffered from dementia had. Some brains will show an accumulation of amyloid plaques and tau protein tangles characteristic of Alzheimer’s disease. Others have thickened walls in small blood vessels, the telltale sign of brain arteriolosclerosis, another disease linked to cognitive impairment. Nelson can distinguish these and a half-dozen other pathologies that may cause dementia.

Fardo has the statistical knowledge to search for connections between these carefully made diagnoses and millions of genetic variants in thousands of research participants. Biostatisticians are especially well-equipped to detangle the complexities that invariably arise in observational genetics studies. For example, multiple pathologies may co-occur in individuals, or a single gene/genetic variant may be associated with multiple pathologies.

The specific work that recently received funding will use some data from UK’s own Alzheimer’s Disease Research Center (ADRC), where Nelson is director of the Neuropathology Core. Additional data will come from other ADRCs — the National Institute on Aging funds 33 centers across the U.S. — as well as from other dementia research consortia.  

The first phase of the five-year project is the monumental task of curating the massive amounts of complex data from these various sources. Assembling these data, storing them and making sure all the datasets are comparable. The second phase is to search for the connections between genetic factors and dementia-related pathologies such as LATE. Lastly, investigators will use their genetic findings and novel statistical methods to characterize physiological pathways involved in disease progression.

At UK, co-investigator Yuriko Katsumata, Ph.D., a research assistant professor in biostatistics, is devising new ways to explore genetic epidemiology data. Mark Ebbert, Ph.D., an assistant professor of biomedical informatics in the College of Medicine Department of Internal Medicine, is also a co-investigator. Ebbert’s specialty is exploring areas of the human genome that historically have been difficult to study. Finally, much of the pathway work will be spearheaded by co-investigator Kristel Van Steen, Ph.D., at the University of Liége in Belgium.

With all that said, Fardo summed up the goal of it all: “Hopefully this will lead to finding treatments and modes of prevention.”

Similar collaborative research by Fardo and Nelson has resulted in an ongoing clinical trial testing a novel therapeutic drug available at UK’s ADRC for research volunteers here. They’ve launched this new project with high confidence that future discoveries will be equally fruitful. 

Research reported in this publication was supported by the National Institute on Aging of the National Institutes of Health under award numbers RF1AG082339, R01AG061111, and P30AG072946. The content is solely the responsibility of the author and does not necessarily represent the official views of the National Institutes of Health.