LEXINGTON, Ky. When is Alzheimer’s disease not Alzheimer’s disease? It sounds like a trick question, but it lies at the heart of a newly funded research project led by University of Kentucky (UK) co-principal investigators and faculty David Fardo, Ph.D., and Peter Nelson, MD, Ph. .D.

Fardo is professor and interim chair of the Department of Biostatistics at the UK College of Public Health. Nelson is Professor and Head of the Division of Neuropathology in the Department of Pathology and Laboratory Medicine at the UK College of Medicine. Both investigators also have appointments at the Sanders-Brown Center on Aging.

Their National Institute on Aging-funded research project, Genetic Architecture of Aging-Related TDP-43 and Mixed Pathology Dementia, aims to untangle how genetic factors contribute to dementia.

Alzheimer’s disease vs. dementia

Most people know that Alzheimer’s disease causes memory loss and a decline in language and problem-solving skills, hallmark symptoms of dementia. However, many people are unaware that diseases other than Alzheimer’s can lead to dementia. In common parlance, Alzheimer’s disease and dementia are often used interchangeably. But when researchers don’t (and often can’t) distinguish between Alzheimer’s disease and other diseases that cause dementia, problems can arise.

Nelson offers an analogy:

Think of asthma and pneumonia, two diseases that can have similar symptoms difficulty breathing. Despite similar symptoms, they have very different causes. Diagnosing any underlying disease is important because giving the wrong therapy (treating for asthma if the patient has pneumonia) can harm the patient.

Nelson adds:

The same is true for dementia: several underlying conditions may be at work. How can we characterize disease mechanisms or find effective therapies by looking at a jumble of diseases caused by different mechanisms?

Fardo puts this idea in the context of genetics:

We are looking for the genetic basis of dementia. A genetic variant may increase the risk of developing Alzheimer’s disease, but play no role in another disease that causes dementia. But while both diseases often coexist, the apparent connections between genetic variants and dementia become fuzzy.

Neuropathology and Biostatistics Collaboration

How do these British researchers avoid the mess? The solution comes largely from the close collaboration of a neuropathologist and a biostatistician.

Nelson (and neuropathologists like him) can definitively diagnose what brain pathologies a person with dementia had by looking at tissue samples during an autopsy. Some autopsied brains have a buildup of amyloid plaques and tangles of tau proteins characteristic of Alzheimer’s disease. Others have thickened walls in small blood vessels, the telltale sign of cerebral arteriosclerosis, another disease linked to cognitive impairment.

Nelson can distinguish these and a half dozen other conditions that can cause dementia.

Fardo has the statistical knowledge (not to mention access to computing power) to look for connections between these carefully formulated diagnoses and millions of genetic variants in thousands of research participants.

Biostatisticians are particularly well equipped to untangle the complexities that invariably arise in studies of observational genetics. For example, multiple pathologies may coexist in individuals or a single gene/genetic variant may be associated with multiple pathologies.

Dementia TARDA and study objective

Of interest to Fardo and Nelson is a recently characterized type of dementia called limbic-dominant age-related TDP-43 encephalopathy, or LATE. LATE is characterized by deposits of a misfolded protein called TDP-43 in the brain.

LATE tends to affect people over the age of 80 and has a different pattern of brain degeneration than that seen in Alzheimer’s patients.

Nelson’s previous work has been instrumental in characterizing LATE and includes the first international consensus document on the disease. Fardo and members of his research team were the first to explore the genetics of LATE. Studying the genetics of LATE and other brain diseases is one way to better understand why and how they develop and are related.

Some of the data used for the study will come from the UK’s Alzheimer’s Disease Research Center (ADRC), where Nelson is director of the Neuropathology Core. More data will come from other ADRCs, the National Institute on Aging funds 33 centers across the United States, and other dementia research consortia.

Fardo actively curated massive amounts of complex data from these various sources. Assembling this data, storing it (one study participant’s whole genome sequence represents 3 billion data points), and ensuring that all data sets are comparable is a monumental task, and completing this is the first goal of the project five-year.

The second goal of the study is to find connections between genetic factors and dementia-related pathologies such as LATE.

Finally, the researchers will use their genetic discoveries and new statistical methods to characterize the physiological pathways involved in disease progression.

In the 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., assistant professor of biomedical informatics in the College of Internal Medicine’s Department of Medicine, is also a co-investigator. Ebbert’s specialty is exploring areas of the human genome that have historically been difficult to study. Finally, much of the work on the pathway will be led by co-researcher Kristel Van Steen, Ph.D., at the University of Lige in Belgium.

Impact of research

The impact of this research could be profound. A better understanding of the mechanisms and relationships between LATE, Alzheimer’s disease and related dementias could pave the way for better diagnostics and prevention.

Similar past research by Fardo and Nelson has led to an ongoing clinical trial testing a new therapeutic drug available at the UK ADRC for research volunteers here. They launched this new project with the utmost confidence that future discoveries will be equally fruitful.

Fardo concludes:

The genetic research conducted on clinically diagnosed Alzheimer’s disease, which is a probable mix of dementias, has been phenomenal. The use of the exquisite autopsy data on the disease phenotype that people like Pete Nelson have advocated represents a critical and complementary approach to the study of dementia. We have assembled a collaborative multi-college and multi-university team that is well equipped to make inroads into the treatment and prevention of the horrific diseases that cause dementia.

#Decoding #complex #genetics #dementia

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