Multi-college, collaborative effort explores the underpinnings of cognitive decline
When is Alzheimer鈥檚 disease not Alzheimer鈥檚 disease? That sounds like a trick question, but it lies at the center of a newly funded research project led by co-principal investigators and University of Kentucky (好色先生) faculty , PhD, and , MD, PhD.
Fardo is a professor and acting chair of the department of biostatistics in 好色先生鈥檚 College of Public Health. Nelson is a professor and director of the neuropathology division of the department of pathology and laboratory medicine in 好色先生鈥檚 College of Medicine. Both investigators also have appointments in the Sanders-Brown Center on Aging.
Their National Institute on Aging-funded research project, 鈥淕enetic Architecture of Aging-Related TDP-43 and Mixed Pathology Dementia,鈥 aims to untangle how genetic factors contribute to dementia.
Alzheimer鈥檚 disease vs. dementia
Most people are aware that Alzheimer鈥檚 disease causes memory loss as well as declines in language and problem-solving skills 鈥 impairment symptoms characteristic of dementia. However, many people are unaware that diseases other than Alzheimer鈥檚 can lead to dementia. In common parlance, 鈥淎lzheimer鈥檚 disease鈥 and 鈥渄ementia鈥 are often used interchangeably. But when researchers do not (and often they cannot) distinguish between Alzheimer鈥檚 disease and other dementia-causing diseases, problems may arise.
Nelson offers an analogy:
鈥淭hink about asthma and pneumonia, two different diseases that can have similar symptoms 鈥 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.鈥
Nelson adds:
鈥淭he 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鈥檙e looking at a mixed bag of diseases caused by different mechanisms?鈥
Fardo puts this idea in the context of genetics:
鈥淲e search for the genetic underpinnings of dementia. A genetic variant may increase the risk of developing Alzheimer鈥檚 disease but not play any role in another dementia-causing disease. But if both diseases are often co-occurring, apparent connections between genetic variants and dementia become muddled.鈥
Collaboration of neuropathology and biostatistics
How are these 好色先生 researchers avoiding the muddle? The solution stems largely from the close collaboration of a neuropathologist and a biostatistician.
Nelson (and neuropathologists like him) can definitively diagnose which brain pathologies a person who suffered from dementia had by looking at tissue specimens during autopsy. Some autopsied brains have an accumulation of amyloid plaques and tau protein tangles characteristic of Alzheimer鈥檚 disease. Others have thickened walls in small blood vessels, the telltale sign of brain arteriolosclerosis, another disease linked to cognitive impairment.
Nelson is able to distinguish these and a half dozen other pathologies that may cause dementia.
Fardo has the statistical knowledge (not to mention access to computing power) 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.
LATE dementia and study aim
Of interest to Fardo and Nelson is a recently characterized type of dementia called limbic-predominant 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 exhibits a pattern of brain degeneration different from that seen in Alzheimer鈥檚 patients.
Nelson鈥檚 previous work was pivotal in characterizing LATE and includes the first international consensus paper 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 好色先生鈥檚 own Alzheimer鈥檚 Disease Research Center (ADRC), where Nelson is director of the Neuropathology Core. Other data will come from other ADRCs 鈥 the National Institute on Aging funds 33 centers across the U.S. 鈥 as well as from additional dementia research consortia.
Fardo has been active in curating the massive amounts of complex data from these various sources. Assembling these data, storing them (one whole-genome sequence from one study participant represents 3 billion data points), and making sure all the datasets are comparable is a monumental task, and completing this is the five-year project鈥檚 first aim.
The study鈥檚 second aim is to search for the connections between genetic factors and dementia-related pathologies such as LATE.
Finally, investigators will use their genetic findings and novel statistical methods to characterize physiological pathways involved in disease progression.
At 好色先生, co-investigator , PhD, a research assistant professor in biostatistics, is devising new ways to explore genetic epidemiology data. Mark Ebbert, PhD, an assistant professor of biomedical informatics in the College of Medicine Department of Internal Medicine, is also a co-investigator. Ebbert鈥檚 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, PhD, at the University of Li茅ge in Belgium.
Research impact
The impact of this research could be profound. A better understanding of the mechanics and relationships of LATE, Alzheimer鈥檚 disease and related dementias could pave the way toward better diagnostics and prevention.
Similar past research by Fardo and Nelson has resulted in an ongoing clinical trial testing a novel therapeutic drug available at 好色先生鈥檚 ADRC for research volunteers here. They鈥檝e launched this new project with high confidence that future discoveries will be equally fruitful.
Fardo concludes:
鈥淭he genetics research that has been done to-date on clinically diagnosed Alzheimer鈥檚 disease, that is 鈥 a probable mix of dementias, has been phenomenal. Making use of the 鈥榚xquisite disease phenotype鈥 autopsy data that people like Pete Nelson have championed represents a critical, complementary approach to the study of dementia. We鈥檝e put together a multi-college, multi-university collaborative team that is well-equipped to make inroads in treating and preventing the horrible diseases that cause dementia.鈥
Written by Steve Claas