Work by several researchers within the University of Kentucky’s Sanders-Brown Center on Aging was recently published in the prestigious journal Nature Genetics. 

David Fardo, Ph.D., the inaugural Stephen W. Wyatt Endowed Professor of Public Health and professor in the Department of Biostatistics in UK’s College of Public Health, led the study. The research team investigated the genetic risk of neuropathological traits commonly seen by neuropathologists performing brain autopsies from elderly people. Lincoln Shade, an M.D./Ph.D. student in the epidemiology and biostatistics Ph.D. program, was the lead author and performed most of the analyses.

The study encompassed collaborative work among Fardo’s lab, Mark Ebbert, Ph.D., assistant professor in the UK College of Medicine, and Peter 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.  

“We know that Alzheimer’s disease and other dementias are highly genetic, and great strides have been made in understanding the basis of genetic risk in dementia. However, most studies focus on clinical diagnoses or family history of dementia. While this approach allows for large sample sizes, it overly simplifies the complex nature of brain pathologies that contribute to dementia,” said Fardo. 

Alzheimer’s and dementia are complicated conditions, and there’s not just one thing that causes them. Many distinct problems in the brain can add up and lead to these diseases. Each of these brain problems, called neuropathologies, has its own set of genes that can make someone more or less likely to develop it. So, when scientists study Alzheimer’s and dementia, they’re not just looking at one thing — they’re trying to understand how all these different factors work together to cause these diseases.

Due to this, researchers on this study approached their work by focusing on finding genetic risk factors for dementia by looking at the relationship between millions of genetic variants and 11 autopsy-measured neuropathologies. Neuropathologies refer to a broad range of diseases and disorders affecting the nervous system, including the brain, spinal cord and peripheral nerves. These conditions can manifest in various ways, such as cognitive impairments, motor dysfunction, sensory deficits or a combination thereof. 

Examples of diseases defined by neuropathologies include Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, amyotrophic lateral sclerosis (ALS), Huntington’s disease, epilepsy, neuropathic pain disorders and many others. These conditions often have complex underlying mechanisms involving genetic, environmental and lifestyle factors, making diagnosis and treatment challenging.

“Most studies of dementia genetics use clinical phenotypes. We use actual neuropathological data, and this represents the largest such study with almost 8,000 participants. We discovered four new genetic loci — or regions — associated with neuropathologies, including a possible mechanism by which one genetic locus may affect irregular protein, or amyloid, deposition in cerebral blood vessels by affecting DNA methylation in the gene APOC2,” said Fardo.

This is significant as amyloid is a protein that can build up in the brain over time. In dementia studies, researchers are interested in amyloid because it’s often found in the brains of people with Alzheimer’s disease and other types of dementia. This buildup is thought to play a role in damaging brain cells and contributing to memory loss and other symptoms of dementia. Understanding amyloid and how it affects the brain can help researchers develop better ways to diagnose, treat and potentially prevent dementia.

“We weren’t the first study to investigate the genetic risk factors of dementia or neuropathologies. But one of the more novel approaches we took was to more precisely adjust for APOE gene variants. By taking this approach, we found a new association between cerebral vascular amyloid deposition and APOC2, a gene near APOE whose signal was likely concealed by the known APOE effect in previous studies,” said Shade. 

This study at UK also examined what known Alzheimer’s disease genes were associated with different neuropathologies. “Alzheimer’s disease is often thought of as a single disease. In reality it is a complex process and is often treated clinically as a disease of exclusion, or in other words, people are sometimes diagnosed with Alzheimer’s once other known causes of dementia are ruled out. Some genes associated with clinical Alzheimer’s are associated with some neuropathologies but not others,” said Shade. 

The research is aimed at better understanding the underlying disease process versus directly impacting patient care. However, Fardo and others who focus their work on these studies believe it will contribute to the ultimate goal. 

“We hope that understanding the risk factors, including genetic risk factors, for each of these pathologies in more detail, will eventually lead to precision therapeutics aimed at preventing and treating the diseases associated with these diverse pathologies,” said Fardo.  

Research reported in this publication was supported by the National Institute on Aging of the National Institutes of Health under Award Numbers RF1AG082339, P30AG028383, R01AG06833, R56AG057191, R01AG082730 and P01AG078116; the National Institute of Neurological Disorders and Stroke of the National Institutes of Health under Award Number F30NS124136; the National Institute of General Medical Science of the National Institutes of Health under Award Number R35GM138636; and  the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Numbers UL1TR001998 and TL1TR0019970. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. 

Acknowledgement is made to the donors of Alzheimer’s Disease Research, a program of BrightFocus Foundation, for support of this research.

This work was supported by a grant from the Alzheimer’s Association 2019-AARG-644082.