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Like so many of us, Lincoln Shade’s life has been touched by memory loss and the related agonies of dementia. He recounts playing board games with his grandmother: “She could remember how to play the game, even how to strategize, but she couldn’t remember whose turn it was.”

Unlike most of us, Lincoln has dedicated years of his fledgling research career to searching for clues that may help solve the mystery of dementia.

ADRD & Arteriolosclerosis

Shade, a University of Kentucky College of Medicine and College of Public Health M.D./Ph.D. student, recently received a National Institutes of Health F30 fellowship award to study how genetic factors may increase the risk for Alzheimer’s disease and related dementias (ADRD).

His project, titled “Elucidating Shared Risk of Brain Arteriolosclerosis and Related Pathologies with Multiple ’Omics Modalities,” is funded by the National Institute of Neurological Disorders and Stroke. Shade is a 4th-year graduate student pursuing a Ph.D. in epidemiology and biostatistics. His primary faculty mentor is David Fardo, Ph.D., professor and acting chair of the Department of Biostatistics.

Shade’s research focuses on how genetic and other molecular factors relate to brain arteriolosclerosis.

Similar to the more familiar term arteriosclerosis, arteriolosclerosis refers to a hardening of the blood vessel wall. That extra syllable in arterioLOsclerosis shifts the focus to arterioles — small-diameter arteries that connect medium-sized arteries to capillaries. Arteriolosclerosis in the brain may play a role in cognitive decline.

Untangling Dementia

Globally, 55 million people are living with ADRD. Alzheimer’s disease can be definitively diagnosed only during autopsy and is characterized by the accumulation of abnormal amounts of a substance called amyloid beta in the brain, followed by eventual nerve cell death and an overall shrinking of the brain.

Alzheimer’s disease is the most common cause of dementia in later life, but it’s not the only cause. Brain arteriolosclerosis (B-ASC) is another likely culprit in cognitive decline. It is well established that genetic factors passed from generation to generation play a role in developing (or not developing) both Alzheimer’s disease and B-ASC.

What is not well established is which genetic factors are important and how those factors function mechanistically during disease development. That’s the gap Shade’s research aims to fill.

“B-ASC is found in over 50% of [study] participants aged 80 years or older at death,” Shade explained. “Despite its clinical importance, the pathophysiology of brain arteriolosclerosis is not well understood.” Because of research like his, that’s beginning to change.

Shade’s proposed research builds upon his previously published study. He and co-authors reported evidence of statistical associations between B-ASC and variants (sometimes colloquially referred to as mutations) in three genes known as ELOVL4, SORCS1, and SORCS3.

The statistical associations do not prove the genes cause the disease, but identifying these associations is still valuable. The associations point to possible physiological mechanisms involved in disease development.

This work boosts the rationale for further study of the relationship between B-ASC and these genes, their protein products, and the physiological pathways they inhabit.

Shade’s research is trying to determine which genes and other molecular markers are statistically associated with the hardening of small blood vessels in the brain and other traits that may play a role in ADRD.

Using existing data from four cohorts (the National Alzheimer’s Coordinating Center, the Religious Orders Study and the Memory and Aging Project, the Adult Changes in Thought Study, and the Alzheimer’s Disease Neuroimaging Initiative Neuropathology Cohort), Shade’s new study first seeks to find associations between B-ASC and molecular markers of gene activity.

Whereas his earlier work looked for associations between B-ASC and variation in the sequence of DNA (DNA can be thought of as a string of beads that serves as the blueprint for proteins), this study will look for associations between B-ASC and the degree to which DNA is “switched on” and making RNA. (RNA is created from the DNA blueprint and serves as the actual template used to build proteins.)

The rate of RNA production for a particular gene (its gene expression) is important: if a gene isn’t switched on and cranking out RNA, any peculiarities about the gene’s sequence are immaterial. Shade will study two markers of gene activity: modifications to DNA itself that can turn genes on and off (“epigenetic” modifications) and gene expression levels.

Shade will look for associations between gene activity and the disease. This work falls into the domains of “epigenomics” and “transcriptomics,” the other “’omics” in the grant’s title.

Shade’s second focus is on related pathologies. Pathologists have a few different ways to characterize brain tissue in those with dementia and healthy control subjects. Shade is planning to conduct genomic association analyses akin to those used in his previously published work, but this time adding additional pathological traits to the picture.

This will allow him to tease out which genes are uniquely associated with one trait and which genes are associated with multiple traits — an essential step in untangling a complex web of dementia symptoms and genomic factors.

Potential Research Impact

The immediate impact of Shade’s research will be most profound for fellow ADRD researchers. His study is poised to generate testable hypotheses for future research. The biomolecular pathways implicated by Shade’s research will need to be further explored for their role in ADRD.

This will lead to a deeper understanding of the disordered physiological processes that are directly causing disease. This deeper understanding of the molecular biology of dementias could be used to create new tools that allow clinicians to definitively diagnose and distinguish different dementias in living patients and could potentially lead to the development of a medication to slow or — in the best of all worlds — prevent or cure the disease.

Shade LM, Katsumata Y, Hohman TJ, Nho K, Saykin AJ, Mukherjee S, Boehme KL, Kauwe JS, Farrer LA, Schellenberg GD, Haines JL, Mayeux RP, Schneider JA, Nelson PT, Fardo DW. Genome-wide association study of brain arteriolosclerosis. J Cereb Blood Flow Metab. 2022 Aug;42:1437-1450. doi: 10.1177/0271678X211066299. Click here to view on PubMed.

Research reported in this publication was supported by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health under Award Number F30NS124136. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Previous story on Lincoln titled "Student, Lincoln Shade, motivated by family to pursue degrees in medicine and public health."

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