A Novel Therapy for Alzheimer’s-Associated Dementia with Cerebrovascular Comorbidity

M. Paul Murphy, MA, PhD
University of Kentucky (Lexington, KY)
Year Awarded:
Grant Duration:
July 1, 2014 to June 30, 2017
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Grant Reference ID:
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Award Region:
US Southern

Co-principal Investigators

Dana Niedowicz, PhD
University of Kentucky

Alzheimer’s Disease with Cerebrovascular Comorbidity: A Novel Therapy


We are only beginning to understand the impact that underlying diseases, including diabetes and cardiovascular disease, have on Alzheimer’s risk and disease progression. Many cases of Alzheimer’s disease (AD) are accompanied by large amounts of vascular pathology in the brain. We have developed a unique mouse model with cognitive deficits reflective of the deficits seen in AD. These mice also experience aneurysms and strokes which indicate the presence of vascular disturbances in the brain. We plan to use this model to test a potential treatment for AD with vascular pathology, involving a drug that already is approved for human use. We will perform MRI imaging at regular timepoints to monitor any effect the drug treatment has on the vascular pathology in the mouse brain, improvement in vascular pathology.


Alzheimer’s disease (AD) is linked to several underlying diseases, including a prior history of type 2 diabetes mellitus —which itself is linked to mid-life obesity. Cerebrovascular pathology also is a major contributor to age-related dementia, including AD. Although most individuals with AD have some degree of comorbid cerebrovascular pathology, individuals with a history of obesity and Type 2 diabetes have substantial amounts of this pathology. In fact, in these cases, it’s not unusual for the amount of AD pathology to go essentially unchanged, while cerebrovascular pathology increases.

As U.S. population demographics shift towards an older average age, the potential confluence of obesity, Type 2 diabetes, and age-related neurological dysfunction could become a public health disaster. To investigate this problem, we developed a mouse model that becomes rapidly obese and diabetic, and also develops amyloid pathology with increasing age. The most remarkable feature of this mouse model is that it develops a striking phenotype of cerebrovascular pathology, including aneurysms and strokes, and displays profound cognitive impairment. We believe that ours is a unique model of AD with significant cerebrovascular disease, an understudied variation of AD for which there are only limited treatment options. Our plan is to utilize this model to investigate a potential treatment approach for AD with cerebrovascular complications.

The central question of this proposal is: Can we take advantage of this novel model for preclinical therapeutic development? We propose to tap into our knowledge of biological processes that lie at the conflux of cerebrovascular disease, obesity, and metabolic dysfunction, and take advantage of an already approved, clinically useful drug that, in theory, might alter the disease course. We hypothesize that this drug will prevent or reverse the age-related cerebrovascular pathology and cognitive dysfunction in mice using the model described above.

This proposal holds potential for making progress towards a new therapeutic option for AD with significant cerebrovascular comorbidity, a neurologic disorder that is both poorly understood and has only limited treatment options. By using a drug that is already approved for human use, we are closer to a clinically viable treatment strategy than if we were attempting a purely theoretical approach. A major innovation is the use of our novel mouse model with unique features, combining obesity and AD, and exhibiting significant age-related cerebrovascular pathology and cognitive dysfunction. This project holds the potential to advance our understanding of the major underlying causes of cerebrovascular disease as a comorbidity in the AD brain.

About the Researcher

M. Paul Murphy has worked as a researcher in the areas of aging and neurodegenerative disease for more than 20 years His focus on AD began while he was a post-doctoral fellow at the Mayo Clinic in Jacksonville, FL. Since moving to the University of Kentucky in 2005, he has authored or co-authored 53 peer reviewed manuscripts, including notable recent publications in the Annals of Neurology and the American Journal of Pathology (2012).

During his career, Dr. Murphy has engaged in basic cell and molecular biology research, preclinical translational research, and early-stage human clinical trials. His lab at the University of Kentucky studies the production of the beta amyloid peptide, its regulation, and how the peptide ultimately forms pathologic structures in the brain. Disease models primarily include genetically modified mice, also higher-order mammals and cell cultures. His expertise extends to studying naturally deposited beta amyloid in several species (humans, dogs and cats).

A major focus area of Dr. Murphy’s research has been two enzymes, beta secretase 1 and gamma secretase, which convert a “raw material” known as amyloid precursor protein (APP), into beta amyloid that forms Alzheimer’s plaques. His discoveries contributed to our knowledge of how these enzymes recognize the APP substrate, and how they function. These advances led to several high-profile publications that were influential in the developing field of AD therapies and ultimately to one of the largest ever (to date) phase III clinical trials of an AD therapeutic, Flurizan, conducted by the University of Kentucky in partnership with Myriad Genetics. Although Flurizan itself was unsuccessful, the concept is still being pursued.

Since his early career, Dr. Murphy has involved in developing several of the mouse models that are now well known and widely used in the AD field.

As a teacher and leader in Alzheimer’s research, Dr. Murphy was honored by the National Institute of Health/National Center for RR, as the 2010 recipient of the Thomas Maciag Award for research excellence and innovation, and for the mentorship of new scientists; and by the University of Kentucky College of Medicine was t2013 recipient of its Abraham Flexner Master Educator Award for Outstanding Teaching and Mentorship. In four separate years, his name appeared on the University of Kentucky’s “Teachers Who Made A Difference” list. He has actively participated in training dozens of undergraduate and graduate students, as well as several postdoctoral scholars and fellows.