Compounded outcomes associated with comorbid Alzheimer's disease, cerebrovascular disease
Researchers from the Sanders-Brown Center on Aging at the University of Kentucky have been able to confirm anecdotal information on patients with both Alzheimer's disease (AD) and cerebrovascular disease (CVD) using mouse models in two different studies.
The alzheimer research findings of these two studies, which were recently published in Acta Neuropathologica and Alzheimer's Research & Therapy, have potentially significant implications for patients with both disorders.
Both papers studied CVD in Alzheimer's disease mouse models using different lifestyle factors.
Paul Murphy, Ph.D, and his group studied the combined effects of type 2 diabetes, Alzheimer's disease, and cerebrovascular disease in a novel mouse genetic model.
Donna Wilcock, Ph.D, and her group used a different mouse model to study the effects of Alzheimer's disease and hyperhomocysteinemia on cognition. An elevated level of homocysteine is associated with a number of disease states, including CVD.
According to Wilcock, both papers came to similar conclusions.
"We found that, while the primary Alzheimer's pathologies were unchanged, the learning and memory outcomes were significantly worse. In other words, in our mouse models, the cognitive effects of Alzheimer's disease combined with cerebrovascular disease were compounded both in terms of severity and the speed of decline," Wilcock says.
Murphy emphasizes the significance of the findings, particularly since approximately 40% of Alzheimer's patients also have cerebrovascular disease.
"We are really excited about these results," Murphy said. "Until now, we have had almost no way to study how Alzheimer's and cerebrovascular disease interact. These new mouse models give us a way to test ideas about the disease, and ultimately develop ways to treat it."
Autopsies have revealed that some individuals develop the cellular changes indicative of Alzheimer's disease without ever showing clinical symptoms in their lifetime.
Vanderbilt University Medical Center memory researchers have discovered a potential genetic variant in these asymptomatic individuals that may make brains more resilient against Alzheimer's.
"Most Alzheimer's research is searching for genes that predict the disease, but we're taking a different approach. We're looking for genes that predict who among those with Alzheimer's pathology will actually show clinical symptoms of the disease," said principal investigator Timothy Hohman, Ph.D., a post-doctoral research fellow in the Center for Human Genetics Research and the Vanderbilt Memory and Alzheimer's Center.
The article, "Genetic modification of the relationship between phosphorylated tau and neurodegeneration," was published online recently in the journal Alzheimer's and Dementia.
The researchers used a marker of Alzheimer's disease found in cerebrospinal fluid called phosphorylated tau. In brain cells, tau is a protein that stabilizes the highways of cellular transport in neurons. In Alzheimer's disease tau forms "tangles" that disrupt cellular messages.
Analyzing a sample of 700 subjects from the Alzheimer's Disease Neuroimaging Initiative, Hohman and colleagues looked for genetic variants that modify the relationship between phosphorylated tau and lateral ventricle dilation -- a measure of disease progression visible with magnetic resonance imaging (MRI). One genetic mutation (rs4728029) was found to relate to both ventricle dilation and cognition and is a marker of neuroinflammation.
"This gene marker appears to be related to an inflammatory response in the presence of phosphorylated tau," Hohman said.
"It appears that certain individuals with a genetic predisposition toward a 'bad' neuroinflammatory response have neurodegeneration. But those with a genetic predisposition toward no inflammatory response, or a reduced one, are able to endure the pathology without marked neurodegeneration."
Hohman hopes to expand the study to include a larger sample and investigate gene and protein expression using data from a large autopsy study of Alzheimer's disease.
"The work highlights the possible mechanism behind asymptomatic Alzheimer's disease, and with that mechanism we may be able to approach intervention from a new perspective. Future interventions may be able to activate these innate response systems that protect against developing Alzheimer's symptoms," Hohman said.
The alzheimer research findings of these two studies, which were recently published in Acta Neuropathologica and Alzheimer's Research & Therapy, have potentially significant implications for patients with both disorders.
Both papers studied CVD in Alzheimer's disease mouse models using different lifestyle factors.
Paul Murphy, Ph.D, and his group studied the combined effects of type 2 diabetes, Alzheimer's disease, and cerebrovascular disease in a novel mouse genetic model.
Donna Wilcock, Ph.D, and her group used a different mouse model to study the effects of Alzheimer's disease and hyperhomocysteinemia on cognition. An elevated level of homocysteine is associated with a number of disease states, including CVD.
According to Wilcock, both papers came to similar conclusions.
"We found that, while the primary Alzheimer's pathologies were unchanged, the learning and memory outcomes were significantly worse. In other words, in our mouse models, the cognitive effects of Alzheimer's disease combined with cerebrovascular disease were compounded both in terms of severity and the speed of decline," Wilcock says.
Murphy emphasizes the significance of the findings, particularly since approximately 40% of Alzheimer's patients also have cerebrovascular disease.
"We are really excited about these results," Murphy said. "Until now, we have had almost no way to study how Alzheimer's and cerebrovascular disease interact. These new mouse models give us a way to test ideas about the disease, and ultimately develop ways to treat it."
Autopsies have revealed that some individuals develop the cellular changes indicative of Alzheimer's disease without ever showing clinical symptoms in their lifetime.
Vanderbilt University Medical Center memory researchers have discovered a potential genetic variant in these asymptomatic individuals that may make brains more resilient against Alzheimer's.
"Most Alzheimer's research is searching for genes that predict the disease, but we're taking a different approach. We're looking for genes that predict who among those with Alzheimer's pathology will actually show clinical symptoms of the disease," said principal investigator Timothy Hohman, Ph.D., a post-doctoral research fellow in the Center for Human Genetics Research and the Vanderbilt Memory and Alzheimer's Center.
The article, "Genetic modification of the relationship between phosphorylated tau and neurodegeneration," was published online recently in the journal Alzheimer's and Dementia.
The researchers used a marker of Alzheimer's disease found in cerebrospinal fluid called phosphorylated tau. In brain cells, tau is a protein that stabilizes the highways of cellular transport in neurons. In Alzheimer's disease tau forms "tangles" that disrupt cellular messages.
Analyzing a sample of 700 subjects from the Alzheimer's Disease Neuroimaging Initiative, Hohman and colleagues looked for genetic variants that modify the relationship between phosphorylated tau and lateral ventricle dilation -- a measure of disease progression visible with magnetic resonance imaging (MRI). One genetic mutation (rs4728029) was found to relate to both ventricle dilation and cognition and is a marker of neuroinflammation.
"This gene marker appears to be related to an inflammatory response in the presence of phosphorylated tau," Hohman said.
"It appears that certain individuals with a genetic predisposition toward a 'bad' neuroinflammatory response have neurodegeneration. But those with a genetic predisposition toward no inflammatory response, or a reduced one, are able to endure the pathology without marked neurodegeneration."
Hohman hopes to expand the study to include a larger sample and investigate gene and protein expression using data from a large autopsy study of Alzheimer's disease.
"The work highlights the possible mechanism behind asymptomatic Alzheimer's disease, and with that mechanism we may be able to approach intervention from a new perspective. Future interventions may be able to activate these innate response systems that protect against developing Alzheimer's symptoms," Hohman said.
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