Comorbidity Could Be Key To Alzheimer’s Clinical Trial Failures

Alzheimer’s disease is the number one cause of dementia, however another condition – known as vascular cognitive impairment and dementia – is a close second. Microinfarcts and strokes can impair blood flow to the brain, leading to the development of symptoms associated with this type of dementia.

While recognized as a distinct form of the disease, vascular cognitive impairment and dementia can occur in patients with Alzheimer’s disease. Researchers estimate that up to 40 percent of Alzheimer’s patients also have vascular cognitive impairment and dementia.

According to Dr. Donna Wilcock, of the University of Kentucky Sanders-Brown Center on Aging, the presence of multiple dementias in patients could be responsible for the failure of some immunotherapies in Alzheimer’s clinical trials. Wilcock and her colleagues published their findings in the Journal of Neuroscience.

“These findings are important in that they provide a possible explanation for why clinical trials of anti-Aβ immunotherapy for Alzheimer’s disease have been historically unsuccessful,” said Wilcock. “If up to 40 percent of people with Alzheimer’s also have vascular cognitive impairment and dementia, treatment candidates that target only the Alzheimer’s disease physiology won’t be effective in those patients. It’s like treating only half the disease.”

As the accumulation of amyloid β (Aβ) containing plaques is thought to be a key factor in Alzheimer’s pathology, much research has been focused on identifying drugs capable of reducing Aβ buildup. Using immunotherapy, researchers have developed anti-Aβ antibodies capable of clearing plaques from the brain of animal models of the disease. Unfortunately, these immunotherapy approaches have so far failed in clinical trials of Alzheimer’s patients, leading developers to wonder why the approach has not be translatable.

“There has been one failure after another in clinical trials, which has been really disheartening for the scientific community and for patients,” said Wilcock. “My work might shed some early light on why they failed and eventually open the door for a combination treatment for vascular cognitive impairment and dementia, and Alzheimer’s disease.”

While mouse models of Alzheimer’s disease are already available, Wilcock and her colleagues needed to develop a combined animal model of both Alzheimer’s disease and vascular cognitive impairment and dementia, in order to perform their research. By comparing this combined model to an Alzheimer’s-only model, the researchers were able to test the efficacy of the anti-Aβ immunotherapy. They found that the antibody was capable of reducing Aβ plaques in both groups, however the combined animal model showed no improvement in cognitive function in response to treatment.

“The failure of anti-Aβ immunotherapy in the mixed Alzheimer’s disease-vascular cognitive impairment and dementia model suggests that both disease processes have to be treated to have a successful outcome,” said Wilcock. “The missing link has been that our animal models usually possess the hallmarks of only one disease, which has led to failure of successful translation to clinic.

“By developing a model that more accurately reflects the brain changes we see in the human brain with dementia, we can better develop our treatment approaches and increase our chances of successful translation. Our next step is to add a treatment for vascular cognitive impairment and dementia on top of the Aβ immunotherapy, to try to overcome the inability to produce a meaningful improvement in learning and memory.”