Dialing up resilience against dementia
By Joyce Dall'Acqua Peterson
Back in 1986, a University of Kentucky research team led by D.A. Snowdon, Ph.D., started a long-term, longitudinal study of 678 Roman Catholic nuns living in several American convents. Over the years the nuns would undergo tests of their cognitive function and dementia, and when each nun died, her brain was examined for damage associated with Alzheimer’s disease. Alzheimer’s can be definitively diagnosed only after a patient’s death.
A study standout was Sister Mary, who had high cognitive test scores before her death at age 101. “What is more remarkable,” Snowdon commented in a 1997 report, “is that she maintained this high status despite having abundant neurofibrillary tangles and senile plaques, the classic lesions of Alzheimer's disease.”
Why do some people, such as Sister Mary, live long, healthy, productive lives even though their brains have been ravaged by Alzheimer’s disease? , Ph.D., associate professor and Evnin Family Endowed Chair in Alzheimer’s Research at The Jackson Laboratory, is on the hunt for the protective factors that improve cognitive resilience to Alzheimer’s disease and other dementias.
“Cognitive resilience to Alzheimer’s disease and brain aging is a phenomenon whereby an individual’s cognitive functioning is better than predicted based on chronological age, genetic risk and advanced neuropathology,” Kaczorowski says.
The National Institute on Aging has awarded Kaczorowski a new five-year grant totaling $6,068,971 to identify the protective factors that improve cognitive resilience. “This requires a comprehensive identification of the protein components of unique brain cell types,” she says.
Significant barriers have limited discovery of the mechanisms of resilience, Kaczorowski notes. “For one thing, for ethical and practical reasons, it’s impossible to conduct longitudinal molecular analyses of human patients’ brain tissues. And, we haven’t had a technology capable of identifying which kinds of brain cells produce proteins that are associated with either susceptibility or resilience to aging and Alzheimer’s disease.”
The Kaczorowski lab developed the first translationally relevant mouse panel to model susceptibility and resilience to cognitive decline. Working with a genetically diverse mouse panel known as BDX, they introduced mutations that are associated with high risk for early-onset or familial Alzheimer’s disease. “These mice model the wide variation in age at onset and progression of cognitive symptoms observed in patients with familial disease mutations as well as the more common, late-onset Alzheimer’s disease,” she says.
Preliminary data suggest that differences in the age at onset and progression of cognitive deficits result from cell type-specific differences in gene expression that ultimately regulate protein synthesis in the hippocampus. The hippocampus is required for spatial memory formation and recall in mice and humans, and hippocampus-dependent memory deficits are common in Alzheimer’s patients. This in-depth, targeted analysis of the proteomes of hippocampal regions and cell types that show different gene expression patterns between mouse lines that are either resilient or susceptible to cognitive decline is a powerful approach to identify novel molecular drivers of Alzheimer’s disease resilience in a “humanized” population.
“Our goal is to identify novel proteins and complexes that could ultimately be therapeutically targeted to delay or prevent cognitive symptoms in patients of Alzheimer’s disease and other dementias,” Kaczorowski says.
Cell Type-Specific Proteins that Promote Resilience to Cognitive Aging and Alzheimer's Disease, National Institute on Aging, Grant Number R01AG075818