Probing Alzheimer’s at Both Ends of the Spectrum

Researchers from Case Western Reserve University School of Medicine have received two grant awards, in partnership with investigators from other institutions, from the National Institutes of Health to conduct major studies on Alzheimer’s disease, the most common form of memory loss and other forms of dementia in older persons.

In the first study, Jonathan L. Haines, PhD, chair of the Department of Population & Quantitative Health Sciences and Mary W. Sheldon MD Professor of Genomic Sciences, and researchers at the University of Miami will seek to identify genetic variations offering protection against Alzheimer’s in elderly Amish men and women.

In the second study, Haines and Jiri G. Safar, MD, director of the National Prion Disease Pathology Surveillance Center, and associate professor in the Departments of Pathology and Neurology at Case Western Reserve School of Medicine, along with Thomas M. Wisniewski, MD, a neurologist at New York University, will seek to determine possible causes of rapidly progressing late-onset Alzheimer’s disease, whose sufferers experience cognitive decline at a faster rate and death in a shorter period of time than patients with the standard form of the disease.

“Alzheimer’s is, as we know, a devastating disease,” said Haines. “Through these two studies, we will be examining both ends of the spectrum: what may prevent the condition in the first place and what causes an especially virulent form characterized by extra-rapid progression of symptoms.”

Amish study
Both genetic and environmental factors contribute to the risk for Alzheimer’s disease, yet despite vast research efforts, including sophisticated genetic sequencing, well over fifty percent of the genetic basis remains unexplained. However, the focus of almost all of these studies has been on identifying genetic variants that increase risk; studies designed to identify genetic variants that may protect from Alzheimer’s are far less common. Haines and his colleagues will seek to do just that by studying DNA and other data from culturally and genetically isolated Amish families in Ohio and Indiana.

The researchers will perform gene sequencing on 200 Amish adults over the age of 80 who don't have Alzheimer’s disease, and then compare their genetic profiles to non-Amish people who do have the disease. As a result, they will be able to identify those genes or their variants in the Amish that are not present in non-Amish people with Alzheimer’s, thereby allowing the conclusion that those genes or their variants in the Amish provide protection against the disease.

“The Amish provide a unique opportunity to identify genetic variants protecting against Alzheimer’s while controlling for some potential confounding factors such as level of education, lifestyle, and diet, since these are relatively similar within the Amish,” said Haines. “Today’s Amish can trace their roots to relatively few

founders and there is not significant marriage outside of the community, reducing genetic variation. These factors maximize the chance that multiple copies of rare genetic variants

which protect against Alzheimer’s are present and will be identified.” The Amish grant is for $7.5 million over five years.

Late-onset study
Between 90 percent and 95 percent of Alzheimer’s patients develop the disease after 65 years of age. (The remaining, early-onset cases occur in people in their 40s and 50s.) In general, patients with typical (post 65-years of age) Alzheimer’s experience cognitive decline over more than a decade before death. But in some cases (“rapid onset”), the decline is much swifter, with death coming within three years.

In this study, the researchers will scan the genomes of rapid-onset patients, for whom there is currently little genetic information available that could help explain the accelerated features of their form of the disease. They will then compare these results to genetic profiles of patients with the typical form of Alzheimer’s, in whom presence of the e4 allele of the APOE gene is the strongest risk factor. They will also assess apparent differences they previously found between the groups in the structures of amyloid beta and tau proteins, which form the typical plaques and tangles found in the brains of Alzheimer’s patients.

“Based on our preliminary data,” said Safar, “We hypothesize that the inordinately quick rates of cognitive decline and other symptoms in rapid onset Alzheimer’s arise from the interaction between differences in the structures of amyloid beta and tau proteins on genetic backgrounds that are also different from typical cases of the disease. As with typical Alzheimer’s, knowing which gene variants and protein differences cause or contribute to rapid onset Alzheimer’s could help us develop prevention and treatment efforts.”

The rapid onset grant is for $3.95 million over five years, with $2.5 million coming to Case Western Reserve University School of Medicine.


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