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New Study Aims to Discover Novel Genomic and Environmental Risk Factors Preceding Alzheimer's

A newly funded R01 is enrolling family members of participants in the Wisconsin Registry for Alzheimer’s Prevention (WRAP) into the Generations of WRAP (GROW) study to investigate genomic and environmental risk factors for neurological changes that precede Alzheimer’s disease.

Despite Alzheimer’s disease being the 6th leading cause of the death in the U.S. and the only leading cause that cannot be prevented, cured, or slowed, we currently know very little about the causes of late onset Alzheimer’s disease. We do know that having high education decreases the risk for Alzheimer’s and that the disease has a tendency to run in families. However, our current knowledge regarding which genetic variants and environmental factors contribute to Alzheimer’s is limited.

A newly funded R01 is inviting participants in the Wisconsin Registry for Alzheimer’s Prevention (WRAP; Dr. Sterling Johnson, PI) to grow their families by enrolling additional family members. WRAP is a study of participants who are cognitively healthy at baseline, most with a parental history of Alzheimer’s disease. Participants are followed longitudinally, tracking factors that change prior to the diagnosis of Alzheimer’s, such as cognitive function, brain volume, and harmful proteins that accumulate in the fluid that surrounds the brain. Additional extended family members, who include those with and without Alzheimer’s, are being enrolled in the GeneRations Of WRAP (GROW) sub-study. GROW participants will undergo whole genome sequencing, which will allow for a deep genomic investigation to identify novel genetic variants that, while less common, have a larger effect on the risk for Alzheimer’s. They will also undergo metabolomics profiling, which will serve as a way of identifying environmental factors an individual has been exposed to. Joint analyses of the genomic and metabolomic data will enable the investigation of complex relationships between the two data types that could be influencing neurological changes that precede Alzheimer’s.

The Principal Investigator of GROW, Dr. Corinne Engelman, and members of her lab previously found that low frequency genetic variants within the TREM2 and PLD3 genes, which are known to increase risk for Alzheimer’s, are also associated with poorer cognitive function within WRAP participants (who do not yet have Alzheimer’s). With the larger families and volume of genomic data that will be collected by GROW, Dr. Engelman anticipates that it will be feasible to identify additional low frequency variants that contribute to the risk for Alzheimer’s and better characterize the genomic architecture of the disease.

Metabolomics profiling has been conducted in the lab of Dr. Joshua Coon on a small number of participants so far, but is already yielding promising results. Preliminary results suggest that a particular metabolite may be present at high levels in younger ages, but decrease to low levels in older ages among individuals showing cognitive decline, and vice-versa among individuals who are cognitively stable.

Although much research is still needed in order to comprehensively understand the underlying biological and environmental mechanisms that lead to the onset of Alzheimer’s disease, studies such as GROW show promise in progressing towards this goal.

Madison team: Shawn Bolin, MS; Ruocheng Dong, MS (Epidemiology PhD program); Corinne Engelman, PhD, MSPH; Burcu Darst (PhD candidate in Epidemiology); Eva Vasiljevic (Population Health PhD program); Diane WilkinsonMadison team: Shawn Bolin, MS; Ruocheng Dong, MS (Epidemiology PhD program); Corinne Engelman, PhD, MSPH; Burcu Darst (PhD candidate in Epidemiology); Eva Vasiljevic (Population Health PhD program); Diane Wilkinson

Milwaukee team: Gina Green-Harris, MBA; Nia Norris, MA; Stephanie Houston, MBAMilwaukee team: Gina Green-Harris, MBA; Nia Norris, MA; Stephanie Houston, MBA

 

2016 Alzheimer’s prevalence and burden facts:
http://www.alz.org/facts/overview.asp

WRAP Newsletter:
http://www.wai.wisc.edu/pdf/wrap/currentissue.pdf

Wisconsin Alzheimer’s Institute:
http://www.wai.wisc.edu/

Wisconsin Alzheimer’s Disease Research Center:
http://www.wai.wisc.edu/