We will carry out Whole Genome Sequencing (WGS) of all subjects in the National Institute of Mental Health (NIMH) Alzheimer’s disease family sample (1,510 subjects; 437 AD families). We will identify functional DNA variants throughout the human genome that are inherited as risk factors for Alzheimer’s disease. We also will analyze DNA from brain samples of subjects who exhibited significant Alzheimer’s pathology at autopsy, but never suffered from dementia; this will allow us to identify protective gene variants as well.
This study constitutes Phase III of the Alzheimer’s Genome Project™. While Phase I and II informed regarding which genes are implicated in risk for Alzheimer’s disease, this study will allow us to assess the entire human genome, including the 96 percent that is not made up of “genes,” per se, but instead includes the DNA that regulates the activity of the genes. While the goal of Phases I and II was to identify all of the genes involved in Alzheimer’s disease susceptibility, in Phase III, we will (1) determine all of the DNA variants in the Alzheimer’s genes that directly influence risk for the disease; and (2) determine all of the DNA variants in the rest—the (intergenic) portions of the genome that regulate the activities of the Alzheimer’s genes.
As in the past, we will use this information to determine exactly how each Alzheimer’s gene (emerging from Phase I and II), functionally affects risk for the disease at the biological level. These findings then will be used not only to better understand the causes of Alzheimer’s disease, but also to guide drug discovery efforts to slow down, stop or, perhaps, even reverse the disease process.