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Novel gene loci tied to risk of Alzheimer’s in African Americans

The molecular pathways that cause Alzheimer’s disease appear to be similar in African Americans and non-Hispanic whites, but there are differences in some of the genetic loci within these pathways, according to recent results from a large genome-wide association study (GWAS). The research, funded in part by NIA, identified several novel DNA regions, or loci, unique to African Americans with Alzheimer’s disease. While many of the genes within these loci differed from those found in studies of Alzheimer’s risk in non-Hispanic white individuals, their functions and biological pathways overlapped. An exception was the pathway for kidney system development. This suggests a new avenue for researchers to explore to understand Alzheimer’s disease risk in African Americans. The findings were published in JAMA Neurology.

Older woman sitting on a sofa looking into the distance thinking.Alzheimer’s disease risk in African Americans is nearly twice that of non-Hispanic whites. Despite this disparity, most large, genetic studies on Alzheimer’s risk have been conducted on non-Hispanic white individuals. To learn about genetic factors linked to Alzheimer’s risk in African Americans, researchers at the University of Miami and Columbia University conducted a large GWAS using data sets from multiple studies. GWAS is a research approach that connects DNA differences, called genetic variants, in a group of people with a certain disease. In this study, the researchers analyzed genetic data from multiple studies to compare the DNA sequences from more than 8,000 African Americans, with and without Alzheimer’s disease.

The researchers found that the main biological pathways linked to Alzheimer’s risk in African Americans largely overlapped with those in non-Hispanic white individuals, but there were several disease-associated genetic loci in these pathways that differed. This suggests that these overall pathways, including those responsible for immune response, intracellular transport, nervous system development, and fat metabolism, are not ethnic-specific and are important in understanding Alzheimer’s disease risk across ethnic groups. But differences in the genetic loci in these pathways could prove to be additional targets for further investigation into ethnic difference in risk. The researchers also found a link between kidney system development and Alzheimer’s risk in African Americans, suggesting another novel disease mechanism to explore to better understand unique differences in disease risk between ethnic groups. African Americans are three times more likely to experience kidney failure than non-Hispanic whites. They are also more likely to have both dementia and kidney disease. Additional research to understand this connection will be important for the prevention and treatment of Alzheimer’s disease for African Americans.

The researchers also sought to determine whether the Alzheimer’s risk genes were connected to the physical changes seen in Alzheimer’s brains, specifically the presence of amyloid plaque and tau tangles. They compared gene expression, or the amount of protein made by each of the identified Alzheimer’s risk genes, with the amount of amyloid plaque or tau tangles in autopsied brains. Only four of the risk genes were linked to higher levels of amyloid plaque and one with increased tau tangles.

This study provides new insights about the biological pathways and genetic factors that contribute to the development of Alzheimer’s in African Americans, and more importantly shows how the genetic loci can differ significantly between ethnic groups. Understanding these differences is essential to develop effective treatments for African Americans and to understand the biology underlying observed health disparities.

This research was supported in part by NIA grants AG0087202, AG030653, AG041718, AG045058, AG064877, P01-AG026276, P01-AG03991, P30-AG010133, P30-AG010161, P30-AG019610, P30-AG062428-01, P30-AG062421-01, P30-AG008051, P30-AG013854, P30-AG008017, P30-AG010161, P30-AG010129, P30-AG062429-01, P30-AG035982, P30-AG028383, P30-AG053760, P30-AG010124, P30-AG012300, P30 AG049638, P30-AG062715-01, P50-AG016574, P50-AG005133, P50-AG005136, P50-AG005142, P50-AG005146, P50-AG005138, P50-AG005681, P50-AG016573, P50-AG023501, P50-AG025688, P50-AG047266, P50-AG047270, P50-AG047366, P50-AG005681, R01-AG009029, R01-AG009956, R01-AG019085, R01-AG027944, R01-AG028786, R01-AG028786, R01-AG030146, R01-AG032990, R01-AG037212, R01-AG11101R01-AG15819, R01-AG17917, R01-AG20688, R01-AG22018, R01-AG30146, R37-AG015473, RC2-AG036650, RF1-AG054023, RF1-AG054080, U01-AG016976, U01-AG032984, U01-AG052410, U01-AG006781, U24-AG021886, U24 AG026390, U24-AG026395, U24-AG041689, and U24-AG056270.

These activities relate to NIH's AD+ADRD Research Implementation Milestone 1.E, Expand existing large scale, open-science molecular profiling efforts by:

  • Increasing the bandwidth for the generation and analysis of high-quality molecular data (genetics and epigenetics, transcriptomics, proteomics, metabolomics, lipidomics, glycomics, exposome, etc.) from human tissues and cell lines.
  • Investing in the development of methods for multi-scale modeling across -omics data-types.
  • Ensuring that diverse cohorts and special populations are included and prioritized in these efforts.

Reference: Kunkle BW, et al. Novel Alzheimer’s disease risk loci and pathways in African American individuals using the African Genome Resources Panel: A meta-analysis. JAMA Neurology. 2020. Epub Oct 19:e203536. doi: 10.1001/jamaneurol.2020.3536.