Novel Alzheimer Disease Risk Loci and Pathways in African American Individuals Using the African Genome Resources...

Area of Science:

• Genetics and Genomics
• Neuroscience
• Population Health

Background:

• African Americans experience a disproportionately higher incidence of Alzheimer disease (AD) compared to non-Hispanic White individuals.
• Previous large-scale genome-wide association studies (GWAS) for AD have been predominantly conducted in non-Hispanic White populations, limiting insights into AD genetic architecture in other ancestries.
• Prior research in African Americans implicated ABCA7, TREM2, and a locus at 5q35 in AD risk.

Purpose of the Study:

• To discover novel Alzheimer disease (AD) risk loci in African American individuals.
• To increase sample size and utilize the African Genome Resource panel for enhanced statistical power in GWAS.
• To investigate genetic underpinnings of AD disparities in African Americans.

Main Methods:

• A large-scale genome-wide association meta-analysis combining case-control and family-based datasets from the Alzheimer Disease Genetics Consortium.
• Inclusion of participants of African American ancestry recruited from multiple sites across the United States.
• Analysis of approximately 2784 individuals with AD and 5222 controls.

Main Results:

• Identification of four novel common risk loci near EDEM1, ALCAM, GPC6, and VRK3, associated with AD in African Americans.
• Discovery of genome-wide significant associations with rare variants near IGF1R, and suggestive associations with API5 and RBFOX1.
• Gene expression data linked ALCAM, ARAP1, GPC6, and RBFOX1 to brain beta-amyloid load; pathway analyses indicated overlap in immunity, lipid processing, and intracellular trafficking, with a novel finding related to the kidney system.

Conclusions:

• While key Alzheimer disease (AD) pathways are shared between African American and non-Hispanic White individuals, the specific genetic loci conferring risk differ.
• The identified novel loci and pathways contribute to a more comprehensive understanding of AD etiology across diverse populations.
• Further research into the kidney system's role in AD pathogenesis is warranted.