Basic Science and Pathogenesis.

Area of Science:

• Genetics and Genomics
• Neuroscience
• Population Health

Background:

• Alzheimer disease (AD) genetic research has historically lacked diversity, limiting understanding of its mechanisms across different ancestries.
• The Recruitment and Retention for Alzheimer's Disease Diversity Genetic Cohorts in the ADSP (READD-ADSP) initiative was established to address this gap.
• Understanding genetic and non-genetic factors influencing AD risk and progression requires diverse population studies.

Purpose of the Study:

• To build a resource for studying AD genetics across diverse populations in the United States and Africa.
• To examine the interplay of genetic, ancestral, and social determinants of health (SDOH) factors in AD.
• To evaluate the generalizability of known AD risk loci to African ancestry populations and identify novel genetic factors.

Main Methods:

• Genomic and epidemiological methods were employed across four U.S. sites and ten African countries.
• Integration of whole-genome sequencing, blood biomarker data, SDOH, and clinical measures.
• Ancestral analyses to define population structure and assess risk-gene effect heterogeneity (e.g., APOE, ABCA7).

Main Results:

• Preliminary analyses revealed substantial ancestral variation within African populations (e.g., West vs. East Africa).
• Identified heterogeneity in AD risk effect sizes (e.g., APOE4) and risk marker variation (e.g., ABCA7) across ancestries.
• Discovered an African-specific protective locus (PSG2) conferring a protective effect in APOE4 carriers.

Conclusions:

• Diverse genomic backgrounds are crucial for uncovering novel protective genetic factors for Alzheimer disease.
• The READD-ADSP initiative enhances understanding of AD etiology and informs globally tailored precision therapies.
• Continued cross-continental collaboration integrating genetic data with SDOH factors is vital for future AD research.