African origin haplotype protective for Alzheimer's disease in ε4 carriers: exploring potential mechanisms.

ε4 is the strongest genetic risk factor for Alzheimer's disease (AD) with approximately 50% of AD patients carrying at least one ε4 allele. Our group identified a protective interaction between ε4 with the African-specific A allele of rs10423769, which reduces the AD risk effect of ε4 homozygotes by approximately 75%. The protective variant lies 2Mb from in a region of segmental duplications (SD) of chromosome 19 containing a cluster of pregnancy specific beta-1 glycoprotein genes () and a long non-coding RNA. Using both short and long read sequencing, we demonstrate that rs10423769_A allele lies within a unique single haplotype inside this region of segmental duplication. We identified the protective haplotype in all African ancestry populations studied, including both West and East Africans, suggesting the variant has an old origin. Long-read sequencing identified both structural and DNA methylation differences between the protective rs10423769_A allele and non-protective haplotypes. An expanded variable number tandem repeat (VNTR) containing multiple MEF2 family transcription factor binding motifs was found associated with the protective haplotype (p-value = 2.9e-10). These findings provide novel insights into the mechanisms of this African-origin protective variant for AD in ε4 carriers and supports the importance of including all ancestries in AD research.