Exploring potential mechanisms of an African protective locus for Alzheimer's disease in APOEε4 carriers

Abstract INTRODUCTION We recently described that the African‐specific A allele of rs10423769, which lies in an area of segmental duplications, reduces Alzheimer's disease (AD) risk by ∼ 75% in apolipoprotein E ( APOE) ε4 homozygotes. METHODS Short and long‐read sequencing were used to identify the haplotype harboring rs10423769_A and examine DNA methylation and structural variation (SV). RESULTS A unique 21 kb haplotype is shared amongst all rs10423769_A carriers (r 2 > 0.95) and is present in all African ancestry tested. We identified methylation differences between the non‐protective and rs10423769_A haplotypes. An expanded variable number tandem repeat (VNTR) containing multiple MEF2‐family transcription factor binding motifs in LD with the protective haplotype. Further, rs10423769 is an eQTL for ZNF222 . DISCUSSION The protective haplotype is unique, with haplotype changes in DNA methylation and SV that could contribute to the protective mechanism of rs10423769_A. The study generates hypothesis for future studies on this important protective mechanism for APOEε4 carriers. Highlights We investigated an African‐specific haplotype harboring a protective locus for APOEε4 carriers that significantly reduces the risk for Alzheimer Disease. The protective locus lies in an area of segmental duplications 2MB from APOE . We found that the protective haplotype is unique within the segmental duplications. The haplotype is found in all African ancestry tested but not in other ancestries. Long read whole genome sequencing identified an expanded VNTR associated with the protective haplotype containing multiple MEF2 transcription factor binding motifs. Differences in DNA methylation were found between the protective and the reference haplotype.