Abstract
Abstract Background The variant G206A in Presenilin‐1 ( PSEN1 ) gene has been identified almost exclusively in Alzheimer Disease (AD) Puerto Rican families. This variant represents a founder effect on the African background. The G206A variant associates with extreme variability in age of onset (AOO), ranging from 30 to 90 years. In contrast, other variants at the same amino acid of PSEN1 (G206N, G206S) have a tighter range of AOO (30‐35 years). We aim to identify the molecular mechanisms involved in the AOO variability between G206A carriers through functional analysis of induced pluripotent stem cells (iPSCs). Method Genotyping data were phased using SHAPEIT to identify local ancestry and RFMix to estimate genetic ancestry. p‐Tau181 levels were tested from plasma using Simoa (Quanterix HD‐X). iPSCs of G206A carriers with different AOO were reprogrammed using non‐integrating Sendai virus. These clonal lines were assessed for pluripotency and chromosomal stability Isogenic construction of G206A iPSC lines is currently in progress. Result We screened for G206A carriers using whole genome from 896 individuals (182 families) and identified 43 carriers (39 AD and 4 cognitively unimpaired <65 years) from 8 families and 3 isolated cases. 55% of AD G206A carriers had AOO <65. A single African haplotype was identified in all G206Acarriers. We observed higher pTau181 levels in AD G206A carriers with early age of onset, compared to those with late onset. Association analysis did not identify APOE4 or SYNJ1 polymorphisms as contributing to the differences in AOO within G206A carriers. To perform functional studies, we selected three with early (<65) and three with late (>65) AOO AD peripheral blood mononuclear cells (PBMCs)that were reprogrammed into iPSC lines. G‐band Karyotype, factor loss analyses, genetic finger printing, immunocytochemistry (ICC) and qRT‐PCR for intracellular and surface pluripotency markers was confirmed in the iPSC lines. Conclusion The PSEN1 G206A variant, originating in African ancestry haplotype revealing a founder effect, is an important contributor to AD in an underserved population. Understanding the role of the G206A variant in AD pathogenesis and the factors that influence its effect on AOO will provide insight on AD pathogenesis, age of onset variation and identification of potential novel therapeutic targets.