AbstractBackgroundAlzheimer’s Disease (AD) is a leading cause of death in the US, with limited treatment options. Most studies assess risk factors for AD; however, protective mechanisms demonstrate higher success rates as therapeutic targets. Here, we examine the genetics of Amish individuals maintaining cognitive preservation into advanced age, aiming to uncover protective mechanisms against AD.MethodOur dataset consisted of individuals of Amish descent, between 76 – 95 years of age and cognitively unimpaired (CU) with at least one first‐degree relative determined to be either CU or cognitively impaired (CI). 946 Amish individuals met our criteria, were genotyped across their genomes, and incorporated into a single 13‐generation pedigree containing 8,222 individuals. Their complex familial relationships were considered in linkage and genome‐wide association analyses (GWAS). GENESIS was used for GWAS, with XWAS used for the X chromosome. Several parametric and non‐parametric linkage analyses were also performed utilizing MERLIN software for the autosomes and MINX for the X chromosome.Result106 SNPs (representing 64 loci) reached an initial significance threshold (LOD≥3.3) in linkage analyses. Adjusting for number of independent SNPs in our dataset, no SNPs reached significance after GWAS (P≤6.4×10−7), but 12 loci were suggestive (P≤5×10−4). No loci were suggestive/significant on the X chromosome. For a locus to be further investigated, 1) a significant or suggestive LOD score was required in two or more linkage analyses or 2) one significant LOD score and a suggestive GWAS association within a 10 Mb region were required. After applying these criteria, 8 loci, on chromosomes 1, 2, 3, 7, 11, and 17, were selected for further evaluation. Loci on chromosomes 7 and 11 are within 10 Mb of known AD risk and protective loci, EPHA1 and PICALM, respectively. Significant LOD score results on chromosomes 7, 11, and 17 overlap with coding regions for TBXAS1, DLG2, and SPNS3, respectively. These three loci have been implicated in cognitive impairment relating to neurological disorders.ConclusionWe identified 8 loci potentially harboring genes promoting cognitive preservation. These are under further investigation and represent potential therapeutic targets but require experimental studies identifying their specific mechanisms in relationship to AD.