Genetic analysis of cognitive preservation in the midwestern Amish reveals a novel locus on chromosome 2

ABSTRACT INTRODUCTION Alzheimer disease (AD) remains a debilitating condition with limited treatments and additional therapeutic targets needed. Identifying AD protective genetic loci may identify new targets and accelerate identification of therapeutic treatments. We examined a founder population to identify loci associated with cognitive preservation into advanced age. METHODS Genome-wide association and linkage analyses were performed on 946 examined and sampled Amish individuals, aged 76-95, who were either cognitively unimpaired (CU) or impaired (CI). RESULTS 12 SNPs demonstrated suggestive association (P≤5x10 -4 ) with cognitive preservation. Genetic linkage analyses identified >100 significant (LOD≥3.3) SNPs, some which overlapped with the association results. Only one locus on chromosome 2 retained significance across multiple analyses. DISCUSSION A novel significant result for cognitive preservation on chromosome 2 includes the genes LRRTM4 and CTNNA2 . Additionally, the lead SNP, rs1402906, impacts the POU3F2 transcription factor binding affinity, which regulates LRRTM4 and CTNNA2 .