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

Introduction: Alzheimer's 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: A total of 12 single nucleotide polymorphisms (SNPs) demonstrated suggestive association (P ≤ 5 × 10^-4) with cognitive preservation. Genetic linkage analyses identified > 100 significant (logarithm of the odds [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.

Highlights: GWAS and linkage identified over 100 loci associated with cognitive preservation. One locus on Chromosome 2 retained significance over multiple analyses. Predicted TFBSs near rs1402906 regulate genes associated with neurocognition.