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

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 . ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was funded by the National Institutes of Health and the National Institute on Human Aging (AG058066) and an Alzheimer's Disease Translational Data Science Training Grant (5T32AG071474-02). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Institutional Review Board of Case Western Reserve University gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data produced in the present work are contained in the manuscript or available upon reasonable request to the authors, barring inquiries impinging upon the privacy of individuals in our dataset. * AD : Alzheimer Disease AGDB : Anabaptist Genealogical Database CI : Cognitively impaired CU : Cognitively unimpaired GWAS : Genome-wide association study HLOD : Heterogeneity logarithm of the odds LD : Linkage disequilibrium LOD : Logarithm of the odds MCI : Mild cognitive impairment MCMC : Markov chain Monte Carlo QC : Quality control