Linkage and association of preserved cognitive function in the midwestern Amish at a higher genetic risk of Alzheimer's disease

INTRODUCTION Genetic factors promoting cognitive preservation in high‐risk older adults for Alzheimer's disease (AD) risk remain understudied. Among Midwestern Amish with elevated AD genetic risk, we hypothesized ranking sibships by mean genetic risk scores during linkage analysis would reveal loci influencing preserved cognition. METHODS We evaluated 1855 Amish adults (≥75 years) using the Modified Mini‐Mental Status Exam (3MS), classifying individuals with education‐adjusted scores ≥87 as cognitively unimpaired (CU) and lower scores as impaired (CI). Non‐parametric linkage analysis (NPL) on 143 sibships with ≥ 2 CU was combined with ordered‐subsets analysis (OSA) to incorporate 25 known European AD risk loci. RESULTS NPL‐OSA and association identified linkage on chromosome 2 (rs6719884) within LINC01122 (logarithm of odds [LOD]* = 3.08) and a significant interaction on chromosome 12 (rs11063479 near KCNA5 ), suggesting synergy with genetic risk. DISCUSSION These findings implicate long intergenic non‐coding RNAs (lincRNAs) and potassium channel genes in maintaining cognition despite high AD risk, informing future research on protective genetic mechanisms. Highlights Non‐parametric linkage and ordered‐subsets analysis in sibships enriched with cognitively unimpaired older adults found significant evidence of linkage on chromosome 2 within the lincRNA LINC01122, along with suggestive evidence at additional loci. Association mapping within significant and suggestively linked regions revealed a significant single nucleoride polymorphism (SNP) x AD genetic risk scores (GRS) interaction effect on chromosome 12, near the potassium channel gene KCNA5. LINC01122 is primarily brain‐expressed, while KCNA5 has been linked to multiple cardiovascular phenotypes, supporting their potential role in cognitive function.