Background: Genetic studies of Alzheimer's disease (AD) have made remarkable progress in identifying genetic factors that increase the risk of AD. However, the genetic determinants that contribute to preserved cognition at older ages, particularly those that mitigate AD risk, are less understood. In the Midwestern Amish community, certain older adults maintain normal cognitive abilities despite carrying a relatively high genetic risk of AD. Our goal was to identify shared genetic factors among high-risk Amish sibships enriched with cognitively unimpaired individuals. We hypothesized that ranking sibships by their mean genetic risk of AD would provide greater evidence of genetic linkage in cognitively preserved sibships at higher risk, identifying genomic regions containing protective loci. Methods: Cognitive status in adult Amish participants (n = 1,855) was evaluated using the Modified Mini Mental Status Exam (3MS). Those aged ≥75 with education-adjusted 3MS scores ≥87 were classified as cognitively unimpaired (CU), while those with education-adjusted 3MS scores below 87 were classified as cognitively impaired (CI). Genome-wide non-parametric linkage analysis was performed on 143 sibships with at least two CU members. To account for known genetic risk, ordered-subsets analysis (OSA) was used to rank families by the mean AD genetic risk score (GRS) of their CU members using effect sizes for 25 established European AD risk loci. Regions exhibiting significant or suggestive increases in the LOD* score during OSA were further evaluated using single-variant and interaction association tests in a sample of 715 CU and 460 CI participants. Results: Significant evidence of linkage following OSA adjustment was detected on chromosome 2 at SNP rs6719884 (~59.0 Mb) within the lincRNA LINC01122 (LOD* = 3.08), suggesting a shared genetic factor influencing preserved cognition in high-risk individuals. Additionally, a significant interaction effect was observed on chromosome 12 at SNP rs11063479 (~5.1 Mb) near the KCNA5 gene. The variant showed increased odds of being cognitively unimpaired in the high-GRS stratum (OR = 2.07) and decreased odds in the low-GRS stratum (OR = 0.70), indicating a potential synergistic effect with genetic risk. Conclusions: Our findings highlight specific genomic regions, particularly on chromosomes 2 and 12, that may harbor genetic loci contributing to preserved cognitive function in aged individuals at high genetic risk for AD. The identification of LINC01122 and KCNA5 as candidate genes underscores the potential role of brain-expressed lincRNAs and potassium channel genes in preserving cognitive function. These results contribute to the understanding of cognitive preservation and may inform future research on protective genetic mechanisms against cognitive decline.

The authors have declared no competing interest.

This study was supported by the National Institutes of Health/National Institute on Aging grant R01AG058066, awarded to Jonathan L. Haines, Margaret Pericak-Vance, and William K. Scott.

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