Linkage and association of preserved cognitive function in the Midwestern Amish at higher genetic risk of Alzheimer disease
Authors: Dorfsman Daniel A. , Prough Michael B. , Gulyayev Alex , Caywood Laura J. , Clouse Jason E. , Herington Sharlene D. , Slifer Susan H. , Adams Larry D. , Laux Renee A. , Song Yeunjoo E. , Lynn Audrey , Fuzzell Sarada L. , Hochstetler Sherri D. , Miskimen Kristy , Main Leighanne R. , Wang Ping , Liu Yining , Moore Noel , Ogrocki Paula , Lerner Alan J. , Vance Jeffery M. , Cuccaro Michael L. , Haines Jonathan L. , Pericak-Vance Margaret A. , Scott William K. 
Published: January 2025

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 ≥ 87 were classified as cognitively unimpaired (CU), while those with education-adjusted 3MS < 87 were classified as cognitively impaired (CI). Genome-wide non-parametric linkage analysis was performed on 143 sibships with ≥ 2 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 lincRNALINC01122(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 theKCNA5gene. 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 ofLINC01122andKCNA5as 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.