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. 2025 Aug;21(8):e70627.
doi: 10.1002/alz.70627.

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

Daniel A Dorfsman  1   2 , Michael B Prough  1 , Alex V Gulyayev  1 , Laura J Caywood  1 , Jason E Clouse  1 , Sharlene D Herington  1 , Susan H Slifer  1 , Larry D Adams  1 , Renee A Laux  3 , Yeunjoo E Song  3 , Audrey Lynn  3 , Sarada L Fuzzell  3 , Sherri D Hochstetler  3 , Kristy Miskimen  3 , Leighanne R Main  3   4 , Ping Wang  3 , Yining Liu  3 , Noel Moore  3 , Paula Ogrocki  5   6 , Alan J Lerner  5   6 , Jeffery M Vance  1   2 , Michael L Cuccaro  1   2 , Jonathan L Haines  3   4 , Margaret A Pericak-Vance  1   2 , William K Scott  1   2
Affiliations

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

Daniel A Dorfsman et al. Alzheimers Dement. 2025 Aug.

Abstract

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.

Keywords: Alzheimer's disease; Amish population; cognitive preservation; genetic risk score; linkage analysis; protective variants.

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Conflict of interest statement

The authors declare no conflicts of interest. Author disclosures are available in the supporting information.

Figures

FIGURE 1
FIGURE 1
Genome‐wide, non‐parametric linkage analysis (NPL) in 143 sibships with two or more cognitively intact individuals aged ≥ 75 years. The affected‐only NPL screen comprising 367 individuals across 143 sibships did not identify significant or suggestive evidence of linkage. The strongest evidence of linkage was observed at 37.4 Mb on chromosome 22 (logarithm of odds [LOD*] = 1.72).
FIGURE 2
FIGURE 2
Comparison of baseline and ordered‐subsets analysis (OSA) sibships on chromosome 2. Ranking families from high to low mean genetic risk scores (GRS) identified a significant logarithm of odds (LOD*) increase (defined as: LOD* > 3, p OSA < 0.05) on chromosome 2 (LOD* = 3.08, p OSA = 0.043, 59.03 Mb, N = 79 families).
See this image and copyright information in PMC

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