Successful aging shows linkage to chromosomes 6, 7, and 14 in the Amish

Successful aging (SA) is a multi-dimensional phenotype involving preservation of cognitive ability, physical function, and social engagement throughout life. Multiple components of SA are heritable, supporting a genetic component. The Old Order Amish are genetically and socially isolated with homogeneous lifestyles, making them a suitable population for studying the genetics of SA. DNA and measures of SA were collected on 214 cognitively intact Amish individuals over age 80. Individuals were grouped into a 13-generation pedigree using the Anabaptist Genealogy Database. A linkage screen of 5,944 single nucleotide polymorphisms (SNPs) was performed using 12 informative sub-pedigrees with an affected-only 2-point and multipoint linkage analysis. Eleven SNPs produced 2-point LOD scores >2, suggestive of linkage. Multipoint linkage analyses, allowing for heterogeneity, detected significant lod scores on chromosomes 6 (HLOD = 4.50), 7 (LOD* = 3.11), and 14 (HLOD = 4.17), suggesting multiple new loci underlying SA

Mitochondrial Haplogroup X is Associated with Successful Aging in the Amish

Avoiding disease, maintaining physical and cognitive function, and continued social engagement in long-lived individuals describe successful aging (SA). Mitochondrial lineages described by patterns of common genetic variants (“haplogroups”) have been associated with increased longevity in different populations. We investigated the influence of mitochondrial haplogroups on SA in an Amish community sample. Cognitively intact volunteers aged ≥80 (n=261) were enrolled in a door-to-door survey of Amish communities in Indiana and Ohio. Individuals scoring in the top third for lower extremity function, needing little assistance with self-care tasks, having no depression symptoms, and expressing high life satisfaction were considered SA (n=74). The remainder (n=187) were retained as controls. These individuals descend from 51 matrilines in a single 13 generation pedigree. Mitochondrial haplogroups were assigned using the 10 mitochondrial single nucleotide polymorphisms (mtSNPs) defining the nine most common European haplogroups. An additional 17 mtSNPs from a genome-wide association panel were also investigated. Associations between haplogroups, mtSNPs, and SA were determined by logistic regression models accounting for sex, age, body mass index, and matriline via generalized estimating equations. SA cases were more likely to carry Haplogroup X (OR=7.56, p=0.0015), and less likely to carry Haplogroup J (OR=0.40, p=0.0003). Our results represent a novel association of Haplogroup X with SA and suggest that variants in the mitochondrial genome may promote maintenance of both physical and cognitive function in older adults

Heritability of Choroidal Thickness in the Amish

To evaluate the heritability of choroidal thickness and its relationship to age-related macular degeneration (AMD). Cohort study. Six hundred eighty-nine individuals from Amish families with early or intermediate AMD. Ocular coherence tomography was used to quantify choroidal thickness, and fundus photography was used to classify eyes into categories using a modified Clinical Age-Related Maculopathy Staging (CARMS) system. Repeatability and heritability of choroidal thickness and its phenotypic and genetic correlations with the AMD phenotype (CARMS category) were estimated using a generalized linear mixed model (GLMM) approach that accounted for relatedness, repeated measures (left and right eyes), and the effects of age, gender, and refraction. Heritability of choroidal thickness and its phenotypic and genetic correlation with the AMD phenotype (CARMS category). Phenotypic correlation between choroidal thickness and CARMS category was moderate (Spearman's rank correlation, r  = -0.24; n = 1313 eyes) and significant (GLMM posterior mean, -4.27; 95% credible interval [CI], -7.88 to -0.79; P = 0.02) after controlling for relatedness, age, gender, and refraction. Eyes with advanced AMD had thinner choroids than eyes without AMD (posterior mean, -73.8; 95% CI, -94.7 to -54.6; P < 0.001; n = 1178 eyes). Choroidal thickness was highly repeatable within individuals (repeatability, 0.78; 95% CI, 0.68 to 0.89) and moderately heritable (heritability, 0.40; 95% CI, 0.14 to 0.51), but did not show significant genetic correlation with CARMS category, although the effect size was moderate (genetic correlation, -0.18; 95% CI, -0.49 to 0.16). Choroidal thickness also varied with age, gender, and refraction. The CARMS category showed moderate heritability (heritability, 0.49; 95% CI, 0.26 to 0.72). We quantify the heritability of choroidal thickness for the first time, highlighting a heritable, quantitative trait that is measurable in all individuals regardless of AMD affection status, and moderately phenotypically correlated with AMD severity. Choroidal thickness therefore may capture variation not captured by the CARMS system. However, because the genetic correlation between choroidal thickness and AMD severity was not significant in our data set, genes associated with the 2 traits may not overlap substantially. Future studies should therefore test for genetic variation associated with choroidal thickness to determine the overlap in genetic basis with AMD

Lower Levels of Education Are Associated with Cognitive Impairment in the Old Order Amish

Background: Lower education has been reported to be associated with dementia. However, many studies have been done in settings where 12 years of formal education is the standard. Formal schooling in the Old Order Amish communities (OOA) ends at 8th grade which, along with their genetic homogeneity, makes it an interesting population to study the effect of education on cognitive impairment. Objective: The objective of this study was to examine the association of education with cognitive function in individuals from the OOA. We hypothesized that small differences in educational attainment at lower levels of formal education were associated with risk for cognitive impairment. Methods: Data of 2,426 individuals from the OOA aged 54–99 were analyzed. The Modified Mini-Mental State Examination (3MS-R) was used to classify participants as CI or normal. Individuals were classified into three education categories: 8 years of education. To measure the association of education with cognitive status, a logistic regression model was performed adding age and sex as covariates. Results: Our results showed that individuals who attained lowest levels of education (8 years (OR = 2.96 and 1.85). Conclusion: Even within a setting of low levels of formal education, small differences in educational attainment can still be associated with the risk of cognitive impairment. Given the homogeneity of the OOA, these results are less likely to be biased by differences in socioeconomic backgrounds

Genome-wide association for protective variants in Alzheimer's disease in the Midwestern Amish

Alzheimer's disease (AD) is a progressive neurological disease that leads to atrophy of the brain and cognitive decline. There are many factors that play a role in the risk of AD, such as age, smoking, gender, and genetics. the genetic influence on AD is strong, with heritability estimates between 40-60%. Identifying genetic factors that either increase or decrease AD risk are critical in the understanding of this disease. Here, we studied a homogeneous, isolated population - the Ohio and Indiana Amish - to identify protective genetic factors for AD. Our previous studies in the Amish documented numerous individuals who are cognitively normal at advanced ages. Here, we have completed a genome wide association study (GWAS) on Amish individuals who are at high risk for AD (i.e., have an affected sibling and are over 76 years of age), but are cognitively normal. We have genotypes on 2096 individuals, 921 of which are being analyzed for association, in which we have a complex 5,000-person, 13-generation pedigree to help inform our results. MEGAex and GSA chips were used for genotyping. Both KING and GENESIS software were used for quality control and association analyses since they control for both population structure and kinship in evaluating association via a generalized linear mixed model (GLMM). We included 601 cognitively normal (CN), 320 cognitively impaired (CI) individuals. Association analysis was done on a total of 921 individuals, with 256,978 SNPs. We had a total of four SNPs reach a significance threshold of p ≤ 5 x 10 to also include suggestive association loci in our examination. (Nearest genes: DISC1, IQGAP2, and LOC401478 on chromosomes 1, 5 and 8. One SNP on chromosome 13, rs1556774, has no gene association currently known, and no known gene within 80kb.) These loci are currently under further examination. We studied cognitively resilient individuals from a founder population to identify potential protective genetic variants for AD. We identified four SNPs associated with CN in at-risk adults over 75. These loci might influence cognitive resilience. Here we have shed some light on possible genetic factors that may contribute to protection from cognitive decline

Search for protective genetic variants in Alzheimer disease in the U.S. Midwestern Amish

Background Most genetic studies on Alzheimer’s disease (AD) have focused on finding risk genes and variants. Taking into account the 30+ loci identified to increase risk of AD, still only around 40‐50% of the estimated heritability of AD is explained. Our goal is to identify genetic variants that delay the onset or protect against the development of AD and to find novel gene interactions or pathways associated with AD. Method Our study focuses on the Amish communities in Ohio and Indiana due to their homogeneous genetics and environment. Studying genetics in the Amish increases our ability to find rare protective variants for AD that do not exist at a detectable frequency in the general population. Our focus is to identify individuals who are cognitively normal (CN), but at high risk for developing AD (i.e. have an affected sibling). Each of these individuals is retested every two years to assess their cognition status. Results Using the extensive genealogical data of families in the Amish population, we have generated a large ∼5,000 person, 13‐generation pedigree. As of January 2020, we have ascertained 652 individuals and are examining over 300,000 SNPs that were retained after preliminary QC. Out of the recently adjudicated enrollments, 55 percent are cognitively normal, 33 percent are borderline or cognitively impaired, and the remainder have been sampled and are awaiting a consensus diagnosis. The frequency of the APOE‐e2 allele in our enrollments is at 5%, while the APOE‐e4 allele is at 14%, is lower than the general European population. We are currently using KING and GENESIS software to QC the data since they take into account more relatedness in a population structure, which is needed for working with the Amish. Association and linkage analyses, taking into account the complex pedigree relationships, is ongoing. Conclusion We are using a founder population to have an increased chance of finding protective genetic variants in AD. We are specifically targeting individuals who are at high risk for developing AD, but seem to be resilient. This is important in discovering novel pathways in which AD functions, which can lead to further functional and pharmaceutical studies

Longitudinal assessment of cognitive decline in the Amish

Background The Modified Mini‐Mental State (3MS) is a widely used measure of global cognition. The Old Order Amish are both genetically and environmentally homogeneous, with similar years of formal education across the population. Here, we investigated the longitudinal course of cognitive function as measured by the distribution of 3MS in the Mid‐Western Amish. Method After extensive QC, the 919 subjects with both baseline 3MS and AD status were analyzed. The change from 1st to 2nd measurement was used as the main longitudinal trait of interest. Mean decline differences in 4 baseline age groups (=90) were assessed. The differences in the average longitudinal decline of 3MS between AD cases and controls was assessed using Kolmogorov‐Smirnov tests and ANCOVA adjusted for age at exam and sibship. Result The overall baseline mean 3MS score was 89.52 [42, 100] at the mean age of exam 75.52 [60, 99]. The overall annual rate of decline was ‐0.3 [‐5, 5] from 1st to 2nd measurement (n=242) and ‐0.6 [‐2.1, 1.3] from 2nd to 3rd measurement (n = 23). The annual rate of decline was ‐0.96 [‐4, 1.7] in AD cases (n=18), ‐0.01 [‐5, 5] in AD controls (n=180) and ‐1.08 [‐5, 0.7] in an ‘Unclear’ group (n = 44). The most rapid annual decline of the 3MS was in age 80 to 90 group and the decline rate was significant (p‐value=0.004) compared to the lowest age group (<70) overall and in AD cases. In the Unclear group, the rate of decline was greatest in age 70 to 80. However, in the control group, cognition improved, with a 1.29 [‐1, 5] annual increase in age 80 to 90. The age and sibship adjusted differences in decline were significant (p‐value<2e‐10) between AD cases vs. controls as well as between Unclear vs. controls. Conclusion We explored the changes of 3MS scores over time and demonstrated different patterns of decline by age and AD status in the Amish. Our study is the first in this homogeneous Amish population, providing a better understanding and insight into the cognitive decline examining the change in 3MS over time

The Genetics of Cognitive Resistance and Resilience in the Ohio and Indiana Amish

Abstract Background Alzheimer’s Disease (AD) is a leading cause of death in the US, with limited treatment options. Most studies assess risk factors for AD; however, protective mechanisms demonstrate higher success rates as therapeutic targets. Here, we examine the genetics of Amish individuals maintaining cognitive preservation into advanced age, aiming to uncover protective mechanisms against AD. Method Our dataset consisted of individuals of Amish descent, between 76 – 95 years of age and cognitively unimpaired (CU) with at least one first‐degree relative determined to be either CU or cognitively impaired (CI). 946 Amish individuals met our criteria, were genotyped across their genomes, and incorporated into a single 13‐generation pedigree containing 8,222 individuals. Their complex familial relationships were considered in linkage and genome‐wide association analyses (GWAS). GENESIS was used for GWAS, with XWAS used for the X chromosome. Several parametric and non‐parametric linkage analyses were also performed utilizing MERLIN software for the autosomes and MINX for the X chromosome. Result 106 SNPs (representing 64 loci) reached an initial significance threshold (LOD≥3.3) in linkage analyses. Adjusting for number of independent SNPs in our dataset, no SNPs reached significance after GWAS (P≤6.4×10 −7 ), but 12 loci were suggestive (P≤5×10 −4 ). No loci were suggestive/significant on the X chromosome. For a locus to be further investigated, 1) a significant or suggestive LOD score was required in two or more linkage analyses or 2) one significant LOD score and a suggestive GWAS association within a 10 Mb region were required. After applying these criteria, 8 loci, on chromosomes 1, 2, 3, 7, 11, and 17, were selected for further evaluation. Loci on chromosomes 7 and 11 are within 10 Mb of known AD risk and protective loci, EPHA1 and PICALM, respectively. Significant LOD score results on chromosomes 7, 11, and 17 overlap with coding regions for TBXAS1, DLG2, and SPNS3, respectively. These three loci have been implicated in cognitive impairment relating to neurological disorders. Conclusion We identified 8 loci potentially harboring genes promoting cognitive preservation. These are under further investigation and represent potential therapeutic targets but require experimental studies identifying their specific mechanisms in relationship to AD