Dataset Information

Association Between APOE Alleles and Change of Neuropsychological Tests in the Long Life Family Study.

ABSTRACT:

Background

The Long Life Family Study (LLFS) is a family based, prospective study of healthy aging and familial longevity. The study includes two assessments of cognitive function that were administered approximately 8 years apart.

Objective

To test whether APOE genotype is associated with change of cognitive function in older adults.

Methods

We used Bayesian hierarchical models to test the association between APOE alleles and change of cognitive function. Six longitudinally collected neuropsychological test scores were modelled as a function of age at enrollment, follow-up time, gender, education, field center, birth cohort indicator (?1935, or >1935), and the number of copies of ?2 or ?4 alleles.

Results

Out of 4,587 eligible participants, 2,064 were male (45.0%), and age at enrollment ranged from 25 to 110 years, with mean of 70.85 years (SD: 15.75). We detected a significant cross-sectional effect of the APOE?4 allele on Logical Memory. Participants carrying at least one copy of the ?4 allele had lower scores in both immediate (-0.31 points, 95% CI: -0.57, -0.05) and delayed (-0.37 points, 95% CI: -0.64, -0.10) recall comparing to non-?4 allele carriers. We did not detect any significant longitudinal effect of the ?4 allele. There was no cross-sectional or longitudinal effect of the ?2 allele.

Conclusion

The APOE?4 allele was identified as a risk factor for poorer episodic memory in older adults, while the APOE?2 allele was not significantly associated with any of the cognitive test scores.

SUBMITTER: Du M

PROVIDER: S-EPMC7952213 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Publications

Association Between APOE Alleles and Change of Neuropsychological Tests in the Long Life Family Study.

Du Mengtian M Andersen Stacy L SL Schupf Nicole N Feitosa Mary F MF Barker Megan S MS Perls Thomas T TT Sebastiani Paola P

Journal of Alzheimer's disease : JAD 20210101 1

<h4>Background</h4>The Long Life Family Study (LLFS) is a family based, prospective study of healthy aging and familial longevity. The study includes two assessments of cognitive function that were administered approximately 8 years apart.<h4>Objective</h4>To test whether APOE genotype is associated with change of cognitive function in older adults.<h4>Methods</h4>We used Bayesian hierarchical models to test the association between APOE alleles and change of cognitive function. Six longitudinall ...[more]

PMID: 33216038

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Project description:Background: Since APOE alleles represent the most impactful genetic risk factors for Alzheimer's disease (AD), their differential mechanism(s) of action are under intense scrutiny. APOE4 is robustly associated with increased AD risk compared to the neutral APOE3 and protective APOE2. APOE alleles have also been associated with differential inflammation and gastrointestinal recovery after insult in human and murine studies, leading us to hypothesize that APOE alleles impact the gut microbiome. Methods: To assess this hypothesis, we compared 16S ribosomal RNA gene amplicon-based microbiome profiles in a cohort of mice that were homozygous for APOE2, APOE3, or APOE4, and included both males and females as well as carriers and non-carriers of five familial AD (5xFAD) mutations. Fecal samples were analyzed from mice at 4 and 6 months of age. APOE genotype, as well as sex and 5xFAD status, was then tested for influence on alpha diversity (Shannon H index) and beta diversity (principal coordinate analyses and PERMANOVA). A Random Forest analysis was used to identify features that predicted APOE, sex and 5xFAD status. Results: The richness and evenness (alpha diversity) of the fecal microbiome was not robustly associated with APOE genotype, 5xFAD status or sex. In contrast, microbial community composition (beta-diversity) was consistently and strongly associated with APOE genotype. The association between beta-diversity and sex or 5xFAD status was less consistent and more modest. Comparison of the differences underlying APOE effects showed that the relative abundance of multiple bacterial taxa was significantly different as a function of APOE genotype. Conclusions: The structure of the gut microbiome was strongly and significantly associated with APOE alleles in this murine model. Further evaluation of these findings in humans, as well as studies evaluating the impact of the APOE-associated microbiota on AD-relevant phenotypes in murine models, will be necessary to determine if alterations in the gut microbiome represent a novel mechanism whereby APOE genotype impacts AD.

Project description:With millions of single-nucleotide polymorphisms (SNPs) identified and characterized, genomewide association studies have begun to identify susceptibility genes for complex traits and diseases. These studies involve the characterization and analysis of very-high-resolution SNP genotype data for hundreds or thousands of individuals. We describe a computationally efficient approach to testing association between SNPs and quantitative phenotypes, which can be applied to whole-genome association scans. In addition to observed genotypes, our approach allows estimation of missing genotypes, resulting in substantial increases in power when genotyping resources are limited. We estimate missing genotypes probabilistically using the Lander-Green or Elston-Stewart algorithms and combine high-resolution SNP genotypes for a subset of individuals in each pedigree with sparser marker data for the remaining individuals. We show that power is increased whenever phenotype information for ungenotyped individuals is included in analyses and that high-density genotyping of just three carefully selected individuals in a nuclear family can recover >90% of the information available if every individual were genotyped, for a fraction of the cost and experimental effort. To aid in study design, we evaluate the power of strategies that genotype different subsets of individuals in each pedigree and make recommendations about which individuals should be genotyped at a high density. To illustrate our method, we performed genomewide association analysis for 27 gene-expression phenotypes in 3-generation families (Centre d'Etude du Polymorphisme Humain pedigrees), in which genotypes for ~860,000 SNPs in 90 grandparents and parents are complemented by genotypes for ~6,700 SNPs in a total of 168 individuals. In addition to increasing the evidence of association at 15 previously identified cis-acting associated alleles, our genotype-inference algorithm allowed us to identify associated alleles at 4 cis-acting loci that were missed when analysis was restricted to individuals with the high-density SNP data. Our genotype-inference algorithm and the proposed association tests are implemented in software that is available for free.

Dataset Information

Association Between APOE Alleles and Change of Neuropsychological Tests in the Long Life Family Study.

Background

Objective

Methods

Results

Conclusion

Publications

Association Between APOE Alleles and Change of Neuropsychological Tests in the Long Life Family Study.

Similar Datasets

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