Dataset Information

The genetic architecture of Alzheimer disease risk in the Ohio and Indiana Amish.

ABSTRACT: Alzheimer disease (AD) is the most common type of dementia and is currently estimated to affect 6.2 million Americans. It ranks as the sixth leading cause of death in the United States, and the proportion of deaths due to AD has been increasing since 2000, while the proportion of many other leading causes of deaths have decreased or remained constant. The risk for AD is multifactorial, including genetic and environmental risk factors. Although APOE ε4 remains the largest genetic risk factor for AD, more than 26 other loci have been associated with AD risk. Here, we recruited Amish adults from Ohio and Indiana to investigate AD risk and protective genetic effects. As a founder population that typically practices endogamy, variants that are rare in the general population may be of a higher frequency in the Amish population. Since the Amish have a slightly lower incidence and later age of onset of disease, they represent an excellent and unique population for research on protective genetic variants. We compared AD risk in the Amish and to a non-Amish population through APOE genotype, a non-APOE genetic risk score of genome-wide significant variants, and a non-APOE polygenic risk score considering all of the variants. Our results highlight the lesser relative impact of APOE and differing genetic architecture of AD risk in the Amish compared to a non-Amish, general European ancestry population.

SUBMITTER: Osterman MD

PROVIDER: S-EPMC9114685 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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The genetic architecture of Alzheimer disease risk in the Ohio and Indiana Amish.

Osterman Michael D MD Song Yeunjoo E YE Adams Larry D LD Laux Renee A RA Caywood Laura J LJ Prough Michael B MB Clouse Jason E JE Herington Sharlene D SD Slifer Susan H SH Lynn Audrey A Fuzzell M Denise MD Fuzzell Sarada L SL Hochstetler Sherri D SD Miskimen Kristy K Main Leighanne R LR Dorfsman Daniel A DA Ogrocki Paula P Lerner Alan J AJ Ramos Jairo J Vance Jeffery M JM Cuccaro Michael L ML Scott William K WK Pericak-Vance Margaret A MA Haines Jonathan L JL

HGG advances 20220427 3

Alzheimer disease (AD) is the most common type of dementia and is currently estimated to affect 6.2 million Americans. It ranks as the sixth leading cause of death in the United States, and the proportion of deaths due to AD has been increasing since 2000, while the proportion of many other leading causes of deaths have decreased or remained constant. The risk for AD is multifactorial, including genetic and environmental risk factors. Although <i>APOE ε4</i> remains the largest genetic risk fact ...[more]

PMID: 35599847

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Project description:ImportanceAn estimated 40% of dementia is potentially preventable by modifying 12 risk factors throughout the life course. However, robust evidence for most of these risk factors is lacking. Effective interventions should target risk factors in the causal pathway to dementia.ObjectiveTo comprehensively disentangle potentially causal aspects of modifiable risk factors for Alzheimer disease (AD) to inspire new drug targeting and improved prevention.Design, setting, and participantsThis genetic association study was conducted using 2-sample univariable and multivariable mendelian randomization. Independent genetic variants associated with modifiable risk factors were selected as instrumental variables from genomic consortia. Outcome data for AD were obtained from the European Alzheimer & Dementia Biobank (EADB), generated on August 31, 2021. Main analyses were conducted using the EADB clinically diagnosed end point data. All analyses were performed between April 12 and October 27, 2022.ExposuresGenetically determined modifiable risk factors.Main outcomes and measuresOdds ratios (ORs) and 95% CIs for AD were calculated per 1-unit change of genetically determined risk factors.ResultsThe EADB-diagnosed cohort included 39 106 participants with clinically diagnosed AD and 401 577 control participants without AD. The mean age ranged from 72 to 83 years for participants with AD and 51 to 80 years for control participants. Among participants with AD, 54% to 75% were female, and among control participants, 48% to 60% were female. Genetically determined high-density lipoprotein (HDL) cholesterol concentrations were associated with increased odds of AD (OR per 1-SD increase, 1.10 [95% CI, 1.05-1.16]). Genetically determined high systolic blood pressure was associated with increased risk of AD after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.22 [95% CI, 1.02-1.46]). In a second analysis to minimize bias due to sample overlap, the entire UK Biobank was excluded from the EADB consortium; odds for AD were similar for HDL cholesterol (OR per 1-SD unit increase, 1.08 [95% CI, 1.02-1.15]) and systolic blood pressure after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.23 [95% CI, 1.01-1.50]).Conclusions and relevanceThis genetic association study found novel genetic associations between high HDL cholesterol concentrations and high systolic blood pressure with higher risk of AD. These findings may inspire new drug targeting and improved prevention implementation.

Dataset Information

The genetic architecture of Alzheimer disease risk in the Ohio and Indiana Amish.

Publications

The genetic architecture of Alzheimer disease risk in the Ohio and Indiana Amish.

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