Dataset Information

Among men, androgens are associated with a decrease in Alzheimer's disease risk.

ABSTRACT:

Introduction

Increased levels of sex hormones have been hypothesized to decrease Alzheimer's disease (AD) risk. We assessed the association between sex steroid hormones with AD using a Mendelian randomization (MR) approach.

Methods

An inverse-variance weighting (IVW) MR analysis was performed using effect estimates from external genome-wide association study (GWAS) summary statistics. We included independent variants (linkage disequilibrium R² < 0.001) and a p-value threshold of 5 × 10^-8 .

Results

An increase in androgens was associated with a decreased AD risk among men: testosterone (odds ratio [OR]: 0.53; 95% confidence interval [CI]: 0.32-0.88; p-value: 0.01; false discovery rate [FDR] p-value: 0.03); dehydroepiandrosterone sulfate (DHEAS; OR: 0.56; 95% CI: 0.38-0.85; p-value: 0.01; FDR p-value: 0.03); and androsterone sulfate (OR: 0.69; 95% CI: 0.46-1.02; p-value: 0.06; FDR p-value: 0.10). There was no association between sex steroid hormones and AD among women, although analysis for estradiol had limited statistical power.

Discussion

A higher concentration of androgens was associated with a decreased risk of AD among men of European ancestry, suggesting that androgens among men might be neuroprotective and could potentially prevent or delay an AD diagnosis.

Highlights

Sex hormones are hypothesized to play a role in developing Alzheimer's disease (AD). The effect of sex hormones on AD was assessed using Mendelian randomization (MR) analysis. Among women, genetically determined effects of sex hormones were limited or null. Among men, a higher concentration of androgens decreased AD risk. This study suggests a causal relationship between androgens and AD among men.

SUBMITTER: Kusters CDJ

PROVIDER: S-EPMC10509321 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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Publications

Among men, androgens are associated with a decrease in Alzheimer's disease risk.

Kusters Cynthia D J CDJ Paul Kimberly C KC Romero Tahmineh T Sinsheimer Janet S JS Ritz Beate R BR

Alzheimer's & dementia : the journal of the Alzheimer's Association 20230320 9

<h4>Introduction</h4>Increased levels of sex hormones have been hypothesized to decrease Alzheimer's disease (AD) risk. We assessed the association between sex steroid hormones with AD using a Mendelian randomization (MR) approach.<h4>Methods</h4>An inverse-variance weighting (IVW) MR analysis was performed using effect estimates from external genome-wide association study (GWAS) summary statistics. We included independent variants (linkage disequilibrium R<sup>2</sup> < 0.001) and a p-value th ...[more]

PMID: 36938850

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Project description:IntroductionThis study aims to clarify the role(s) of endogenous sex hormones to influence health outcomes in men, specifically to define the associations of plasma testosterone with incidence of cardiovascular events, cancer, dementia and mortality risk, and to identify factors predicting testosterone concentrations. Data will be accrued from at least three Australian, two European and four North American population-based cohorts involving approximately 20?000 men.Methods and analysisEligible studies include prospective cohort studies with baseline testosterone concentrations measured using mass spectrometry and 5?years of follow-up data on incident cardiovascular events, mortality, cancer diagnoses or deaths, new-onset dementia or decline in cognitive function recorded. Data for men, who were not taking androgens or drugs suppressing testosterone production, metabolism or action; and had no prior orchidectomy, are eligible. Systematic literature searches were conducted from 14 June 2019 to 31 December 2019, with no date range set for searches. Aggregate level data will be sought where individual participant data (IPD) are not available. One-stage IPD random-effects meta-analyses will be performed, using linear mixed models, generalised linear mixed models and either stratified or frailty-augmented Cox regression models. Heterogeneity in estimates from different studies will be quantified and bias investigated using funnel plots. Effect size estimates will be presented in forest plots and non-negligible heterogeneity and bias investigated using subgroup or meta-regression analyses.Ethics and disseminationEthics approvals obtained for each of the participating cohorts state that participants have consented to have their data collected and used for research purposes. The Androgens In Men Study has been assessed as exempt from ethics review by the Human Ethics office at the University of Western Australia (file reference number RA/4/20/5014). Each of the component studies had obtained ethics approvals; please refer to respective component studies for details. Research findings will be disseminated to the scientific and broader community via the publication of four research articles, with each involving a separate set of IPD meta-analyses (articles will investigate different, distinct outcomes), at scientific conferences and meetings of relevant professional societies. Collaborating cohort studies will disseminate findings to study participants and local communities.Prospero registration numberCRD42019139668.

Project description:Alzheimer's disease (AD) is a chronic neurodegenerative disorder characterized by progressive deterioration of cognitive function. Evidence suggests a role for epigenetic regulation, in particular the cytosine modifications 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC,) in AD. 5hmC is highly enriched in the nervous system and displays neurodevelopment and age-related changes. To determine the role of 5hmC in AD, we performed genome-wide analyses of 5hmC in DNA from prefrontal cortex of post-mortem AD as well as RNA-Seq to correlate changes in methylation status with transcriptional changes. We also utilized the existing AD fly model to further test the functional significance of these epigenetically altered loci. We identified 325 genes containing differentially hydroxymethylated loci (DhMLs) in both the discovery and replication datasets, and these are enriched for pathways involved in neuron projection development and neurogenesis. Of the 325 genes identified, 140 also showed changes in gene expression by RNA-Seq. Proteins encoded by genes identified in the current analysis form direct protein-protein interactions with AD-associated genes, expanding the network of genes implicated in AD. Furthermore, we identified AD-associated single nucleotide polymorphisms (SNPs) located within or near DhMLs, suggesting that these SNPs may identify regions of epigenetic gene regulation that play a role in AD pathogenesis. Finally using the existing AD fly model we showed that some of these genes could modulate the toxicity associated with AD. Our data implicate neuron projection development and neurogenesis pathways as potential targets in AD. These results indicate that incorporating epigenomic and transcriptomic data with GWAS data can expand the known network of genes involved in disease pathogenesis. Combination of epigenome profiling and Drosophila model enables us to identify the epigenetic modifiers of Alzheimer's disease. University of Kentucky Alzheimer's Disease Research Center (3 control, 3 Alzheimer's) and Emory University Alzheimer's Disease Research Center (2 control, 2 Alzheimer's)

Dataset Information

Among men, androgens are associated with a decrease in Alzheimer's disease risk.

Introduction

Methods

Results

Discussion

Highlights

Publications

Among men, androgens are associated with a decrease in Alzheimer's disease risk.

Similar Datasets

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