Dataset Information

A Twin Study of Sex Differences in Genetic Risk for All Dementia, Alzheimer's Disease (AD), and Non-AD Dementia.

ABSTRACT:

Background

While sex differences in incidence of Alzheimer's disease (AD) and potential explanations have received considerable attention, less attention has been paid to possible sex differences in genetic risk for AD.

Objective

We examined sex differences in genetic and environmental influences on disease risk and age at onset for All Dementia, AD Only, and Non-AD Dementia.

Methods

Twin pairs were drawn from the Swedish Twin Registry. All Dementia analysis included 9,467 pairs; AD only, 8,696 pairs; and non-AD dementia, 8,195 pairs. APOE analyses included 1,740 individual twins with measured ?4 alleles. Dementia diagnoses were based on clinical workup and national health registry linkage.

Results

Although within-pair correlations for All Dementia and AD Only were higher for women than for men, sex differences did not statistically differ for genetic or environmental etiology of All Dementia, AD Only, and Non-AD dementia. Similar results were observed when looking at specific genetic effects (APOE?4). Co-twin control analyses indicated that among twin pairs discordant for dementia, female twins without dementia had approximately 40% greater risk of developing dementia, compared with their male counterparts, in the 2-5 years following the first twin's diagnosis.

Conclusion

For All Dementia, AD Only, and Non-AD Dementia, genetic influences could be equated across sex. Co-twin analyses, however, suggest greater risk to female than to male co-twins of dementia cases even though sex differences in either genetic or shared environmental influences on the risk of dementia could not be differentiated.

SUBMITTER: Beam CR

PROVIDER: S-EPMC7817251 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Publications

A Twin Study of Sex Differences in Genetic Risk for All Dementia, Alzheimer's Disease (AD), and Non-AD Dementia.

Beam Christopher R CR Kaneshiro Cody C Jang Jung Yun JY Reynolds Chandra A CA Pedersen Nancy L NL Gatz Margaret M

Journal of Alzheimer's disease : JAD 20200101 2

<h4>Background</h4>While sex differences in incidence of Alzheimer's disease (AD) and potential explanations have received considerable attention, less attention has been paid to possible sex differences in genetic risk for AD.<h4>Objective</h4>We examined sex differences in genetic and environmental influences on disease risk and age at onset for All Dementia, AD Only, and Non-AD Dementia.<h4>Methods</h4>Twin pairs were drawn from the Swedish Twin Registry. All Dementia analysis included 9,467 ...[more]

PMID: 32538833

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Project description:Age being the main risk factor for Alzheimer's disease, it is particularly challenging to disentangle structural changes related to normal brain ageing from those specific to Alzheimer's disease. Most studies aiming to make this distinction focused on older adults only and on a priori anatomical regions. Drawing on a large, multi-cohort dataset ranging from young adults (n = 468; age range 18-35 years), to older adults with intact cognition (n = 431; age range 55-90 years) and with Alzheimer's disease (n = 50 with late mild cognitive impairment and 71 with Alzheimer's dementia, age range 56-88 years), we investigated grey matter organization and volume differences in ageing and Alzheimer's disease. Using independent component analysis on all participants' structural MRI, we first derived morphometric networks and extracted grey matter volume in each network. We also derived a measure of whole-brain grey matter pattern organization by correlating grey matter volume in all networks across all participants from the same cohort. We used logistic regressions and receiver operating characteristic analyses to evaluate how well grey matter volume in each network and whole-brain pattern could discriminate between ageing and Alzheimer's disease. Because increased heterogeneity is often reported as one of the main features characterizing brain ageing, we also evaluated interindividual heterogeneity within morphometric networks and across the whole-brain organization in ageing and Alzheimer's disease. Finally, to investigate the clinical validity of the different grey matter features, we evaluated whether grey matter volume or whole-brain pattern was related to clinical progression in cognitively normal older adults. Ageing and Alzheimer's disease contributed additive effects on grey matter volume in nearly all networks, except frontal lobe networks, where differences in grey matter were more specific to ageing. While no networks specifically discriminated Alzheimer's disease from ageing, heterogeneity in grey matter volumes across morphometric networks and in the whole-brain grey matter pattern characterized individuals with cognitive impairments. Preservation of the whole-brain grey matter pattern was also related to lower risk of developing cognitive impairment, more so than grey matter volume. These results suggest both ageing and Alzheimer's disease involve widespread atrophy, but that the clinical expression of Alzheimer's disease is uniquely associated with disruption of morphometric organization.

Project description:BACKGROUND:Alzheimer's disease results from a neurodegenerative process that starts well before the diagnosis can be made. New prognostic or diagnostic markers enabling early intervention into the disease process would be highly valuable. Environmental and lifestyle factors largely modulate the disease risk and may influence the pathogenesis through epigenetic mechanisms, such as DNA methylation. As environmental and lifestyle factors may affect multiple tissues of the body, we hypothesized that the disease-associated DNA methylation signatures are detectable in the peripheral blood of discordant twin pairs. RESULTS:Comparison of 23 disease discordant Finnish twin pairs with reduced representation bisulfite sequencing revealed peripheral blood DNA methylation differences in 11 genomic regions with at least 15.0% median methylation difference and FDR adjusted p value ??0.05. Several of the affected genes are primarily associated with neuronal functions and pathologies and do not display disease-associated differences in gene expression in blood. The DNA methylation mark in ADARB2 gene was found to be differentially methylated also in the anterior hippocampus, including entorhinal cortex, of non-twin cases and controls. Targeted bisulfite pyrosequencing of the DNA methylation mark in ADARB2 gene in 62 Finnish and Swedish twin pairs revealed that, in addition to the disease status, DNA methylation of this region is influenced by gender, age, zygosity, APOE genotype, and smoking. Further analysis of 120 Swedish twin pairs indicated that this specific DNA methylation mark is not predictive for Alzheimer's disease and becomes differentially methylated after disease onset. CONCLUSIONS:DNA methylation differences can be detected in the peripheral blood of twin pairs discordant for Alzheimer's disease. These DNA methylation signatures may have value as disease markers and provide insights into the molecular mechanisms of pathogenesis. We found no evidence that the DNA methylation marks would be associated with gene expression in blood. Further studies are needed to elucidate the potential importance of the associated genes in neuronal functions and to validate the prognostic or diagnostic value of the individual marks or marker panels.

Dataset Information

A Twin Study of Sex Differences in Genetic Risk for All Dementia, Alzheimer's Disease (AD), and Non-AD Dementia.

Background

Objective

Methods

Results

Conclusion

Publications

A Twin Study of Sex Differences in Genetic Risk for All Dementia, Alzheimer's Disease (AD), and Non-AD Dementia.

Similar Datasets

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