Dataset Information

Rate of brain aging and APOE ?4 are synergistic risk factors for Alzheimer's disease.

ABSTRACT: Advanced age and the APOE ?4 allele are the two biggest risk factors for Alzheimer's disease (AD) and declining cognitive function. We describe a universal gauge to measure molecular brain age using transcriptome analysis of four human postmortem cohorts (n = 673, ages 25-97) free of neurological disease. In a fifth cohort of older subjects with or without neurological disease (n = 438, ages 67-108), we show that subjects with brains deviating in the older direction from what would be expected based on chronological age show an increase in AD, Parkinson's disease, and cognitive decline. Strikingly, a younger molecular age (-5 yr than chronological age) protects against AD even in the presence of APOE ?4 An established DNA methylation gauge for age correlates well with the transcriptome gauge for determination of molecular age and assigning deviations from the expected. Our results suggest that rapid brain aging and APOE ?4 are synergistic risk factors, and interventions that slow aging may substantially reduce risk of neurological disease and decline even in the presence of APOE ?4.

SUBMITTER: Glorioso CA

PROVIDER: S-EPMC6537750 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Rate of brain aging and <i>APOE ε4</i> are synergistic risk factors for Alzheimer's disease.

Glorioso Christin A CA Pfenning Andreas R AR Lee Sam S SS Bennett David A DA Sibille Etienne L EL Kellis Manolis M Guarente Leonard P LP

Life science alliance 20190527 3

Advanced age and the <i>APOE ε4</i> allele are the two biggest risk factors for Alzheimer's disease (AD) and declining cognitive function. We describe a universal gauge to measure molecular brain age using transcriptome analysis of four human postmortem cohorts (n = 673, ages 25-97) free of neurological disease. In a fifth cohort of older subjects with or without neurological disease (n = 438, ages 67-108), we show that subjects with brains deviating in the older direction from what would be exp ...[more]

PMID: 31133613

Similar Datasets

Project description:African descent populations have a lower Alzheimer disease risk from ApoE ε4 compared to other populations. Ancestry analysis showed that the difference in risk between African and European populations lies in the ancestral genomic background surrounding the ApoE locus (local ancestry). Identifying the mechanism(s) of this protection could lead to greater insight into the etiology of Alzheimer disease and more personalized therapeutic intervention. Our objective is to follow up the local ancestry finding and identify the genetic variants that drive this risk difference and result in a lower risk for developing Alzheimer disease in African ancestry populations. We performed association analyses using a logistic regression model with the ApoE ε4 allele as an interaction term and adjusted for genome-wide ancestry, age, and sex. Discovery analysis included imputed SNP data of 1,850 Alzheimer disease and 4,331 cognitively intact African American individuals. We performed replication analyses on 63 whole genome sequenced Alzheimer disease and 648 cognitively intact Ibadan individuals. Additionally, we reproduced results using whole-genome sequencing of 273 Alzheimer disease and 275 cognitively intact admixed Puerto Rican individuals. A further comparison was done with SNP imputation from an additional 8,463 Alzheimer disease and 11,365 cognitively intact non-Hispanic White individuals. We identified a significant interaction between the ApoE ε4 allele and the SNP rs10423769_A allele, (β = -0.54,SE = 0.12,p-value = 7.50x10-6) in the discovery data set, and replicated this finding in Ibadan (β = -1.32,SE = 0.52,p-value = 1.15x10-2) and Puerto Rican (β = -1.27,SE = 0.64,p-value = 4.91x10-2) individuals. The non-Hispanic Whites analyses showed an interaction trending in the "protective" direction but failing to pass a 0.05 significance threshold (β = -1.51,SE = 0.84,p-value = 7.26x10-2). The presence of the rs10423769_A allele reduces the odds ratio for Alzheimer disease risk from 7.2 for ApoE ε4/ε4 carriers lacking the A allele to 2.1 for ApoE ε4/ε4 carriers with at least one A allele. This locus is located approximately 2 mB upstream of the ApoE locus, in a large cluster of pregnancy specific beta-1 glycoproteins on chromosome 19 and lies within a long noncoding RNA, ENSG00000282943. This study identified a new African-ancestry specific locus that reduces the risk effect of ApoE ε4 for developing Alzheimer disease. The mechanism of the interaction with ApoEε4 is not known but suggests a novel mechanism for reducing the risk for ε4 carriers opening the possibility for potential ancestry-specific therapeutic intervention.

Dataset Information

Rate of brain aging and APOE ?4 are synergistic risk factors for Alzheimer's disease.

Publications

Rate of brain aging and <i>APOE ε4</i> are synergistic risk factors for Alzheimer's disease.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets