Epigenetic age of the pre-frontal cortex is associated with neuritic plaques, amyloid load, and Alzheimer’s disease related cognitive functioning
There is an urgent need to develop molecular biomarkers of brain age in order to advance our understanding of age related neurodegeneration. Recently, we developed a highly accurate epigenetic biomarker of tissue age (known as epigenetic clock) which is based on DNA methylation levels. Here we use n...
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| Published in | Aging (Albany, NY.) Vol. 7; no. 12; pp. 1198 - 1211 |
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| Main Authors | , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
Impact Journals LLC
01.12.2015
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| Subjects | |
| Online Access | Get full text |
| ISSN | 1945-4589 1945-4589 |
| DOI | 10.18632/aging.100864 |
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| Abstract | There is an urgent need to develop molecular biomarkers of brain age in order to advance our understanding of age related neurodegeneration. Recently, we developed a highly accurate epigenetic biomarker of tissue age (known as epigenetic clock) which is based on DNA methylation levels. Here we use n=700 dorsolateral prefrontal cortex (DLPFC) samples from Caucasian subjects of the Religious Order Study and the Rush Memory and Aging Project to examine the association between epigenetic age and Alzheimer's disease (AD) related cognitive decline, and AD related neuropathological markers. Epigenetic age acceleration of DLPFC is correlated with several neuropathological measurements including diffuse plaques (r=0.12, p=0.0015), neuritic plaques (r=0.11, p=0.0036), and amyloid load (r=0.091, p=0.016). Further, it is associated with a decline in global cognitive functioning (β=-0.500, p=0.009), episodic memory (β=-0.411, p=0.009) and working memory (β=-0.405, p=0.011) among individuals with AD. The neuropathological markers may mediate the association between epigenetic age and cognitive decline. Genetic complex trait analysis (GCTA) revealed that epigenetic age acceleration is heritable (h2=0.41) and has significant genetic correlations with diffuse plaques (r=0.24, p=0.010) and possibly working memory (r=-0.35, p=0.065). Overall, these results suggest that the epigenetic clock may lend itself as a molecular biomarker of brain age. |
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| AbstractList | There is an urgent need to develop molecular biomarkers of brain age in order to advance our understanding of age related neurodegeneration. Recently, we developed a highly accurate epigenetic biomarker of tissue age (known as epigenetic clock) which is based on DNA methylation levels. Here we use n=700 dorsolateral prefrontal cortex (DLPFC) samples from Caucasian subjects of the Religious Order Study and the Rush Memory and Aging Project to examine the association between epigenetic age and Alzheimer’s disease (AD) related cognitive decline, and AD related neuropathological markers.
Epigenetic age acceleration of DLPFC is correlated with several neuropathological measurements including diffuse plaques (r=0.12, p=0.0015), neuritic plaques (r=0.11, p=0.0036), and amyloid load (r=0.091, p=0.016). Further, it is associated with a decline in global cognitive functioning (β=−0.500, p=0.009), episodic memory (β=−0.411, p=0.009) and working memory (β=−0.405, p=0.011) among individuals with AD. The neuropathological markers may mediate the association between epigenetic age and cognitive decline. Genetic complex trait analysis (GCTA) revealed that epigenetic age acceleration is heritable (h
2
=0.41) and has significant genetic correlations with diffuse plaques (r=0.24, p=0.010) and possibly working memory (r=−0.35, p=0.065). Overall, these results suggest that the epigenetic clock may lend itself as a molecular biomarker of brain age. There is an urgent need to develop molecular biomarkers of brain age in order to advance our understanding of age related neurodegeneration. Recently, we developed a highly accurate epigenetic biomarker of tissue age (known as epigenetic clock) which is based on DNA methylation levels. Here we use n=700 dorsolateral prefrontal cortex (DLPFC) samples from Caucasian subjects of the Religious Order Study and the Rush Memory and Aging Project to examine the association between epigenetic age and Alzheimer's disease (AD) related cognitive decline, and AD related neuropathological markers. Epigenetic age acceleration of DLPFC is correlated with several neuropathological measurements including diffuse plaques (r=0.12, p=0.0015), neuritic plaques (r=0.11, p=0.0036), and amyloid load (r=0.091, p=0.016). Further, it is associated with a decline in global cognitive functioning (β=-0.500, p=0.009), episodic memory (β=-0.411, p=0.009) and working memory (β=-0.405, p=0.011) among individuals with AD. The neuropathological markers may mediate the association between epigenetic age and cognitive decline. Genetic complex trait analysis (GCTA) revealed that epigenetic age acceleration is heritable (h2=0.41) and has significant genetic correlations with diffuse plaques (r=0.24, p=0.010) and possibly working memory (r=-0.35, p=0.065). Overall, these results suggest that the epigenetic clock may lend itself as a molecular biomarker of brain age. There is an urgent need to develop molecular biomarkers of brain age in order to advance our understanding of age related neurodegeneration. Recently, we developed a highly accurate epigenetic biomarker of tissue age (known as epigenetic clock) which is based on DNA methylation levels. Here we use n=700 dorsolateral prefrontal cortex (DLPFC) samples from Caucasian subjects of the Religious Order Study and the Rush Memory and Aging Project to examine the association between epigenetic age and Alzheimer's disease (AD) related cognitive decline, and AD related neuropathological markers. Epigenetic age acceleration of DLPFC is correlated with several neuropathological measurements including diffuse plaques (r=0.12, p=0.0015), neuritic plaques (r=0.11, p=0.0036), and amyloid load (r=0.091, p=0.016). Further, it is associated with a decline in global cognitive functioning (β=-0.500, p=0.009), episodic memory (β=-0.411, p=0.009) and working memory (β=-0.405, p=0.011) among individuals with AD. The neuropathological markers may mediate the association between epigenetic age and cognitive decline. Genetic complex trait analysis (GCTA) revealed that epigenetic age acceleration is heritable (h2=0.41) and has significant genetic correlations with diffuse plaques (r=0.24, p=0.010) and possibly working memory (r=-0.35, p=0.065). Overall, these results suggest that the epigenetic clock may lend itself as a molecular biomarker of brain age.There is an urgent need to develop molecular biomarkers of brain age in order to advance our understanding of age related neurodegeneration. Recently, we developed a highly accurate epigenetic biomarker of tissue age (known as epigenetic clock) which is based on DNA methylation levels. Here we use n=700 dorsolateral prefrontal cortex (DLPFC) samples from Caucasian subjects of the Religious Order Study and the Rush Memory and Aging Project to examine the association between epigenetic age and Alzheimer's disease (AD) related cognitive decline, and AD related neuropathological markers. Epigenetic age acceleration of DLPFC is correlated with several neuropathological measurements including diffuse plaques (r=0.12, p=0.0015), neuritic plaques (r=0.11, p=0.0036), and amyloid load (r=0.091, p=0.016). Further, it is associated with a decline in global cognitive functioning (β=-0.500, p=0.009), episodic memory (β=-0.411, p=0.009) and working memory (β=-0.405, p=0.011) among individuals with AD. The neuropathological markers may mediate the association between epigenetic age and cognitive decline. Genetic complex trait analysis (GCTA) revealed that epigenetic age acceleration is heritable (h2=0.41) and has significant genetic correlations with diffuse plaques (r=0.24, p=0.010) and possibly working memory (r=-0.35, p=0.065). Overall, these results suggest that the epigenetic clock may lend itself as a molecular biomarker of brain age. |
| Author | Horvath, Steve Levine, Morgan E Bennett, David A Lu, Ake T |
| AuthorAffiliation | 5 Biostatistics, School of Public Health, University of California Los Angeles, Los Angeles, CA 90095, USA 3 Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL 60612, USA 1 Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA 4 Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA 2 Center for Neurobehavioral Genetics, University of California Los Angeles, Los Angeles, CA 90095, USA |
| AuthorAffiliation_xml | – name: 3 Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL 60612, USA – name: 4 Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA – name: 1 Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA – name: 2 Center for Neurobehavioral Genetics, University of California Los Angeles, Los Angeles, CA 90095, USA – name: 5 Biostatistics, School of Public Health, University of California Los Angeles, Los Angeles, CA 90095, USA |
| Author_xml | – sequence: 1 givenname: Morgan E surname: Levine fullname: Levine, Morgan E organization: Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA, Center for Neurobehavioral Genetics, University of California Los Angeles, Los Angeles, CA 90095, USA – sequence: 2 givenname: Ake T surname: Lu fullname: Lu, Ake T organization: Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA – sequence: 3 givenname: David A surname: Bennett fullname: Bennett, David A organization: Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL 60612, USA, Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA – sequence: 4 givenname: Steve surname: Horvath fullname: Horvath, Steve organization: Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA, Biostatistics, School of Public Health, University of California Los Angeles, Los Angeles, CA 90095, USA |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/26684672$$D View this record in MEDLINE/PubMed |
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| Cites_doi | 10.1056/NEJMcp0910237 10.1016/j.jalz.2011.03.003 10.1037/1528-3542.2.2.118 10.1212/WNL.54.11.2045 10.2174/156720512801322663 10.1371/journal.pgen.1000529 10.2174/156720512801322573 |
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| Keywords | amyloids memory DNA methylation cognitive functioning Alzheimer's disease epigenetics epigenetic clock neuritic plaques |
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| SubjectTerms | Aged Aged, 80 and over Alzheimer Disease - metabolism Amyloidogenic Proteins - metabolism Biomarkers Epigenesis, Genetic - physiology Female Humans Male Plaque, Amyloid - metabolism Prefrontal Cortex - physiology Research Paper |
| Title | Epigenetic age of the pre-frontal cortex is associated with neuritic plaques, amyloid load, and Alzheimer’s disease related cognitive functioning |
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