title: Epigenetic age of the pre-frontal cortex is associated with neuritic plaques, amyloid load, and Alzheimer's disease related cognitive functioning.
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.
authors.affiliation: 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.
authors.forename: Morgan E
authors.initials: ME
authors.lastname: Levine
authors.affiliation: Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Ake T
authors.initials: AT
authors.lastname: Lu
authors.affiliation: 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.
authors.forename: David A
authors.initials: DA
authors.lastname: Bennett
authors.affiliation: 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.
authors.forename: Steve
authors.initials: S
authors.lastname: Horvath
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism*; D058227:Amyloidogenic Proteins / Q000378:metabolism*; D015415:Biomarkers; D044127:Epigenesis, Genetic / Q000502:physiology*; D005260:Female; D006801:Humans; D008297:Male; D058225:Plaque, Amyloid / Q000378:metabolism*; D017397:Prefrontal Cortex / Q000502:physiology*
chemical_list: D058227:Amyloidogenic Proteins; D015415:Biomarkers
keywords: Alzheimer's disease; DNA methylation; amyloids; cognitive functioning; epigenetic clock; epigenetics; memory; neuritic plaques