Author Insight: Epigenetic Age of the Pre-frontal Cortex



January 4, 2022

Aging-US published "Epigenetic age of the pre-frontal cortex is associated with neuritic plaques, amyloid load, and Alzheimer’s disease related cognitive functioning" in 2015, which reported that there is an urgent need to develop molecular biomarkers of brain age in order to advance our understanding of age related neurodegeneration. Here the authors use n=700 dorsolateral prefrontal cortex 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 related cognitive decline, and AD related neuropathological markers. The neuropathological markers may mediate the association between epigenetic age and cognitive decline. Genetic complex trait analysis revealed that epigenetic age acceleration is heritable and has significant genetic correlations with diffuse plaques and possibly working memory. Overall, these results suggest that the epigenetic clock may lend itself as a molecular biomarker of brain age. Dr. Steve Horvath said, "Cognitive aging is on a continuum from normality, to mild cognitive impairment (MCI), to dementia." After the age of 65 the risk of developing a neurodegenerative form of dementia, such as Alzheimer’s Disease, has been shown to double every five years, and by age 85, the prevalence of dementia is estimated to be as high as 31%. Epigenetic alterations, such as DNA methylation, have been linked to both AD pathology and cognitive aging in the absence of AD dementia. Given that aging is associated with a normal loss in cognitive ability as well as the rapidly increasing susceptibility to AD, an aging biomarker based on DNAm could account for between-person differences in either the rate of cognitive aging among non-demented individuals or the rate of disease progression among those with AD. As a result, the goals of their study were to: 1) Examine the association between DNAm age and AD neuropathology, 2) Test whether DNAm age relates to AD dementia status and measures of cognitive functioning, 3) Determine if differences in DNAm age reflect cognitive decline in persons with or with AD-dementia, 4) Examine whether neuropathology underlies the association between higher DNAm age and worse cognitive functioning. They hypothesize that participants who have higher levels of neuropathology, lower cognitive functioning, and/or who are diagnosed with AD will have higher DNAm age in PFC samples at death—signifying that their brains are biologically older. They also hypothesize that neuropathology will mediate the association between DNAm age and cognition. The Horvath Research Team concluded in their Aging-US Research Output, "There are limitations to this study. First, DNAm age was only measured postmortem, which prevented us from determining if it was predictive of AD status or cognitive decline. Furthermore, DNAm age changes with time, yet in our sample it was only measured at a single time-point. For that reason we were unable to examine if larger changes in DLPFC DNAm age were associated with steeper cognitive decline or AD. Nevertheless, our study was strengthened by the inclusion of neuropathological variables, longitudinal measurements of multiple cognitive functioning domains, measurement of DNAm age in DLPFC rather than whole blood, and availability of postmortem data for neuropathologic indices. Overall, our study shows that epigenetic aging in DLPFC is associated with the severity of cognitive decline as well as neuropathological hallmarks of AD. These results strongly suggests that the epigenetic clock lend itself as a molecular biomarker of brain age." Full Text - Correspondence to: Steve Horvath email: Keywords: epigenetics, neuritic plaques, amyloids, cognitive functioning, memory, Alzheimer's disease, epigenetic clock, DNA methylation About Aging-US Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research as well as topics beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, cancer, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR among others), and approaches to modulating these signaling pathways. Please visit our website at​​ or connect with us on: SoundCloud - Facebook - Twitter - Instagram - YouTube -​ LinkedIn - Pinterest - Aging-US is published by Impact Journals, LLC please visit​​ or connect with @ImpactJrnls Media Contact 18009220957 MEDIA@IMPACTJOURNALS.COM

Cell ScienceGenomicsMolecular BiologyNeuroscience

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