Epigenetic age of the pre-frontal cortex is associated with neuritic plaques, amyloid load, and Alzheimer's disease related cognitive functioning

Morgan E Levine, Ake T Lu, David A Bennett, Steve Horvath, Morgan E Levine, Ake T Lu, David A Bennett, Steve Horvath

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.

Keywords: Alzheimer's disease; DNA methylation; amyloids; cognitive functioning; epigenetic clock; epigenetics; memory; neuritic plaques.

Conflict of interest statement

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1. Epigenetic age of DLPFC samples…
Figure 1. Epigenetic age of DLPFC samples versus neuropathological measures
(A) Scatter plot relating the DNAm age of each PFC sample (y-axis) versus chronological age at time of death (x-axis). The red line depicts a linear regression line. The y-axis of the remaining panels (B-I) involves the measure of epigenetic age acceleration which has been adjusted for sex. The scatter plots relate epigenetic age acceleration (y-axis) to (B) diffuse plaques, (D) neuritic plaques, (F) NFTs, and (H) amyloid load. The title of each scatter plot reports a robust correlation coefficient (biweight midcorrelation) and a corresponding p-value. (C,E,G,I) The x-axis of the bar plots involve a binary grouping variable that results from using the median value for dichotomizing (C) diffuse plaques, (E) neuritic plaques, (G) NFT, and (I) beta-amyloid load, respectively. Each bar plot depicts the mean value, one standard error, and reports the p-value results from a non-parametric group comparison test (Kruskal Wallis test). The title of each scatter plot reports a robust correlation coefficient (biweight midcorrelation) and a corresponding p-value.
Figure 2. Causal scenarios that might explain…
Figure 2. Causal scenarios that might explain the significant genetic correlations between epigenetic age, neuropathology and cognitive decline
Genetic variants form a causal anchor that affect biological age (and associated measures such as epigenetic age) and various measures of neuropathology and cognitive decline.

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