Epigenetic measurement of biological age associates with tau load in normal brain aging

Abstract

AbstractBackgroundAging is the most established risk factor for sporadic Alzheimer’s Disease (AD). However, relative risk of AD varies greatly across individuals. One potential explanation for this heterogeneity is that chronological age may not reflect differences in biological aging. One measure of biological age is the “epigenetic clock” which utilizes a weighted statistical model from >350 CpG sites that captures the cumulative work of an individual’s epigenetic maintenance system and has been demonstrated to relate to age, mortality, and survival. In this study, we test the hypothesis that the epigenetic clock will be related to two regional brain aging signatures associated with AD, including neurofibrillary tau tangle (NFTs) load and reduced cortical thickness.MethodsWe evaluated 40 cognitively normal, amyloid‐negative (PET‐Aβ <= 1.11) individuals from the Alzheimer’s Disease Neuroimaging Initiative dataset with DNA methylation, 18F‐Flortaucipr PET, and volumetric MRI data. 18F‐Flortaucipr PET and volumetric MRI data were processed using ANTs Cortical Thickness in 100 neocortical regions of interest (ROI) from the BrainColor/MindBoggle parcellation. 18F‐Flortaucipr PET and T1‐weighted MRI data was additionally processed using ASHS to derive 12 hippocampal subfield parcellations. Regression analyses related chronological age and Horvath’s “epigenetic clock” measurement of biological age to 18F‐Flortaucipr SUVR, mean cortical thickness, and hippocampal subfield volumes.ResultsIn healthy adults, we observed a positive association with increasing epigenetic age related to increased tau SUVR in the entorhinal cortex and the hippocampus (p = 0.029, R = 0.36; p = 0.028, R = 0.397). There was no association of epigenetic age with any of the neocortical tau SUVR ROIs and chronological age was not associated with tau SUVR in any of the hippocampal subfields or neocortical ROIs. In contrast, both epigenetic age and chronological age both trended toward associations of reduced cortical thickness in the neocortex.ConclusionsThis study suggests that epigenetic changes that occur with age may provide a risk factor for tau accumulation, more so than chronological age, and that is more tightly linked with age‐related tau pathological accumulation than age‐related cortical neurodegeneration.