Developing a DNAm Surrogate to Predict Cognitive Functioning among Older Adults

Abstract

AbstractBackgroundBlood‐based epigenetic measures are being developed and used to predict aging‐related health outcomes. Specifically, researchers have developed “epigenetic clocks” based on predictions of chronological age and age‐related health declines by DNA methylation. However, these markers are meant to predict aging per se and are not disease specific. Recently, scholars have developed “DNAm surrogates” to predict specific outcomes. This methodological technique has yet to be applied to cognitive functioning despite its potential to improve prediction of cognitive health in later life and provide insight into the role of biological aging.MethodThis study developed a novel DNAm surrogate measure for cognitive functioning (DNAmCogScore) based on an elastic net approach linking using 833,865 CpG sites predicting the Telephone Interview Cognitive Status score (TICS) available in the Health and Retirement Study (HRS), a nationally representative sample of older adults in the United States. Additionally, we evaluate the association of this DNAm surrogate and other neuropathology biomarkers. We used used ridge regression to create DNAmCogScore with 50% of the sample for training and 50% for testing (N = 2009 for each subsample). The Irish Longitudinal Study of Aging (TILDA) will be used for validation (results forthcoming).ResultWe find a positive association and modest predictive value between DNAmCogScore and TICS (see Figure 1, r = .4). Table 1 shows the strong associations with the DNAmCogScore and demographic characteristics. Overall, we find a strong positive coefficient between DNAmCogScore with attenuation after controlling for demographic characteristics, from 1.12 in Model 1 to .20 in Model 3, but remaining statistically significant throughout. Table 3 shows modest negative correlations between DNAmCogScore and NfL, pTau181, and GFAP (ranging from ‐.24 to ‐.36) and no correlation with AB42:40.ConclusionThis study is among the first to create a DNA methylation surrogate measure of cognitive functioning. Our measure is associated with cognitive functioning, even after adjusting for key demographic characteristics. And it has the expected association with other more neuropathology biomarkers. Overall, it suggests that changes in DNA methylation may be a molecular‐level mechanisms by which biological aging impacts cognitive health, and this measure may provide useful prediction of cognitive impairment before the onset of symptoms.