Abstract
The proportion of aging populations affected by dementia is increasing. There is an urgent need to identify biological aging markers in mid-life before symptoms of age-related dementia present for early intervention to delay the cognitive decline and the onset of dementia. In this cohort study involving 1,676 healthy participants (mean age 40) with up to 15 years of follow up, we evaluated the associations between cognitive function and two classes of novel biological aging markers: blood-based epigenetic aging and neuroimaging-based brain aging. Both accelerated epigenetic aging and brain aging were prospectively associated with worse cognitive outcomes. Specifically, every year faster epigenetic or brain aging was on average associated with 0.19-0.28 higher (worse) Stroop score, 0.04-0.05 lower (worse) RAVLT score, and 0.23-0.45 lower (worse) DSST (all false-discovery-rate-adjusted p <0.05). While epigenetic aging is a more stable biomarker with strong long-term predictive performance for cognitive function, brain aging biomarker may change more dynamically in temporal association with cognitive decline. The combined model using epigenetic and brain aging markers achieved the highest accuracy (AUC: 0.68, p<0.001) in predicting global cognitive function status. Accelerated epigenetic age and brain age at midlife may aid timely identification of individuals at risk for accelerated cognitive decline and promote the development of interventions to preserve optimal functioning across the lifespan.
Highlights
By the year 2030, 75 to 82 million people worldwide are projected to be affected by dementia [1, 2]
Significant and moderate correlations were only observed across the epigenetic aging markers (GrimAA, PhenoAge Acceleration (PhenoAA), Epigenetic Age Acceleration (EEAA), and Intrinsic Epigenetic Age Acceleration www.aging-us.com (IEAA), see Methods) but the correlations were weak with Spatial Patterns of Abnormality for REcognition (SPARE)-Brain Age Acceleration (BAA). (Supplementary Figure 1)
Epigenetic age and SPAREBA were both moderately correlated with chronological age (Pearson’s r=0.37 to 0.55, Supplementary Figure 2)
Summary
By the year 2030, 75 to 82 million people worldwide are projected to be affected by dementia [1, 2]. Despite cumulative downward trajectories of cognition, prior studies have shown marked heterogeneity in the rate of decline across individuals [7–11] This highlights the need for new approaches for the early detection of cognitive decline, based on biomarkers of systematic age-related biological degeneration including molecular aging markers in blood, as well as the degeneration directly in brain captured by structural brain imaging [12]. As both of these markers have high potential to inform and predict future cognitive status at the individual level, identifying biological bloodand imaging-based aging markers associated with cognitive function in mid-life, decades before symptoms of age-related dementia present, may aid in early detection of possible disease in people with mild symptoms, and facilitate the identification of vulnerable individuals before the onset of irreversible neuronal damage and extend opportunities for intervention
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