Accelerated epigenetic age and cognitive decline among urban-dwelling adults

Abstract

Objectives: Epigenetic modifications are closely linked with aging, but their relationship with cognition remains equivocal. Given known sex differences in epigenetic aging, we explored sex-specific associations of 3 DNA methylation (DNAm)-based measures of epigenetic age acceleration (EAA) with baseline and longitudinal change in cognitive performance among middle-aged urban adults.

Methods: We used exploratory data from a subgroup of participants in the Healthy Aging in Neighborhoods of Diversity across the Life Span study with complete DNA samples and whose baseline ages were >50.0 years (2004-2009) to estimate 3 DNAm EAA measures: (1) universal EAA (AgeAccel); (2) intrinsic EAA (IEAA); and (3) extrinsic EAA (EEAA). Cognitive performance was measured at baseline visit (2004-2009) and first follow-up (2009-2013) with 11 test scores covering global mental status and specific domains such as learning/memory, attention, visuospatial, psychomotor speed, language/verbal, and executive function. A series of mixed-effects regression models were conducted adjusting for covariates and multiple testing (n = 147-156, ∼51% men, k = 1.7-1.9 observations/participant, mean follow-up time ∼4.7 years).

Results: EEAA, a measure of both biological age and immunosenescence, was consistently associated with greater cognitive decline among men on tests of visual memory/visuoconstructive ability (Benton Visual Retention Test: γ₁₁ = 0.0512 ± 0.0176, p = 0.004) and attention/processing speed (Trail-Making Test, part A: γ₁₁ = 0.219 ± 0.080, p = 0.007). AgeAccel and IEAA were not associated with cognitive change in this sample.

Conclusions: EEAA capturing immune system cell aging was associated with faster decline among men in domains of attention and visual memory. Larger longitudinal studies are needed to replicate our findings.

Figure 1. Participant flow chart

Sample 1 is the initial visit 1, phase 1 selected Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) sample of adults aged 30–64 years (white and African American). Samples 1a and 1b are the subsamples ≤50.0 years and >50.0 years at baseline. Out of sample 1a, sample 2a/2b is the sample of participants with complete and reliable data at visits 1 and 2, respectively, on cognitive test scores. Of those, samples 3a/3b have in addition complete epigenetic data. Finally, excluding those with missing covariates, the result is sample 4a/4b, of whom 147–156 constitute the final analytic sample included in the mixed-effects regression models, k = 1.7–1.9 observations/participant.

Figure 2. Predictive margins for Benton Visual Retention Test (BVRT) by epigenetic clock 3 in male participants: mixed-effects regression model

Epigenetic clock 3: extrinsic epigenetic age acceleration uses the Hannum et al. algorithm and combines epigenetic age acceleration with white blood cell proportion changes reflecting immunosenescence. Model 3 for BVRT (# incorrect), among men, table 3. 1 SD EpiClock3 ∼6.2 years.

Figure 3. Predictive margins for Trail-Making Test (TMT), part A, by epigenetic clock 3 in male participants: mixed-effects regression model

Epigenetic clock 3: extrinsic epigenetic age acceleration uses the Hannum et al. algorithm and combines epigenetic age acceleration with white blood cell proportion changes reflecting immunosenescence. Model 3 for TMT, part A (time to completion, in seconds), among men, table 3. 1 SD EpiClock3 ∼6.2 years.