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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.
Glossary
- AA=
- African American;
- AD=
- Alzheimer disease;
- BMI=
- body mass index;
- BTA=
- Brief Test of Attention;
- BVRT=
- Benton Visual Retention Test;
- CES-D=
- Center for Epidemiologic Studies–Depression scale;
- CVLT=
- California Verbal Learning Test;
- DFR=
- delayed free recall;
- DNAm=
- DNA methylation;
- EAA=
- epigenetic age acceleration;
- EEAA=
- extrinsic epigenetic age acceleration;
- FA=
- fractional anisotropy;
- HANDLS=
- Healthy Aging in Neighborhoods of Diversity across the Life Span;
- HEI=
- Healthy Eating Index;
- HS=
- high school;
- IEAA=
- intrinsic epigenetic age acceleration;
- IRB=
- institutional review board;
- MD=
- mean diffusivity;
- MMSE=
- Mini-Mental State Examination;
- MRV=
- medical research vehicle;
- NK=
- natural killer;
- NSAID=
- nonsteroidal anti-inflammatory drug;
- PI=
- principal investigator;
- TMT=
- Trail-Making Test
Footnotes
Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
↵* These authors contributed equally as co–senior authors.
- Received February 27, 2019.
- Accepted in final form August 21, 2019.
- © 2019 American Academy of Neurology
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