Association of Pace of Aging Measured by Blood-Based DNA Methylation With Age-Related Cognitive Impairment and Dementia

Karen Sugden; Avshalom Caspi; Maxwell L Elliott; Kyle J Bourassa; Kartik Chamarti; David L Corcoran; Ahmad R Hariri; Renate M Houts; Meeraj Kothari; Stephen Kritchevsky; George A Kuchel; Jonathan S Mill; Benjamin S Williams; Daniel W Belsky; Terrie E Moffitt; Alzheimer's Disease Neuroimaging Initiative*

doi:10.1212/WNL.0000000000200898

Association of Pace of Aging Measured by Blood-Based DNA Methylation With Age-Related Cognitive Impairment and Dementia

Neurology. 2022 Sep 27;99(13):e1402-e1413. doi: 10.1212/WNL.0000000000200898. Epub 2022 Jul 6.

Authors

Karen Sugden¹, Avshalom Caspi², Maxwell L Elliott², Kyle J Bourassa², Kartik Chamarti², David L Corcoran², Ahmad R Hariri², Renate M Houts², Meeraj Kothari², Stephen Kritchevsky², George A Kuchel², Jonathan S Mill², Benjamin S Williams², Daniel W Belsky², Terrie E Moffitt²; Alzheimer's Disease Neuroimaging Initiative*

Affiliations

¹ From the Department of Psychology and Neuroscience (K.S., A.C., M.L.E., K.C., A.R.H., R.M.H., B.S.W., T.E.M.), and Center for Genomic and Computational Biology (K.S., A.C., B.S.W., T.E.M.), Duke University, Durham, NC; Department of Psychiatry and Behavioral Sciences (A.C., T.E.M.), Duke University School of Medicine, Durham, NC; Social, Genetic, and Developmental Psychiatry Centre (A.C, T.E.M.), Institute of Psychiatry, Psychology, and Neuroscience, King's College London, UK. Center for the Study of Aging and Human Development (K.J.B.), Duke University, Durham, NC; Department of Genetics (D.L.C.), University of North Carolina School of Medicine, Chapel Hill; Butler Columbia Aging Center (M.K., D.W.B.), Columbia University, New York, New York; Sticht Center for Healthy Aging and Alzheimer's Prevention (S.K.), Wake Forest School of Medicine, Winston-Salem, NC; UConn Center on Aging (G.A.K.), University of Connecticut, Farmington, Connecticut, USA; College of Medicine and Health (J.S.M.), University of Exeter Medical School, Devon, UK; and Department of Epidemiology (D.W.B.), Columbia University Mailman School of Public Health, New York, New York. karen.sugden@duke.edu.
² From the Department of Psychology and Neuroscience (K.S., A.C., M.L.E., K.C., A.R.H., R.M.H., B.S.W., T.E.M.), and Center for Genomic and Computational Biology (K.S., A.C., B.S.W., T.E.M.), Duke University, Durham, NC; Department of Psychiatry and Behavioral Sciences (A.C., T.E.M.), Duke University School of Medicine, Durham, NC; Social, Genetic, and Developmental Psychiatry Centre (A.C, T.E.M.), Institute of Psychiatry, Psychology, and Neuroscience, King's College London, UK. Center for the Study of Aging and Human Development (K.J.B.), Duke University, Durham, NC; Department of Genetics (D.L.C.), University of North Carolina School of Medicine, Chapel Hill; Butler Columbia Aging Center (M.K., D.W.B.), Columbia University, New York, New York; Sticht Center for Healthy Aging and Alzheimer's Prevention (S.K.), Wake Forest School of Medicine, Winston-Salem, NC; UConn Center on Aging (G.A.K.), University of Connecticut, Farmington, Connecticut, USA; College of Medicine and Health (J.S.M.), University of Exeter Medical School, Devon, UK; and Department of Epidemiology (D.W.B.), Columbia University Mailman School of Public Health, New York, New York.

Abstract

Background and objectives: DNA methylation algorithms are increasingly used to estimate biological aging; however, how these proposed measures of whole-organism biological aging relate to aging in the brain is not known. We used data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the Framingham Heart Study (FHS) Offspring Cohort to test the association between blood-based DNA methylation measures of biological aging and cognitive impairment and dementia in older adults.

Methods: We tested 3 "generations" of DNA methylation age algorithms (first generation: Horvath and Hannum clocks; second generation: PhenoAge and GrimAge; and third generation: DunedinPACE, Dunedin Pace of Aging Calculated from the Epigenome) against the following measures of cognitive impairment in ADNI: clinical diagnosis of dementia and mild cognitive impairment, scores on Alzheimer disease (AD) / Alzheimer disease and related dementias (ADRD) screening tests (Alzheimer's Disease Assessment Scale, Mini-Mental State Examination, and Montreal Cognitive Assessment), and scores on cognitive tests (Rey Auditory Verbal Learning Test, Logical Memory test, and Trail Making Test). In an independent replication in the FHS Offspring Cohort, we further tested the longitudinal association between the DNA methylation algorithms and the risk of developing dementia.

Results: In ADNI (N = 649 individuals), the first-generation (Horvath and Hannum DNA methylation age clocks) and the second-generation (PhenoAge and GrimAge) DNA methylation measures of aging were not consistently associated with measures of cognitive impairment in older adults. By contrast, a third-generation measure of biological aging, DunedinPACE, was associated with clinical diagnosis of Alzheimer disease (beta [95% CI] = 0.28 [0.08-0.47]), poorer scores on Alzheimer disease/ADRD screening tests (beta [Robust SE] = -0.10 [0.04] to 0.08[0.04]), and cognitive tests (beta [Robust SE] = -0.12 [0.04] to 0.10 [0.03]). The association between faster pace of aging, as measured by DunedinPACE, and risk of developing dementia was confirmed in a longitudinal analysis of the FHS Offspring Cohort (N = 2,264 individuals, hazard ratio [95% CI] = 1.27 [1.07-1.49]).

Discussion: Third-generation blood-based DNA methylation measures of aging could prove valuable for measuring differences between individuals in the rate at which they age and in their risk for cognitive decline, and for evaluating interventions to slow aging.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Aged
Aging / genetics
Alzheimer Disease* / complications
Alzheimer Disease* / diagnostic imaging
Alzheimer Disease* / genetics
Cognitive Dysfunction* / complications
Cognitive Dysfunction* / diagnostic imaging
Cognitive Dysfunction* / genetics
DNA Methylation
Humans
Neuropsychological Tests

Abstract

Publication types

MeSH terms

Grants and funding