Epigenetic aging as a biomarker of dementia and related outcomes: a systematic review

Figures & data

Figure 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram showing the number of articles identified through the original database searches, those that were screened and eligible for inclusion and the final number included in the systematic review.

Table 1. Studies investigating the association between accelerated epigenetic aging and neurodegenerative disorders.

Study, design (country)	Characteristics: N, mean age (standard deviation), sex, ethnicity if stated	Dementia	Main findings with epigenetic aging	Adjustments	Ref.
Prospective cohort Betula (Sweden)	16 maintained memory, 57.8 y (3.6); 20 average, 58.0 y (3.5); 16 decline, 57.9 y (3.6); 48% ♀; 15 y FU	Dementia	Logistic regression, β log odds Horvath: 0.16, p = 0.03 (FU) AAH: not reported	Age, sex	[18]
Prospective cohort, LBC1921 (UK)	n = 488, 79.1 y (0.6), 57.3% ♀, 16 y FU	Dementia	Cox regression EEAA, IEAA, PhenoAA, GrimAA: NS	Sex, APOE, smoking, health measures	[20]
Case–cohort ASPREE (AUS)	n = 160; 73 presymptomatic dementia, 77.6 y (5.1), 57.5% ♀; 87 controls, 76.4 y (4.6), 57.5% ♀; 3 y FU	Dementia	t-test AAH, AAHa, IEAA, EEAA, PhenoAA, GrimAA: NS	Age, education, cognition, smoking, cell %, batch	[21]
Prospective cohort WHIMS (USA)	n = 578, 70.2 y (3.9), 100% ♀, 89.6% White, 7.4% African–American, 2.9% Hispanic, 11.2 y (5.5) FU	Dementia	Cox regression IEAA, EEAA, GrimAA, PhenoAA: NS	Age, ethnicity, education, BMI, smoking, alcohol, health	[28]
		Mild cognitive impairment	Cox regression IEAA, EEAA, GrimAA, PhenoAA: NS
Cohort, AD neuroimaging initiative (USA, Canada)	n = 640, 75.4 (7.5), 44.4%♀, 97.8% White	MCI and/or AD	Linear mixed models AAH, IEAA, GrimAA, PhenoAA: NS	Age, sex, APOE	[29]
Case–cohort, Whitehall II imaging (UK)	n = 47; 23 cognitively intact, 72.8 y (6.0), 17.4% ♀; 24 cognitively impaired, 72.3 (6.0); 16.7% ♀	CI, MoCA	Linear regression AAH, AAHa: NS	Age, sex, cell %, technical	[30]
Cohort Genetic Investigation in FTD (USA)	n = 154 probable AD, n = 116 FTD, n = 334 nondemented; ♀ not stated	AD and/or FTD	Group comparison PhenoAge: ↑, p = 0.02		[14]
Case–control PD, Environment & Genes (USA)	Caucasians: n = 289 PD, 71 y (0.6), 43% ♀; n = 291 controls, 68 y (0.8), 47% ♀; Hispanics: n = 46 PD, 67.3 y (1.6), 30% ♀; n = 38 controls, 65 y (2.1), 53% ♀	PD	Logistic regression, β log odds AAH: 0.036, p = 0.04; EEAA: 0.031, p = 0.03 IEAA: NS	Age, sex, cell %, education, smoking, ethnicity, coffee, pesticides	[16]
			Group comparison: PhenoAge, p = 0.03		[14]
	n = 807: 569 PD, 70.5 y (9.8), 37.4% ♀, 82% White, 14% Hispanic; 238 controls, 67.5 y (12.8), 46.6% ♀, 96% White, 4% Hispanic	PD	Logistic regression, odds ratio (95% CI) epiTOC-AA: 2.11 (1.56–2.86), p < 0.001	Age, sex, smoking, ancestry, cell %, batch	[17]
Cohort C9orf72 patients (Canada)	46 ALS, 58.8 y (1.2), 50% ♀, 100% Caucasian	FTD, ALS	Linear regression, β AAH: Age of onset: -0.33, p = 0.03;disease duration: -0.52, p < 0.001	Sex, genetics, disease phenotype	[19]
Case–control, study of HAND (USA)	n = 86 HIV, 47.1 y (12.2), 36% ♀; n = 83 controls, 43.7 y (14.7), 48% ♀; ∼68% Caucasian, ∼28% African–American, ∼3% Asian	HAND	t-test AAH-AAHa consensus model: NS	Age, sex, ethnicity, cell %	[31]

AAH: Horvath age acceleration; AAHa: Hannum age acceleration; AD: Alzheimer’s disease; ALS: Amyotrophic lateral sclerosis; APOE: Genetic variants in the APOE gene; AUS: Australia; CI: Cognitive impairment; EEAA: Extrinsic epigenetic age acceleration; FTD: Frontotemporal dementia; FU: Follow-up; GrimAA: GrimAge age acceleration; HAND: HIV-associated neurocognitive disorder; Horvath: Horvath epigenetic age; IEAA: Intrinsic epigenetic age acceleration (Horvath); MoCA: Montreal Cognitive Assessment; NS: Not significant; PD: Parkinson’s disease; PhenoAA: PhenoAge age acceleration; y: Years.

Table 2. Studies investigating the association between accelerated epigenetic aging and cognitive function in adulthood.

Study, design (country)	N participants, mean age (standard deviation), sex, ethnicity (if stated)	Cognition	Main findings with epigenetic aging	Model adjustments	Ref.
Prospective cohort LBC1936 (UK)	Year 1: n = 1091, 69.5 y (0.83), 49.8% ♀; year 6: n = 697, 76.2 y (0.68), 48.4% ♀	IQ, change	AAH: ↓ IQ	Age, sex, cell %	[32]
Cohort war veterans (USA)	n = 281, 31.9 y (8.4), 12.1% ♀, mixed ethnicity	Working memory	AAH: NS AAHa: ↓	Age, sex, cell %, ancestry	[33]
Prospective cohort Betula (Sweden)	n = 16 maintained memory, 57.8 y (3.6); N = 20 average, 58.0 y (3.5); N = 16 decline, 57.9 y (3.6); 48% ♀, 15 y FU	Episodic memory	AAH: ↓	Age, sex	[18]
Prospective cohort twin study (Denmark)	n = 243 pairs of MZ twins, 65.9 y (6.1), 45.7% ♀, 10 y FU	Composite cognitive score	AAH, AAHa: NS	Age, sex, genetics	[22]
Prospective cohort Dunedin study (NZ)	n = 818, 38 y, ♀ not stated, 93% White, 12 y FU	IQ current and since childhood	AAHa: ↓ AAH, Weidner: NS	Sex	[34]
Case–cohort, pain and mobility study (USA)	n = 20 with chronic pain, 70.2 y (5.1), 85% ♀, 100% Caucasian; n = 9 no chronic pain, 71.2 y (8.0), 66.7% ♀, 89% Caucasian, 11% Asian/Pacific Islander	Cognitive battery (7 tests)	AAH: ↓ fluid cognition, episodic memory, working memory	Age, sex, ethnicity	[35]
Prospective cohort LBC1936 (UK)	n = 889, 69.5 y (0.83), 49.5% ♀, 9 y FU	Global cognition, processing speed, verbal fluency	PhenoAA: ↓	Age, sex	[36]
Prospective cohort, Dunedin study (NZ)	n = 795, 38 y, ♀ not stated, ∼12 y FU	Processing speed, reasoning, working memory, IQ decline	DunedinPoAm: ↓ PhenoAA: ↓ reasoning, working memory, processing speed AAH, AAHa: NS	Sex, cell %	[13]
Prospective cohort HANDLS (USA)	n = 199, 56.1 (0.4), 48.9% ♀, 51.3% African–American, 48.7% White, 4.7 y FU	Cognitive battery (8 tests), cognitive decline	EEAA: ↓ visual memory and processing speed decline AAH, IEAAH: NS	Age, health, ethnicity, sex, social, education	[37]
Cohorts; ARIC (USA), Generation Scotland, GS (UK)	ARIC: n = 2157 African–American, 56.0 y (5.7), 64.5% ♀; n = 708 European-American, 58.5 y (5.2), 61.0% ♀; GS: n = 1670, 55.7 y (5.7), 57.9% ♀	Verbal fluency, processing speed, memory	AAHa: ↓ (African–American only) AAH: NS	Age, health, education APOE, sex, smoking	[38]
Prospective cohort, adoption/twin study (Sweden)	n = 845, 63.6 y (8.6), 59.5% ♀ (only 387 included), 20 y FU	Composite cognitive score	AAH, AAHa, GrimAA, PhenoAA: ↓	Age, smoking BMI, sex, education	[39]
Cohorts, NSHD NCDS TwinsUK (UK)	NSHD: N = 1375, 53.4 y (0.2), 52.4% ♀ and N = 672, 63.0 y (1.0), 48.7% ♀; NCDS: N = 240, 45.1 y (0.4), 48.7% ♀; TwinsUK: N = 120, 64.9 y (9.3), 100% ♀	Episodic memory, mental speed	GrimAA: ↓ PhenoAA: ↓ mental speed AAH, AAHa: NS	Age, height, smoking, cell %, SES, BMI, sex	[40]
Cohort aging in HIV (USA)	n = 68 HIV-negative, 44.7 y (15.0), 48.5% ♀	Selective attention	Consensus model AAH-AAHa: ↓	Age	[41]
Cohort LBC1936 (UK)	n = 709, 72.5 y (0.7), 47.6% ♀	IQ, memory, reaction time, PCA	GrimAA: ↓ IQ, memory, reaction time	Age, sex, IQ at age 11	[42]
Cohort, frailty and aging (South Korea)	n = 29, 75.7 y (4.3), 55.2% ♀	Top 50% cognition and battery (7 tests)	AAH: ↓ cognition and executive function IEAAH: ↓ cognition EEAA: ↓ cognition and word recognition		[43]
Cross-sectional study (USA)	n = 31 perinatally acquired HIV, 26.2 y (4.0), 54.8% ♀; n = 30 controls, 28 y (3.6), 56.7% ♀; all African–American	5 cognitive tests	AAH: ↓ language EEAA: ↓ language, executive function IEAAH: NS		[45]
Cross-sectional study (USA)	n = 69 HIV, 64.6 y (4.4), 49.3% ♀; N = 38 seronegative controls, 66.0 y (5.0), 42.1% ♀; all African–American	5 cognitive tests, MoCA	AAH: ↓ executive function, working memory, MoCA EEAA: ↓ attention IEAA: ↓ executive function, working memory PhenoAA: ↓ executive function, attention, MoCA GrimAA: NS		[44]
Prospective cohort Emory twin study (USA)	n = 133 twin pairs, 56 y (3), 0% ♀, 57 pairs with longitudinal data. 11.5 (2.2) y FU	Memory and executive function and decline	AAH and IEAA:↓ executive function and memory change AAHa, EEAA, PhenoAA and GrimAA: NS	Age, education, cell %, health, BMI, smoking	[46]
Prospective cohort Dunedin study (NZ)	n = 814, 45 y, ♀ not stated, 20 y FU	Processing speed, reasoning, working memory	DunedinPACE, GrimAA: ↓ AAH: ↓ processing speed AAHa: ↓ reasoning, working memory PhenoAA: ↓ reasoning	Sex, smoking, cell %	[12]
Prospective cohort CARDIA (USA)	n = 1115, 50.3 y (3.5), 50.1% ♀, 15 y FU	Processing speed, verbal memory, executive function	GrimAA: ↓ IEAA, EEAA, PhenoAA: all NS	Age, education, sex, ethnicity	[47]

AAH: Horvath age acceleration; AAHa: Hannum age acceleration; APOE: Genetic variants in the APOE gene; DunedinPACE: Dunedin pace of aging; EEAA: Extrinsic epigenetic age acceleration; FU: Follow-up; GrimAA: GrimAge age acceleration; IEAAH: Intrinsic epigenetic age acceleration (Horvath); MoCA: Montreal Cognitive Assessment; MZ: Monozygotic; NS: Not significant; NZ: New Zealand; PCA: Principal component analysis; PhenoAA: PhenoAge age acceleration; SES: Socio-economic status; y: Years.

Degerman S , JosefssonM , NordinAdolfsson Aet al. Maintained memory in aging is associated with young epigenetic age. Neurobiol. Aging55, 167–171 (2017).

 PubMed Web of Science ®Google Scholar

Sibbett RA , AltschulDM , MarioniRE , DearyIJ , StarrJM , RussTC. DNA methylation-based measures of accelerated biological ageing and the risk of dementia in the oldest-old: a study of the Lothian Birth Cohort 1921. BMC Psychiatry20(1), 91 (2020).

 PubMed Web of Science ®Google Scholar

Fransquet PD , LacazeP , SafferyRet al. Accelerated epigenetic aging in peripheral blood does not predict dementia risk. Curr Alzheimer Res.18(5), 443–451 (2021).

 PubMed Web of Science ®Google Scholar

Shadyab AH , McEvoyLK , HorvathSet al. Association of epigenetic age acceleration with incident mild cognitive impairment and dementia among older women. J. Gerontol. A Biol. Sci. Med. Sci. doi:10.1093/gerona/glab245 (2021 (Epub ahead of print).

 Web of Science ®Google Scholar

Inkster AM , Duarte-GutermanP , AlbertAY , BarhaCK , GaleaLAM , RobinsonWP. Are sex differences in cognitive impairment reflected in epigenetic age acceleration metrics?Neurobiol. Aging109, 192–194 (2022).

 PubMed Web of Science ®Google Scholar

Chouliaras L , PishvaE , HaapakoskiRet al. Peripheral DNA methylation, cognitive decline and brain aging: pilot findings from the Whitehall II imaging study. Epigenomics10(5), 585–595 (2018).

 PubMed Web of Science ®Google Scholar

Levine ME , LuAT , QuachAet al. An epigenetic biomarker of aging for lifespan and healthspan. Aging10(4), 573–591 (2018).

 PubMedGoogle Scholar

Horvath S , RitzBR. Increased epigenetic age and granulocyte counts in the blood of Parkinson’s disease patients. Aging7(12), 1130–1142 (2015).

 PubMedGoogle Scholar

Paul KC , BinderAM , HorvathSet al. Accelerated hematopoietic mitotic aging measured by DNA methylation, blood cell lineage, and Parkinson’s disease. BMC Genomics22(1), 696 (2021).

 PubMed Web of Science ®Google Scholar

Zhang M , TartagliaM , MorenoDet al. DNA methylation age acceleration is associated with disease duration and age at onset in C9orf72 patients. Amyotroph. Lateral Scler. Frontotemporal Degener.18(Suppl. 2), S50–S51 (2017).

 Google Scholar

Lew BJ , SchantellMD , O’NeillJet al. Reductions in gray matter linked to epigenetic HIV-associated accelerated aging. Cereb. Cortex31(8), 3752–3763 (2021).

 PubMed Web of Science ®Google Scholar

Marioni RE , ShahS , McRaeAFet al. The epigenetic clock is correlated with physical and cognitive fitness in the Lothian Birth Cohort 1936. Int. J. Epidemiol.44(4), 1388–1396 (2015).

 PubMed Web of Science ®Google Scholar

Wolf EJ , LogueMW , HayesJPet al. Accelerated DNA methylation age: associations with PTSD and neural integrity. Psychoneuroendocrinology63, 155–162 (2016).

 PubMed Web of Science ®Google Scholar

Starnawska A , TanQ , LenartAet al. Blood DNA methylation age is not associated with cognitive functioning in middle-aged monozygotic twins. Neurobiol. Aging50, 60–63 (2017).

 PubMed Web of Science ®Google Scholar

Belsky DW , MoffittTE , CohenAAet al. Eleven telomere, epigenetic clock, and biomarker-composite quantifications of biological aging: do they measure the same thing? Am. J. Epidemiol. 187(6), 1220–1230 (2018).

 PubMed Web of Science ®Google Scholar

Cruz-Almeida Y , SinhaP , RaniA , HuoZ , FillingimRB , FosterT. Epigenetic aging is associated with clinical and experimental pain in community-dwelling older adults. Mol. Pain15, 1744806919871819 (2019).

 Web of Science ®Google Scholar

Stevenson AJ , McCartneyDL , HillaryRFet al. Childhood intelligence attenuates the association between biological ageing and health outcomes in later life. Transl. Psychiatry9(1), 323 (2019).

 PubMedGoogle Scholar

Belsky DW , CaspiA , ArseneaultLet al. Quantification of the pace of biological aging in humans through a blood test, the DunedinPoAm DNA methylation algorithm. eLIFEe54870, 9 (2020).

 Google Scholar

Beydoun MA , ShakedD , TajuddinSM , WeissJ , EvansMK , ZondermanAB. Accelerated epigenetic age and cognitive decline among urban-dwelling adults. Neurology94(6), e613–e625 (2020).

 PubMed Web of Science ®Google Scholar

Bressler J , MarioniRE , WalkerRMet al. Epigenetic age acceleration and cognitive function in African American adults in midlife: the Atherosclerosis Risk in Communities study. J. Gerontol. A Biol. Sci. Med. Sci.75(3), 473–480 (2020).

 PubMed Web of Science ®Google Scholar

Li X , PlonerA , WangYet al. Longitudinal trajectories, correlations and mortality associations of nine biological ages across 20-years follow-up. eLife9, e51507 (2020).

 PubMed Web of Science ®Google Scholar

Maddock J , Castillo-FernandezJ , WongAet al. DNA methylation age and physical and cognitive aging. J. Gerontol. A Biol. Sci. Med. Sci.75(3), 504–511 (2020).

 PubMed Web of Science ®Google Scholar

Wiesman AI , RezichMT , O’NeillJet al. Epigenetic markers of aging predict the neural oscillations serving selective attention. Cereb. Cortex30(3), 1234–1243 (2020).

 PubMed Web of Science ®Google Scholar

Hillary RF , StevensonAJ , CoxSRet al. An epigenetic predictor of death captures multi-modal measures of brain health. Mol. Psychiatry26(8), 3806–3816 (2021).

 PubMed Web of Science ®Google Scholar

Park J , WonCW , SaliganLN , KimYJ , KimY , LukkahataiN. Accelerated epigenetic age in normal cognitive aging of Korean community-dwelling older adults. Biol. Res. Nurs.23(3), 464–470 (2021).

 PubMed Web of Science ®Google Scholar

Shiau S , CantosA , RamonCVet al. Epigenetic age in young African American adults with perinatally acquired HIV. J. Acquir. Immune Defic. Syndr.87(4), 1102–1109 (2021).

 PubMed Web of Science ®Google Scholar

Shiau S , ArpadiSM , ShenYet al. Epigenetic aging biomarkers associated with cognitive impairment in older African American adults with human immunodeficiency virus (HIV). Clin. Infect. Dis.73(11), 1982–1991 (2021).

 PubMed Web of Science ®Google Scholar

Vaccarino V , HuangM , WangZet al. Epigenetic age acceleration and cognitive decline: a twin study. J. Gerontol. A Biol. Sci. Med. Sci.76(10), 1854–1863 (2021).

 PubMed Web of Science ®Google Scholar

Belsky DW , CaspiA , CorcoranDLet al. DunedinPACE, a DNA methylation biomarker of the pace of aging. eLife11, e73420 (2022).

 PubMed Web of Science ®Google Scholar

Zheng Y , HabesM , GonzalesMet al. Mid-life epigenetic age, neuroimaging brain age, and cognitive function: coronary artery risk development in young adults (CARDIA) study. Aging14(4), 1691–1712 (2022).

 PubMedGoogle Scholar