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

Abstract

Background: Biological aging may be a robust biomarker of dementia or cognitive performance. This systematic review synthesized the evidence for an association between epigenetic aging and dementia, mild cognitive impairment and cognitive function. Methods: A systematic search was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Results: 30 eligible articles were included. There was no strong evidence that accelerated epigenetic aging was associated with dementia/mild cognitive impairment (n = 7). There was some evidence of an association with poorer cognition (n = 20), particularly with GrimAge acceleration, but this was inconsistent and varied across cognitive domains. A meta-analysis was not performed due to high study heterogeneity. Conclusion: There is insufficient evidence to indicate that current epigenetic aging clocks can be clinically useful biomarkers of dementia or cognitive aging.

DNA methylation-based measures of biological aging and cognitive decline over 16-years: preliminary longitudinal findings in midlife

“…Links between DNAm measures and risk for cognitive decline have been less well characterized, despite the substantial and growing burden of cognitive decline and dementia [ 4 ]. The majority of existing evidence on DNAm measures and neuropsychologically assessed cognitive function is cross-sectional [ 5 ] and cannot address whether changes in biological aging are associated with changes in cognition. Four studies to date [ 6 – 9 ] have examined but did not find changes in cognitive function relating to changes in first- or second-generation epigenetic clocks.…”

Epigenetic Association Analyses and Risk Prediction of RLS

“…Therefore, we applied Shireby's cortical clock 15 which has been trained on brain tissues and found to indicate advanced epigenetic aging in cortical tissue of brain samples with neurodegeneration 21 while other clocks have not been proven to detect dementia and cognitive aging sufficiently. 39 Shireby's cortical clock also did not show advanced epigenetic aging in RLS. Indeed, there also is no other evidence for an increased risk of RLS patients to develop neurodegenerative diseases.…”

Epigenetic clocks in neurodegenerative diseases: a systematic review

“…Using the first-generation epigenetic clocks (Horvath and Hannum clocks) or the second-generation clocks (PhenoAge and GrimAge) or the Skin & Blood clock, neither consistent nor significant differences of DNAm age were found among different cognitive status groups (CN, MCI and AD) 39 43. A very recent review focused on epigenetic ageing in dementia, a broad concept of cognitive dysfunction not just limited to AD, claimed that there was no strong evidence supporting individuals with dementia had accelerated DNAm age (based on existing 11 blood-based epigenetic clocks) 56. It was not surprising that some epigenetic clocks did not significantly reflect AD progression, as they were designed and trained not for predicting cognitive decline originally: Horvath15 and Hannum24 clocks were meant to predict chronological age, PhenoAge25 and GrimAge26 were mainly for longevity and mortality prediction.…”

“…Great enthusiasm has been paid for blood DNAm as a potential biomarker of dementia 55. The role of DNAm age in predicting cognitive decline and progression from mild cognitive impairment (MCI) to AD is also gaining attention 56. Three ‘generations’ of epigenetic clocks (first generation: Horvath and Hannum clocks; second generation: PhenoAge and GrimAge and third generation: DunedinPACE) have been applied in the ADNI cohort (n=649), to test the associations between DNAm age and cognitive status 43.…”

“…Among these, epigenetic alterations (eg, DNAm and hydroxymethylation, histone modifications, chromatin remodelling and non-coding RNAs mediations), especially DNAm, could represent a bridge connecting genetic and environmental factors involved in ageing and neurodegeneration 60–62. As shown in figure 2, epigenetic clocks quantifying biological ageing (DNAm age) have been widely used in many age-related diseases such as cancer, cardiovascular diseases and neurodegenerative diseases 19 56. Importantly, the DNAm age is reversible and modulated by a variety of environmental factors, raising opportunities to modify ageing and diseases 14 30 34.…”