A new biomarker for cognitive abilities in adulthood?

A new study has unveiled a significant connection between the aging of our genes and our cognitive abilities. This discovery opens doors to a deeper understanding of how our genes may influence our brain health in adulthood. The findings have been published in Neurobiology of Stress.

The human brain is an astonishingly complex organ, responsible for our thoughts, memories, and problem-solving abilities. Over the years, scientists have been intrigued by the relationship between aging and cognitive function. As we age, it’s common for cognitive abilities to decline, but the exact mechanisms behind this process have remained elusive.

Previous research has hinted at the role of genetics in cognitive aging, but a team of researchers wanted to dig deeper. They were particularly interested in understanding how the process of epigenetic aging might be linked to our cognitive abilities. Epigenetic aging refers to the changes that occur in our DNA over time due to environmental factors and lifestyle choices, which can influence how our genes function.

“This study was part of a series of grant-funded studies looking at how epigenetic age acceleration could serve as a biomarker for long-term consequences following early life adversities and a midlife biomarker for cognitive impairment,” said study author John M. Felt, an assistant research professor in the Center for Healthy Aging at Pennsylvania State University.

“This is important because many of the morbidities of aging, notably mild cognitive impairment and Alzheimer’s disease and related dementias, may have underlying biological changes that can be detected years (or even decades) before they manifest. If we can detect advanced aging earlier in life, we may be able to develop preventative interventions for those at greatest risk for advanced aging.”

To unravel the connection between epigenetic aging and cognitive function, the researchers analyzed data from two distinct groups of individuals: the Female Growth and Development Study (FGDS) and the Biological Classification of Mental Disorders (BeCOME) cohort.

In the FGDS cohort, which included 86 individuals, participants were originally recruited between the ages of 6 and 16, with follow-up assessments conducted when they were between 29 and 45 years old. In contrast, the BeCOME cohort consisted of 313 individuals between the ages of 18 and 65, recruited for the evaluation of psychiatric diagnoses.

Both cohorts underwent a comprehensive neurocognitive battery that assessed various cognitive domains. The specific tests administered varied between the FGDS and BeCOME cohorts but covered areas such as language abilities, memory, reasoning, working memory, processing speed, attention, and more. In addition, genomic DNA was extracted from whole blood samples collected from the participants in both cohorts.

The researchers found that a two-factor solution was a suitable fit for understanding cognitive abilities in both cohorts. These two factors represented general cognitive abilities and speeded cognitive abilities, reflecting different aspects of cognitive function.

General cognitive abilities represent an individual’s overall cognitive capacity. These abilities encompass a wide range of cognitive processes, including reasoning, problem-solving, memory, learning, and abstract thinking. Speeded cognitive abilities refer to an individual’s capacity to perform cognitive tasks quickly and efficiently. These abilities emphasize the speed at which cognitive processes can be executed, often under time constraints.

When examining the first-generation epigenetic clocks, known as the Horvath and Hannum clocks, the study found no significant associations with general cognitive abilities in either cohort. This suggests that the aging of genes measured by these clocks does not strongly correlate with overall cognitive function. These first-generation clocks were initially trained to estimate chronological age.

Surprisingly, the Horvath clock did show a significant association with speeded cognitive abilities in the BeCOME cohort, indicating that the rate of epigenetic aging might influence how quickly people can perform cognitive tasks. However, this association was not statistically significant in the FGDS cohort.

The second-generation epigenetic clocks, called GrimAge and PhenoAge, revealed different associations. GrimAge acceleration was nearly significantly linked to lower general cognitive abilities in the FGDS cohort but not in the BeCOME cohort. Importantly, GrimAge acceleration was not associated with speeded cognitive abilities in either cohort. These second-generation epigenetic clocks were designed with a focus on aging-related health issues and mortality. These clocks capture aging-related morbidities, going beyond mere chronological age.

The Dunedin Pace of Aging Methylation (DunedinPoAm) Clock, a specialized clock designed to estimate the pace of biological aging in various systems, showed interesting results. Acceleration of epigenetic age as measured by the DunedinPoAm clock was almost significantly associated with lower general cognitive abilities in the FGDS cohort and significantly associated with lower general cognitive abilities in the BeCOME cohort. While this acceleration wasn’t significantly associated with slower speeded cognitive abilities in the FGDS cohort, it was nearly significant in the BeCOME cohort.

“I was surprised to find differential associations between the clocks and cognitive function between the cohorts,” Felt told PsyPost. “The first-generation clocks that were trained on chronological age (Horvath and Hannum) were only significant predictors in the BeCOME cohort, whereas the second-generation clocks that were trained on aging-related morbidities and mortality (GrimAge and PhenoAge) were only significant predictors in the FGDS cohort.”

“It’s possible that differences in how the cohorts were sampled (e.g., large age range in BeCOME and Wave 7 of a 30 year prospective cohort study in the FGDS) and cultural differences could have contributed to the differential associations.”

Overall, the study provides evidence that epigenetic age acceleration may be associated with neurocognitive function, but the specific associations depend on the epigenetic clock used and the characteristics of the study cohort.

“From this study, the average person can take away that accelerated epigenetic age was associated with lower general cognitive abilities and slower speed-related cognitive abilities,” Felt said. “They should note that there are several different estimates of epigenetic age and that associations differed by clock and by cohort we studied.”

The researchers controlled for factors such as childhood maltreatment, psychological trauma, psychiatric diagnoses, and polygenic scores for educational attainment. But it’s important to note that the study used peripheral blood to assess epigenetic aging, which may not directly reflect brain aging. Additionally, the associations found in this study were based on cross-sectional data, making it challenging to determine the direction of causality.

To further our understanding of these intriguing findings, future research may explore these associations longitudinally, tracking changes in epigenetic age acceleration and cognitive abilities over time. This approach could help elucidate when epigenetic age acceleration might serve as an early indicator of cognitive impairments associated with later-life neurocognitive degeneration.

Moreover, the research team emphasizes the importance of conducting more extensive studies with larger and more diverse samples to confirm and expand upon these findings. Additionally, future research should consider optimizing epigenetic clocks for biomarkers of neurocognitive function, potentially enhancing their utility for diagnosing and addressing cognitive impairments, especially in psychiatric and maltreated populations.

“I think the biggest caveat is that these are all cross-sectional analyses, and we were unable to determine directionality,” Felt told PsyPost. “Future work needs to investigate how longitudinal changes in epigenetic age acceleration are associated with longitudinal changes in cognitive function so we can test directionality of effects and identify sensitive periods that may be better to target interventions during.”

“This was an exciting collaboration between researchers at Penn State, Stanford University, McGill University, Yale University, and The Max Planck Institute for Psychiatry. Working with researchers from so many different universities across the U.S. and in Europe can be challenging (especially with time), but it allowed us to test these complicated and important research questions.”

The study, “Epigenetic age acceleration as a biomarker for impaired cognitive abilities in adulthood following early life adversity and psychiatric disorders“, was authored by John M. Felt, Natan Yusupov, Karra D. Harrington, Julia Fietz, Zhenyu “Zach” Zhang, Martin J. Sliwinski, Nilam Ram, Kieran J. O’Donnell, BeCOME Working Group, Michael J. Meaney , Frank W. Putnam, Jennie G. Noll, Elisabeth B. Binder, and Chad E. Shenk.