The Role of DNA Methylation in Dopaminergic Neuromodulation of Cognitive Aging
Age-related cognitive impairments compromise the functional capacity of aging individuals, and create major individual and societal costs. Therefore, understanding the mechanisms underlying cognitive aging is of great importance. The neurotransmitter dopamine (DA) supports molecular mechanisms of various cognitive functions. Aging-related decline in dopaminergic neuromodulation contributes to cognitive aging. Genes and environmental factors are the two major forces that may be responsible for the often larger between-person differences in cognitive functions among older compared to younger adults. Environmental and lifestyle factors can influence gene expression through epigenetic mechanisms, such as DNA methylation. Based on initial evidence, we test whether higher DNA methylation of DA-related genes in blood, reflecting lower gene expression, is associated with (1) older age, (2) interindividual differences in and decline of DA receptor availability in the living human brain, (3) impaired cognitive and brain functioning in old age, and (4) a disadvantageous lifestyle (i.e., physical inactivity, poor cardiovascular health). Taken together, this program of research will determine the role of DA DNA methylation as a mechanism of change underlying aging-related decline in DA and cognitive functioning. Overall, our findings will contribute to a better understanding of individual cognitive and brain aging trajectories.
Final report
The project progressed according to plan, with minor logistical delays but no major scientific or financial deviations. Several publications and manuscripts have been produced, addressing the original research questions. Using the two largest dopamine (DA) positron-emission tomography (PET) studies so far, we tested whether higher DNA methylation of DA-related genes in blood, reflecting lower gene expression, is associated with (1) older age, (2) interindividual differences in and decline of DA receptor availability in the living human brain, (3) impaired cognitive and brain functioning in old age, and (4) a disadvantageous lifestyle (i.e., physical inactivity, poor cardiovascular health).
1. Epigenetic markers and dopamine receptor availability: For D2 receptors, we identified only one specific CpG site within the DRD2 gene that predicts lower D2 receptor availability in the brain (PET imaging), explains 6–10% of variance, and is associated with lower self-related physical activity, but not with chronological age. These findings address research questions 1, 2, and 4. There were no such association for D1 receptors.
2. Biological pace of aging and longitudinal dopamine and cognitive decline: Instead of focusing on single CpGs, we investigated whether methylation-based scores, reflecting biological aging, are associated with the variables of interest. Using DunedinPACE, we demonstrated that faster biological aging predicts lower D1 and D2 receptor availability and worse cognitive performance, independent of chronological age. Critically, in a 5-year longitudinal analysis of older adults (n = 129), individuals with the fastest biological aging showed the most extensive D2 receptor decline across striatal and extrastriatal regions and the greatest working memory decline. Higher DunedinPACE was also linked to a higher cardiovascular risk score and greater volume of white matter lesions, suggesting that DunedinPACE may capture cardiovascular processes associated with DA receptor decline. These findings address research questions 2, 3, and 4.
3. Development of a non-invasive new methylation-based DA biomarkers: We developed a blood-based DNA methylation marker of central dopamine function using PET imaging. Specifically, we applied elastic net regression to associate whole-blood DNA methylation profiles with the two PET-derived measures of dopamine system function. Next, we validated our methylation-based measure of DA in Parkinson’s disease patients and healthy controls, showing that the DA methylation score was significantly associated with striatal binding ratio in both groups. This approach opens scalable avenues for studying DA-related processes without neuroimaging. These findings extend the original aims to the development of a new and reliable methylation-based DA score.
We have successfully addressed all research questions detailed in our original proposal, resulting in one published paper (Karalija et al., 2022) and two manuscripts currently under preparation (Kusnetzov and colleagues; Dove and collogues). The data have also been used to address related question of whether inflammation, based on methylation scores, would negatively predict DA receptors (Crine et al., 2025). Results were presented in scientific conferences, which include Dopamine 2022, Dopamine 2026, CNS 2023. All results are or will be published open access.
1. Epigenetic markers and dopamine receptor availability: For D2 receptors, we identified only one specific CpG site within the DRD2 gene that predicts lower D2 receptor availability in the brain (PET imaging), explains 6–10% of variance, and is associated with lower self-related physical activity, but not with chronological age. These findings address research questions 1, 2, and 4. There were no such association for D1 receptors.
2. Biological pace of aging and longitudinal dopamine and cognitive decline: Instead of focusing on single CpGs, we investigated whether methylation-based scores, reflecting biological aging, are associated with the variables of interest. Using DunedinPACE, we demonstrated that faster biological aging predicts lower D1 and D2 receptor availability and worse cognitive performance, independent of chronological age. Critically, in a 5-year longitudinal analysis of older adults (n = 129), individuals with the fastest biological aging showed the most extensive D2 receptor decline across striatal and extrastriatal regions and the greatest working memory decline. Higher DunedinPACE was also linked to a higher cardiovascular risk score and greater volume of white matter lesions, suggesting that DunedinPACE may capture cardiovascular processes associated with DA receptor decline. These findings address research questions 2, 3, and 4.
3. Development of a non-invasive new methylation-based DA biomarkers: We developed a blood-based DNA methylation marker of central dopamine function using PET imaging. Specifically, we applied elastic net regression to associate whole-blood DNA methylation profiles with the two PET-derived measures of dopamine system function. Next, we validated our methylation-based measure of DA in Parkinson’s disease patients and healthy controls, showing that the DA methylation score was significantly associated with striatal binding ratio in both groups. This approach opens scalable avenues for studying DA-related processes without neuroimaging. These findings extend the original aims to the development of a new and reliable methylation-based DA score.
We have successfully addressed all research questions detailed in our original proposal, resulting in one published paper (Karalija et al., 2022) and two manuscripts currently under preparation (Kusnetzov and colleagues; Dove and collogues). The data have also been used to address related question of whether inflammation, based on methylation scores, would negatively predict DA receptors (Crine et al., 2025). Results were presented in scientific conferences, which include Dopamine 2022, Dopamine 2026, CNS 2023. All results are or will be published open access.