An Epigenetic Clock for Brain Age and Alzheimer’s Disease

This epigenetic clock is less correlated with chronological age and more correlated with pathology.


Alzheimer's MRIsAlzheimer's MRIs

The risk of Alzheimer’s disease goes up with age, and the number of people living with Alzheimer’s is growing. While it is known to be associated with the loss of proteostasis, it has also been found to be associated with epigenetic alterations. An advanced online preprint in bioRxiv was published by Dr. Morgan E. Levine and colleagues, who created a methylation clock called PCBrainAge. They wanted to determine if PCBrainAge is predictive of Alzheimer’s disease [1].

PCBrainAge is associated with Alzheimer’s disease in the dorsal prefrontal cortex

The prefrontal cortex, a part of the brain, is where much of our executive function takes place. Executive function aids in functions such as decision making and cognitive control.

Using data from the dorsal prefrontal cortices of 700 participants in the Religious Orders Study and the Memory and Aging Project, the researchers generated linear models comparing PCBrainAge to the participants’ neuronal composition and true ages at death. As part of their analysis, the researchers determined these participants’ CERAD scores.

The first result indicates that the post-mortem stage of Alzheimer’s disease, according to CERAD scores, was significantly associated with increased brain aging and BRAAK staging, which is used to score the progression of Alzheimer’s disease and Parkinson’s disease.


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PCBrainAge was shown to be significantly associated with Alzheimer’s disease when the disease had reached neocortical tissue, showing that it had reached its final stages. PCBrainAge acceleration was also positively associated with the pre-mortem clinical diagnosis of Alzheimer’s disease dementia. Additionally, carriers of one or two APOE e4 alleles, which are associated with Alzheimer’s disease, were significantly more likely to experience PCBrainAge acceleration.

This study also used a methylation clock known as DNAmClockCortical [2], which, like PCBrainAge, is used to measure both age and age acceleration. DNAmClockCortical is more strongly correlated with chronological age than PCBrainAge, but PCBrainAge takes into account the biological heterogeneity of aging, and its link to Alzheimer’s disease may give it more clinical value.

Additional results comparing these two clocks demonstrate that DNAmClockCortical showed less significant association with the pathological and clinical phenotypes of Alzheimer’s disease and APOE e4 carrier status than PCBrainAge. This suggests that DNAmClockCortical may not be sensitive enough to detect the genetic and aging signals associated with Alzheimer’s disease.

Furthermore, large increases in DNAmClockCortical acceleration were not correlated with increased pathological Alzheimer’s disease in an examination of amyloid and neuritic plaques. PCBrainAge demonstrated a closer correlation to Alzheimer’s disease pathology and was more balanced across post-mortem metrics of this pathology.

Unlike DNAmClockCortical, significantly increased PCBrainAge acceleration also showed an increase in the probability of dementia. The authors hypothesize that this result is due to the reduction in the noise from CpGs and the improved resolution of the PCBrainAge clock.


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Alzheimer’s disease is correlated with PCBrainAge across many brain regions

The study then went on to use PCBrainAge to measure aging trends across brain regions and specific associations with Alzheimer’s disease.

This analysis examined 333 individuals from the APOE e4 carrier subcohort of this study. This data examined novel DNA methylation of three specific brain regions: the dorsolateral prefrontal cortex, the striatum and the cerebellum.

Age acceleration in the prefrontal cortex and the striatum were both associated with Alzheimer’s disease neuropathology and pre-mortem clinical diagnosis. A weaker association showed that age acceleration in the striatum was increased in APOE4 e4 carriers. The researchers believe that this weaker association was due to this dataset being smaller than the overall study.

In the cerebellum, PCBrainAge acceleration was not significantly correlated with Alzheimer’s disease or APOE e4 carrier status. Prior research also agrees that epigenetic clocks do not show correlations with cerebellum age acceleration and Alzheimer’s disease neuropathology [3].



While this is a preprint that has not yet been peer reviewed, its results show a link between DNA methylation patterns and advanced Alzheimer’s disease. Along with the PhenoAge clock, this research has unlocked epigenetic clues to the complex nature of Alzheimer’s disease.

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[1] Kyra L. Thrush, David A. Bennett, Christopher Gaiteri, Steve Horvath, Christopher H. van Dyck, Albert T. Higgins-Chen, Morgan E. Levine. bioRxiv (2022) bioRxiv preprint. doi: https://doi.org/10.1101/2022.02.28.481849

[2] Sierra, F. Geroscience and the Role of Aging in the Etiology and Management of Alzheimer’s Disease. J Prev Alzheimers Dis 7, 2–3 (2020). https://doi.org/10.14283/jpad.2019.49

[3] Horvath, S., Mah, V., Lu, A. T., Woo, J. S., Choi, O. W., Jasinska, A. J., Riancho, J. A., Tung, S., Coles, N. S., Braun, J., Vinters, H. V., & Coles, L. S. (2015). The cerebellum ages slowly according to the epigenetic clock. Aging, 7(5), 294–306. https://doi.org/10.18632/aging.100742

About the author


Tovah has been a Registered Dietitian Nutritionist (RDN) for the past 11 years in clinical, research, teaching, community, and industry roles. Her dissertation work was focused on nutritional and behavioral neuroscience approaches for chronic disease prevention. She was a writer for Lifespan.io from 2021-22 and is still an active volunteer with the org.