Blood Biomarkers Identified for Brain Aging and Disease

As the global population ages, understanding the molecular mechanisms of brain aging has become increasingly urgent.

A study conducted by researchers from Fudan University and Zhengzhou University, published in Nature Aging, identified key blood-based biomarkers that could aid the early detection of and interventions in brain aging and neurodegenerative diseases, like dementia and stroke.

Identifying biomarkers of brain aging

The world’s population is aging rapidly, with projections suggesting that over 2.1 billion people will be aged 60 or older by 2050. This demographic shift underscores the pressing need to address the challenges of aging, particularly its impact on the brain. Aging is closely associated with cognitive decline and structural brain changes, which contribute to the rising prevalence of neurodegenerative disorders such as Alzheimer’s disease and dementia.

Early identification of brain aging biomarkers is critical for developing preventive interventions. Traditional approaches have explored imaging traits and histologic features to assess brain health. However, these methods offer limited molecular insights into the mechanisms underlying brain aging. As a result, researchers are increasingly turning to blood-based biomarkers, using non-invasive, accessible and cost-effective tools.

Blood plasma holds strong potential as it reflects systemic physiological changes, including those in the brain, through the presence of specific proteins. Yet, little is known about how plasma proteins evolve during brain aging.

“Investigating the dynamics of plasma proteome during brain aging is essential for revealing the molecular mechanisms associated with brain disorders. Bridging this knowledge gap also provides potential for the early identification and intervention of neurodegenerative disorders,” said the authors.

Key proteins in brain aging

The team combined multimodal brain imaging with plasma proteomics. They analyzed brain imaging data from 10,949 healthy adults aged 45 to 82 years and assessed over 2,900 proteins in the blood plasma of 4,696 participants using the UK Biobank. Using statistical tools, they looked for proteins in the blood whose levels were consistently linked with differences in brain age or structural changes.

“We identified 13 plasma proteins associated with brain aging and validated 6 of them,” said the authors.

Out of the 13 proteins, 2 in particular stood out:

• Brevican (BCAN) – a neural proteoglycan found mostly in the brain and nervous system, where it helps maintain brain structure and supports neuron connections.
• Growth Differentiation Factor 15 (GDF15) – a protein released in response to stress and damage in the body.

BCAN was closely tied to healthier brain structures and lower risk of conditions like dementia and stroke. On the other hand, GDF15 was strongly associated with higher risks of dementia and stroke, likely due to its involvement in harmful processes like inflammation. These proteins, alongside others, were linked to key biological processes, including stress, inflammation and neuronal regeneration. Their levels also varied in patterns that reflected biological brain age.

“We uncovered the existence of undulating changes during brain aging, with proteomic alterations peaking in the late fifth, seventh and late seventh decades of brain age, suggesting that these are essential periods for intervention in the brain aging process,” they added.

These periods corresponded to shifts in plasma proteomics:

• At 57 years: Metabolic and immune pathways were altered, indicating early molecular signs of brain aging.
• At 70 years: Neural development and plasticity peaked, signaling a critical point for cognitive health.
• At 78 years: Stress and inflammation-related pathways became dominant, suggesting heightened vulnerability to neurodegenerative processes.

Early intervention and personalized treatments

“These findings contribute to bridging essential knowledge gaps in clarifying the molecular mechanisms of brain aging, with substantial implications for the future development of systemic and pragmatic biomarkers for brain aging, as well as personalized therapeutic targets for subsequent age-related brain disorders,” said the researchers.

Identifying biomarkers, including proteins like BCAN and GDF15, has the potential to aid early detection and monitoring of brain health. Currently, diagnosing age-related brain disorders typically occurs once symptoms appear, often when damage is already significant. However, by tracking protein levels in the blood, these biomarkers could allow for earlier diagnosis, even before clinical symptoms manifest. This would enable healthcare providers to intervene sooner, potentially slowing or even reversing the effects of brain aging before irreversible damage occurs.

Understanding the proteins involved in critical biological processes like stress, inflammation and neuronal regeneration is not only valuable for diagnosis but also for developing novel treatments. By tailoring treatments to the specific molecular mechanisms at play in brain aging, researchers could develop therapies that are more effective and personalized.

To ensure the biomarkers and insights are broadly applicable, future studies must include more diverse populations, encompassing different ages, ethnicities and genetic backgrounds. Longitudinal studies that track brain health over time will also be crucial for understanding how these proteins change across the lifespan and how early interventions might impact long-term outcomes.

Reference: Liu WS, You J, Chen SD, et al. Plasma proteomics identify biomarkers and undulating changes of brain aging. Nat Aging. 2024. doi: 10.1038/s43587-024-00753-6

This article is a rework of a press release issued by Springer Nature. Material has been edited for length and content.