NEW YORK – New research from China has identified more than a dozen blood plasma proteins that appear to coincide with brain aging, providing insights into age-related brain changes and pointing to the possibility of developing blood-based biomarkers of aging and related brain conditions.
The findings help clarify 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," co-senior and co-corresponding authors Wei Cheng and Jin-Tai Yu, neurology researchers at Fudan University, and Yu-Ming Xu, of Zhengzhou University, and their colleagues wrote in a study published in Nature Aging on Monday.
The investigators began using machine-learning models and multimodal magnetic resonance imaging-based brain imaging data to gauge the brain age gap (BAG) — estimated differences between chronological age and predicted brain age — for 10,949 healthy participants in the UK Biobank.
From a set of 1,705 brain imaging-derived phenotypes (IDPs), they settled on a set of 864 IDPs with ties to brain age, which were then used in a proteome-wide association study for BAG contributors — an effort aimed at expanding on findings from previous studies focused on specific age-related brain features such as brain region atrophy.
"[T]hough previous studies have utilized omics-based data to illustrate that aging was an undulating process, little was known about the brain aging process," Cheng said in an email, noting that the new work uncovered brain aging-linked proteins that are expected to help in understanding or predicting brain disorders.
Based on Olink Explore proximity extension assay-based blood plasma profiles spanning 2,922 proteins in 4,696 participants, the team narrowed in on 13 BAG-associated plasma proteins — a set that included eight proteins that increased with a higher BAG and five potentially protective proteins that were negatively associated with BAG. Six of the 13 plasma protein associations were further validated using data from repeat brain imaging visits.
From there, the investigators went on to look for additional ties between BAG-related plasma proteins and brain features or disorders, highlighting BAG proteins associated with cortical volume, cortical surface area, or subcortical volume and conditions ranging from all-cause dementia to anxiety or depression.
Another protein, the extracellular matrix perineuronal net proteoglycan protein BCAN, was linked to lower-than-usual risk of brain disorders ranging from all-cause dementia or Alzheimer's disease to stroke in a subsequent association analysis that included all 13 proteins from the initial BAG PWAS.
Unexpectedly, though, the team saw age-related waves in the BAG-associated proteomic patterns, which tended to peak in participants who were around 57, 70, and 78 years old. That, in turn, suggested that certain points in life may act as so-called "transitional time points" for brain aging.
"[W]e 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," the authors reported, "suggesting that these are essential periods for intervention in the brain aging process."
Cheng noted that he and his colleagues are planning more detailed functional analyses on the candidate biomarkers they identified. This will include in vivo and ex vivo experiments aimed at teasing out the consequences of tweaking expression of the proteins in neuron and glial cells in the brain as well as experiments aimed at understanding the mechanisms by which the proteins contribute to brain aging or neurodegenerative brain conditions.
"By understanding how these biomarkers impact neuronal and glial functions, we hope to uncover potential therapeutic targets for slowing or reversing age-related cognitive decline and preventing neurodegenerative diseases," he explained. "This research could provide critical insights into the biological processes underlying brain aging and open up new avenues for developing interventions to preserve brain function in aging populations."