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Plasma proteomics-based brain aging signature and incident dementia risk

GeroScience, 2024

Kou M., Ma H., Wang X., Heianza Y., Qi L.

Disease areaApplication areaSample typeProducts
Neurology
Aging
Pathophysiology
Plasma
Olink Explore 3072/384

Olink Explore 3072/384

Abstract

Investigating brain-enriched proteins with machine learning methods may enable a brain-specific understanding of brain aging and provide insights into the molecular mechanisms and pathological pathways of dementia. The study aims to analyze associations of brain-specific plasma proteomic aging signature with risks of incident dementia. In 45,429 dementia-free UK Biobank participants at baseline, we generated a brain-specific biological age using 63 brain-enriched plasma proteins with machine learning methods. The brain age gap was estimated, and Cox proportional hazards models were used to study the association with incident all-cause dementia, Alzheimer’s disease (AD), and vascular dementia. Per-unit increment in the brain age gap z-score was associated with significantly higher risks of all-cause dementia (hazard ratio [95% confidence interval], 1.67 [1.56–1.79], P < 0.001), AD (1.85 [1.66–2.08], P < 0.001), and vascular dementia (1.86 [1.55–2.24], P < 0.001), respectively. Notably, 2.1% of the study population exhibited extreme old brain aging defined as brain age gap z-score > 2, correlating with over threefold increased risks of all-cause dementia and vascular dementia (3.42 [2.25–5.20], P < 0.001, and 3.41 [1.05–11.13], P = 0.042, respectively), and fourfold increased risk of AD (4.45 [2.32–8.54], P < 0.001). The associations were stronger among participants with healthier lifestyle factors (all P-interaction < 0.05). These findings were corroborated by magnetic resonance imaging assessments showing that a higher brain age gap aligns global pathophysiology of dementia, including global and regional atrophy in gray matter, and white matter lesions (P < 0.001). The brain-specific proteomic age gap is a powerful biomarker of brain aging, indicative of dementia risk and neurodegeneration.

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