Tian Qu, Greig Erin E, Duggan Michael R, Walker Keenan A, Ferrucci Luigi
Longitudinal Studies Section, Translational Gerontology Branch, National Institute on Aging, 251 Bayview Blvd., Suite 100, Baltimore, MD, USA, 21224.
Longitudinal Studies Section, Translational Gerontology Branch, National Institute on Aging, 251 Bayview Blvd., Suite 100, Baltimore, MD, USA, 21224.
EBioMedicine. 2025 Aug;118:105858. doi: 10.1016/j.ebiom.2025.105858. Epub 2025 Aug 4.
The simultaneous memory and gait decline is linked to greater dementia risk than memory decline alone. We aim to identify dual decline-related protein changes that may offer valuable insights into biological processes.
We compared longitudinal changes in 7268 plasma proteomic markers in older adults experiencing dual decline, memory decline, and gait decline from no decline (reference) using linear mixed-effects regression and related to brain MRI and blood biomarkers.
There were no baseline group differences in proteins. Longitudinally, only dual decline showed significant changes in 75 proteins, with PGP9.5 showing the most alteration (p-FDR < 0.05), implicated in synaptic function, proteostasis, and regulation of amyloid precursor protein and amyloid β protein. The top-enriched pathway pointed to mitochondrial protein degradation. Of 75, changes in select proteins were related to future cognitive impairment, brain atrophy patterns, and blood biomarkers of AD, neuroinflammation, and neurodegeneration, with TRI72 being the top significant protein related to cognitive impairment and pTau181 progression.
Older adults experiencing dual decline exhibit longitudinal protein changes, indicating mitochondrial dysfunction, proteostasis, neuroinflammation, and immune responses.
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与单纯记忆衰退相比，记忆与步态同时衰退与更高的痴呆风险相关。我们旨在确定与双重衰退相关的蛋白质变化，这可能为生物学过程提供有价值的见解。
我们使用线性混合效应回归比较了7268个血浆蛋白质组学标志物在经历双重衰退、记忆衰退和步态衰退（无衰退作为对照）的老年人中的纵向变化，并将其与脑MRI和血液生物标志物相关联。
各蛋白质组在基线时无差异。纵向来看，只有双重衰退组的75种蛋白质有显著变化，其中PGP9.5变化最为明显（p-FDR < 0.05），涉及突触功能、蛋白质稳态以及淀粉样前体蛋白和淀粉样β蛋白的调节。富集程度最高的通路指向线粒体蛋白质降解。在这75种蛋白质中，特定蛋白质的变化与未来的认知障碍、脑萎缩模式以及阿尔茨海默病、神经炎症和神经退行性变的血液生物标志物相关，其中TRI72是与认知障碍和pTau181进展最显著相关的蛋白质。
经历双重衰退的老年人表现出纵向蛋白质变化，表明存在线粒体功能障碍、蛋白质稳态、神经炎症和免疫反应。
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