Organ aging signatures in the plasma proteome track health and diseaseAbstract Animal studies show aging varies between individuals as well as between organs within an individual 1–4 , but whether this is true in humans and its effect on age-related diseases is unknown. We utilized levels of human blood plasma proteins originating from specific organs to measure organ-specific aging differences in living individuals. Using machine learning models, we analysed aging in 11 major organs and estimated organ age reproducibly in five independent cohorts encompassing 5,676 adults across the human lifespan. We discovered nearly 20% of the population show strongly accelerated age in one organ and 1.7% are multi-organ agers. Accelerated organ aging confers 20–50% higher mortality risk, and organ-specific diseases relate to faster aging of those organs. We find individuals with accelerated heart aging have a 250% increased heart failure risk and accelerated brain and vascular aging predict Alzheimer’s disease (AD) progression independently from and as strongly as plasma pTau-181 (ref. 5 ), the current best blood-based biomarker for AD. Our models link vascular calcification, extracellular matrix alterations and synaptic protein shedding to early cognitive decline. We introduce a simple and interpretable method to study organ aging using plasma proteomics data, predicting diseases and aging effects.
CD4 <sup>+</sup> T cells contribute to neurodegeneration in Lewy body dementiaAutoimmunity in Lewy body dementia Lewy body dementia (LBD) is a brain disease that leads to progressive decline in thinking, movement, and independent function. It results from the build-up of microscopic deposits called Lewy bodies, which develop from the aggregation of a misfolded protein called α-synuclein. Gate et al . observed immune cells known as T cells in the brains of LBD patients (see the Perspective by Krot and Rolls). Genomics analysis revealed that T cells traffic to the LBD brain and are associated with neuronal damage. When stimulated with α-synuclein, LBD patient T cells secrete an inflammatory protein known to damage neurons. These findings suggest an unexpected detrimental role of the immune system in LBD. —SMH
Proteomics of brain, CSF, and plasma identifies molecular signatures for distinguishing sporadic and genetic Alzheimer’s diseaseYun Ju Sung, Chengran Yang, Joanne Norton et al.|Science Translational Medicine|2023 Proteomic studies for Alzheimer’s disease (AD) are instrumental in identifying AD pathways but often focus on single tissues and sporadic AD cases. Here, we present a proteomic study analyzing 1305 proteins in brain tissue, cerebrospinal fluid (CSF), and plasma from patients with sporadic AD, TREM2 risk variant carriers, patients with autosomal dominant AD (ADAD), and healthy individuals. We identified 8 brain, 40 CSF, and 9 plasma proteins that were altered in individuals with sporadic AD, and we replicated these findings in several external datasets. We identified a proteomic signature that differentiated TREM2 variant carriers from both individuals with sporadic AD and healthy individuals. The proteins associated with sporadic AD were also altered in patients with ADAD, but with a greater effect size. Brain-derived proteins associated with ADAD were also replicated in additional CSF samples. Enrichment analyses highlighted several pathways, including those implicated in AD (calcineurin and Apo E), Parkinson’s disease (α-synuclein and LRRK2), and innate immune responses (SHC1, ERK-1, and SPP1). Our findings suggest that combined proteomics across brain tissue, CSF, and plasma can be used to identify markers for sporadic and genetically defined AD.