Post-translational modifications linked to preclinical Alzheimer's disease-related pathological and cognitive changes.

INTRODUCTION: In this study, we leverage proteomic techniques to identify communities of proteins underlying Alzheimer's disease (AD) risk among clinically unimpaired (CU) older adults. METHODS: We constructed a protein co-expression network using 3869 cerebrospinal fluid (CSF) proteins quantified by SomaLogic, Inc., in a cohort of participants along the AD clinical spectrum. We then replicated this network in an independent cohort of CU older adults and related these modules to clinically-relevant outcomes. RESULTS: We discovered modules enriched for phosphorylation and ubiquitination that were associated with abnormal amyloid status, as well as p-tau181 (M4: ß = 2.44, p < 0.001, M7: ß = 2.57, p < 0.001) and executive function performance (M4: ß = -2.00, p = 0.005, M7: ß = -2.39, p < 0.001). DISCUSSION: In leveraging CSF proteomic data from individuals spanning the clinical spectrum of AD, we highlight the importance of post-translational modifications for early cognitive and pathological changes.

Organ aging signatures in the plasma proteome track health and disease.

Animal studies show aging varies between individuals as well as between organs within an individual1-4, 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.

Intrinsic Functional Connectivity is Organized as Three Interdependent Gradients.

The intrinsic functional architecture of the brain supports moment-to-moment maintenance of an internal model of the world. We hypothesized and found three interdependent architectural gradients underlying the organization of intrinsic functional connectivity within the human cerebral cortex. We used resting state fMRI data from two samples of healthy young adults (N's = 280 and 270) to generate functional connectivity maps of 109 seeds culled from published research, estimated their pairwise similarities, and multidimensionally scaled the resulting similarity matrix. We discovered an optimal three-dimensional solution, accounting for 98% of the variance within the similarity matrix. The three dimensions corresponded to three gradients, which spatially correlate with two functional features (external vs. internal sources of information; content representation vs. attentional modulation) and one structural feature (anatomically central vs. peripheral) of the brain. Remapping the three dimensions into coordinate space revealed that the connectivity maps were organized in a circumplex structure, indicating that the organization of intrinsic connectivity is jointly guided by graded changes along all three dimensions. Our findings emphasize coordination between multiple, continuous functional and anatomical gradients, and are consistent with the emerging predictive coding perspective.