This study evaluates plasma-based proteomic profiles for predicting amyloid positivity in adults with Down syndrome (DS) and examines the impact of apolipoprotein E ε4 (APOE ε4) on test performance. C Show more
This study evaluates plasma-based proteomic profiles for predicting amyloid positivity in adults with Down syndrome (DS) and examines the impact of apolipoprotein E ε4 (APOE ε4) on test performance. Cross-sectional data from 290 adults with DS were analyzed using single molecule array (SIMOA) technology to measure plasma amyloid beta (Aβ)42, Aβ40, neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), tau phosphorylated at threonine 181, and total tau. Amyloid burden was quantified using Pittsburgh Compound B and (18)F-florbetapir Aβ positron emission tomography. Support vector machine analyses were conducted with biomarkers as predictors and age, sex, and APOE ε4 carrier status as covariates. Age, GFAP, and NfL contributed the most to the model performance. The proteomic profile achieved an area under the curve (AUC) of 96% in models with and without APOE ε4. These findings suggest that plasma proteomic biomarkers can effectively identify amyloid positivity in adults with DS and may support clinical triage, monitoring, and selection for clinical trials, independent of APOE ε4 status. Show less
Preclinical data have shown that low levels of metabolites with anti-inflammatory properties may impact metabolic disease processes. However, the association between mid-life levels of such metabolite Show more
Preclinical data have shown that low levels of metabolites with anti-inflammatory properties may impact metabolic disease processes. However, the association between mid-life levels of such metabolites and long-term ASCVD risk is not known. We characterised the plasma metabolomic profile (1228 metabolites) of 1852 participants (58.1 ± 7.5 years old, 69.6% female, 43.6% self-identified as Black) enrolled in the Heart Strategies Concentrating on Risk Evaluation (Heart SCORE) study. Logistic regression was used to assess the impact of metabolite levels on ASCVD risk (nonfatal MI, revascularisation, and cardiac mortality). We additionally explored the effect of genetic variants neighbouring ASCVD-related genes on the levels of metabolites predictive of ASCVD events. The Atherosclerosis Risk in Communities (ARIC) study (n = 4790; 75.5 ± 5.1 years old, 57.4% female, 19.5% self-identified as Black) was used as an independent validation cohort. In fully adjusted models, alpha-ketobutyrate [AKB] (OR 0.62 [95% CI, 0.49-0.80]; p < 0.001), and 1-palmitoyl-2-linoleoyl-GPI [OR, 0.62, 95% CI, 0.47-0.83; p < 0.001], two metabolites in amino acid and phosphatidylinositol lipid pathways, respectively, showed a significant protective association with incident ASCVD risk in both Heart SCORE and ARIC cohorts. Three plasmalogens and a bilirubin derivative, whose levels were regulated by genetic variants neighbouring FADS1 and UGT1A1, respectively, exhibited a significant protective association with ASCVD risk in the Heart SCORE only. Higher mid-life levels of AKB and 1-palmitoyl-2-linoleoyl-GPI metabolites may be associated with lower risk late-life ASCVD events. Further research can determine the causality and therapeutic potential of these metabolites in ASCVD. This study was funded by the Pennsylvania Department of Health (ME-02-384). The department specifically disclaims responsibility for any analyses, interpretations, or conclusions. Additional funding was provided by National Institutes of Health (NIH) grant R01HL089292 and UL1 TR001857 (Steven Reis). Further, NIH funded R01HL141824 and R01HL168683 were used for the ARIC study validation (Bing Yu). Show less