A Novel Panel of Plasma Proteins Predicts Progression in Prodromal Alzheimer’s Disease

Abstract

Background: A cheap and minimum-invasive method for early identification of Alzheimer’s disease (AD) pathogenesis is key to disease management and the success of emerging treatments targeting the prodromal phases of the disease. Objective: To develop a machine learning-based blood panel to predict the progression from mild cognitive impairment (MCI) to dementia due to AD within a four-year time-to-conversion horizon. Methods: We created over one billion models to predict the probability of conversion from MCI to dementia due to AD and chose the best-performing one. We used Alzheimer’s Disease Neuroimaging Initiative (ADNI) data of 379 MCI individuals in the baseline visit, from which 176 converted to AD dementia. Results: We developed a machine learning-based panel composed of 12 plasma proteins (ApoB, Calcitonin, C-peptide, CRP, IGFBP-2, Interleukin-3, Interleukin-8, PARC, Serotransferrin, THP, TLSP 1-309, and TN-C), and which yielded an AUC of 0.91, accuracy of 0.91, sensitivity of 0.84, and specificity of 0.98 for predicting the risk of MCI patients converting to dementia due to AD in a horizon of up to four years. Conclusion: The proposed machine learning model was able to accurately predict the risk of MCI patients converting to dementia due to AD in a horizon of up to four years, suggesting that this model could be used as a minimum-invasive tool for clinical decision support. Further studies are needed to better clarify the possible pathophysiological links with the reported proteins.

Large-Scale Mendelian Randomization Study Reveals Circulating Blood-based Proteomic Biomarkers for Psychopathology and Cognitive Task Performance

“…However, circulating levels of ApoB have been associated with risk for Alzheimer’s disease 62,63 and age-related cognitive decline 64,65 . Similarly, we observed that increased levels of circulating PCMT1, which has been shown to be neuroprotective in animal models of cognitive aging 66 , were causally associated with better cognitive task performance.…”

“…For example, the apolipoprotein B receptor (APOBR) was the strongest cis-pQTL signal associated with cognitive task performance in the present study, and has not been previously reported in comparable studies. However, circulating levels of ApoB have been associated with risk for Alzheimer’s disease 38,39 and age-related cognitive decline 40,41 . Similarly, we observed that increased levels of circulating PCMT1, which has been shown to be neuroprotective in animal models of cognitive aging 42 , were causally associated with better cognitive task performance.…”

Proteomic Analysis of the Senescence-Associated Secretory Phenotype: GDF-15, IGFBP-2, and Cystatin-C Are Associated With Multiple Aging Traits

“…In addition, IGFBP-2 was found to mediate the relationship between RDW and mortality ( 42 ). IGFBP-2 has also been shown to be associated with early stages of Alzheimer’s disease progression ( 43 ). Our findings of adverse and beneficial trait associations with IGFBP-2 reflect the complicated nature of SASP and cellular senescence that can have different context-dependent effects.…”

Blood-Based Proteomic Profiling Identifies Potential Biomarker Candidates and Pathogenic Pathways in Dementia

“…CSF and plasma IGFBP-2 levels are elevated in AD, and plasma levels of IGFBP-2 are associated with smaller hippocampal volumes and brain atrophy [55][56][57][58][59]. Moreover, high plasma levels of IGFBP2 have been shown to predict the risk of MCI conversion to dementia [60][61][62][63].…”