IDENTIFICATION OF A PLASMA PROTEIN SIGNATURE FOR ALZHEIMER’S DISEASE

A blood-based diagnostic test for Alzheimer's disease (AD) is desperately needed to help confirm disease diagnosis, monitor disease progression and effectiveness of treatments. We have used a Sequential Window Acquisition of all Theoretical fragment ion mass spectrometry (SWATH-MS)-based plasma proteomics approach in a small discovery cohort to identify a panel of proteins able to discriminate individuals with AD and healthy age-matched controls. Our discovery cohort was selected from our well-characterised Leeds cohort (30 AD vs 30 age-matched controls). The samples were immunodepleted of highly abundant plasma proteins, digested with trypsin and analysed by liquid chromatography-MS. Indexed retention time (iRT) peptides were used as retention time anchor points as reference standards for normalisation. Quantitation was carried out using targeted data extraction from the SWATH maps based on the spectral library produced using the iRT peptides. Fragment ion chromatographs for each peptide of interest were extracted from the SWATH-MS maps and their abundances compared between the different conditions for analysis of peptide expression. The false discovery rate was set to 1% and a filter applied across all samples to ensure only the most abundant peptides were used for discrimination, we also removed 20 proteins, linked to the immunodepletion step. We identified over 900 proteins in total, 127 of which were significantly altered in AD compared to age-matched controls (p<0.05). Receiver operating characteristic (ROC) analysis demonstrated a significant discrimination between the AD and control samples with 91% accuracy (90% sensitivity, 92% specificity, area under the curve = 0.90). Using SWATH-MS we have identified a panel of plasma proteins for potential use as a blood-based diagnostic test for AD. This test will offer many advantages to more expensive and time-consuming tests such as cerebrospinal fluid sampling and magnetic resonance imaging. While several of the proteins identified have been previously linked to AD, some of the most discriminatory proteins have not previously been identified, offering up new potential targets to investigate in the pathogenesis of AD.