Serum protein markers along the Alzheimer's disease trajectory in the population-based longitudinal AGES Reykjavik study and their offsprings - Abstract: The incidence of Late Onset Alzheimer's Disease (LOAD) is rising as the world's population ages, making effective interventions for slowing or halting the disease progression one of the fastest growing unmet medical needs. With promising medications on the horizon, minimally invasive biomarkers such as plasma phosphorylated Tau (pTau)-217 can detect a prodromal stage prior to clinically presenting dementia which may aid in the implementation of LOAD precision medicine. However, not everyone with early amyloid pathology will progress to develop symptomatic LOAD nor at the same rate. New approaches are needed to identify additional molecular markers that can inform on the prodromal progression towards LOAD and shed light on its complex etiology. The proposed study will leverage unique datasets such as the deep circulating proteome (~10,500 proteins) including different proteoforms, rich genotype data and gene regulatory protein networks, all linked to Aβ and pTau-217 plasma levels, changes in brain volumes and cognitive functioning, and new-onset LOAD from the prospective population-based cohort AGES Reykjavik study (n = 5,377 at baseline, including 3,215 with follow-up measurements). Furthermore, by including an offspring cohort of AGES-RS from LOAD parents, the proposed study will span two generations. The findings will be investigated in the context of APOE-ε4 carrier status, to follow-up on the apparent dependence or independence of circulating proteins from the high-risk genotype for links to incident LOAD. Four specific aims are proposed: In Aim 1, the temporal changes in the circulating proteome along the LOAD-related trajectory will be identified. In Aim 2, a high-throughput Seer Proteograph mass spectrometry approach will be deployed to orthogonally examine previously established serum protein relationships with incident LOAD as well as identify novel proteoform links to LOAD. In Aim 3, a dense genotype imputation and recently acquired whole-genome sequencing data will be used to determine the mechanisms underlying APOE-ε4 and LOAD related proteome shifts. The results of Aims 1-3 will offer Aim 4 with a panel of unique and robust protein biomarker candidates for further validation in detecting early signs of cognitive decline, as assessed in a younger population enriched for offspring of LOAD parents. The proposed project is significant for many reasons including for instance: i) the depth of the genotype, proteome, and clinical data in a well-established prospective population-based cohort. ii) The use of longitudinal data to evaluate both intra-individual and inter-individual variations in circulating protein levels over time on LOAD-related outcomes provides unique prospects for robust biomarker findings. Finally, iii) the proposed study will use a novel and recently developed protein detection technique to identify protein isoforms that may be linked to incident LOAD. In conclusion, the proposed study findings will set the framework for the development of robust protein biomarkers that represent different stages of the LOAD trajectory, allowing for early detection and intervention management when effective primary prevention treatments become available.
