Data-driven analyses are increasingly valued in modern medicine. We integrate quantitative proteomics and transcriptomics from over 1000 post-mortem brains from six cohorts representing Alzheimer’s disease (AD), asymptomatic AD, Progressive Supranuclear Palsy (PSP), and control patients, from the Accelerating Medicines Partnership–Alzheimer’s Disease consortium. We define robust co-expression trajectories related to disease progression including early neuronal, microglial, astrocyte, and immune response modules, and later mRNA splicing and mitochondrial modules. The majority, but not all modules are conserved at the transcriptomic level, including module C3, which is only observed in proteome networks and enriched in MAPK signaling. Genetic risk variants are specifically enriched in modules changing early in disease and demonstrate that AD and PSP have distinct causal biological drivers at the pathway level, despite aspects of similar pathology, including synaptic loss and glial inflammatory changes. The conserved, high confidence proteomic changes enriched in genetic risk represent targets for drug discovery.
Swarup, V. et al. Identification of Conserved Proteomic Networks in Neurodegenerative Dementia ll ll Identification of Conserved Proteomic Networks in Neurodegenerative Dementia. CellReports 31, 107807 (2020).
Johnson, E. C. B. et al. Large-scale proteomic analysis of Alzheimer’s disease brain and cerebrospinal fluid reveals early changes in energy metabolism associated with microglia and astrocyte activation. Nat. Med. 1–12 (2020). doi:10.1038/s41591-020-0815-6
Developed in the Swarup Lab by Sam Morabito .