Clinical and molecular heterogeneity of Alzheimer disease (AD) is increasingly recognized as a major factor impacting the diagnosis, the design of therapeutic interventions and clinical trials, and therefore possibly delaying the development of effective treatments for AD. We sought to determine whether cross-omics integration reveals molecular profiles of AD with clinical and biological relevance. By leveraging cross-omics approaches, we integrated high-throughput transcriptomic, proteomic, metabolomic, and lipidomic profiles from AD and control cases from multiple cortical regions and cohorts. We identified four distinct molecular profiles in which a specific profile was associated with significantly higher Clinical Dementia Rating (CDR) at death, shorter survival after onset, more severe neurodegeneration and astrogliosis, and decreased levels of metabolomic profiles. Its molecular signatures show significant dysregulation of synaptic genes indicating neuron/synapse losses and dysfunction at later stages of AD, and present in multiple cortical regions. Among other molecules, we found that the expression of alpha-synuclein (SNCA) andSNAP25were downregulated in this profile. Overall, our results suggest that AD has a more prominent synaptic loss and dysfunction associated with worse cognition. These novel molecular findings open the possibility for new biomarkers for the molecular staging of AD and potential therapeutic targets to ameliorate cognitive decline and AD progression.
