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BACKGROUND: Previous studies showed alterations in protein expression in the brain tissue of individuals with Alzheimer's disease (AD). However, despite a link between AD dementia and diabetes mellitus (DM), little to no studies examined cross-tissue proteome to detect central-peripheral associations and the link with AD with/without DM.

METHOD: We used data from the Rush Memory and Aging Project (MAP). AD status was determined using the NIA-AA pathology criteria. Participants were matched by DM status (self-reported medical history and/or the use of anti-diabetic medications). TMT-based Phosphoproteome profiling in postmortem human brain prefrontal cortex (N = 191) and deltoid muscle (N = 191) tissues and antemortem serum samples (N = 96) of older adults were measured.

RESULT: The mean (SD) death age was 89.9 (5.7), 65% were women, 64% met pathologic criteria for AD, and 50% had DM. 1,655 and 5,181 annotated phosphorylated and unphosphorylated peptides, respectively, overlapped between the brain and muscle tissues (-0.4610.824, 52="">

CONCLUSION: Overall, muscle peptides were mostly related to pathological AD, while serum peptides were more likely to be related to IR in AD. The crosstalk between central and peripheral peptide expression may be the first step in uncovering AD markers in distant tissues.