Brain‐peripheral proteome crosstalk in Alzheimer's disease with and without diabetes mellitus

BACKGROUND: Although considerable research has investigated diabetes mellitus (DM) as a risk factor for Alzheimer's disease (AD) dementia, the mechanistic understanding of the associations between peripheral and central biological processes in AD and AD within DM remains limited. METHODS: We performed tandem mass tag-based phosphoproteome profiling on postmortem prefrontal cortex (n = 191), deltoid muscle (n = 191), and antemortem serum (n = 96) from older adults with/without pathologic AD and with/without DM (DM/NDM). RESULTS: We observed significant brain-muscle and brain-serum correlations in phosphorylated and unphosphorylated peptides. Among individuals with DM, 59 were with AD and 36 were without. Among NDM, 63 were with AD and 33 were without. In a differential expression analysis, muscle phosphorylated seryl-tRNA synthetase 2 (SARS2)-S126 was significantly expressed in pathologic AD, whereas relative abundance of serum alpha-2-HS-glycoprotein (AHSG)-S346 and insulin-like growth factor binding protein 2 (IGFBP2)-S142 showed marginal expression for AD within the DM strata. CONCLUSIONS: Elucidating central and peripheral proteome crosstalk is valuable for uncovering potential AD biomarkers in accessible (peripheral) biospecimens. HIGHLIGHTS: We profiled peptides in brain, muscle, and serum biosamples. The study design allowed discovery of diabetes-associated peptides in Alzheimer's disease (AD). Strong brain-muscle, but weaker brain-serum peptide correlations were identified. Muscle seryl-tRNA synthetase 2-S126 was linked to AD pathology. Serum insulin-like growth factor binding protein 2-S142 and alpha-2-HS-glycoprotein-S346 were linked to AD in persons with diabetes.