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

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.

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).

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.

Elucidating central and peripheral proteome crosstalk is valuable for uncovering potential AD biomarkers in accessible (peripheral) biospecimens.

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.