Molecular biosignatures of cognitive impairment in late-life depression and alzheimer's disease

Abstract

Background: The biological mechanisms underlying cognitive impairment and the increased risk of dementia in late-life depression (LLD) are complex and likely involve abnormalities in multiple pathways reflected in specific biomarkers. Our aim was to evaluate blood-based evidence for biological pathways associated with cognitive impairment in older adults with LLD. Methods: we used a data-driven comprehensive proteomic analysis (multiplex immunoassay including 242 proteins), along with measures of structural brain abnormalities (gray matter atrophy and white matter hyperintensity volume via magnetic resonance imaging), and brain amyloid-β (Aβ) deposition (PiBPET). We used a random intercept model with variable selection to detect the proteins differentially expressed related to cognitive impairment, gray matter atrophy), cerebrovascular burden, and brain Aβ deposition. False discovery rate was set at 0.30 and statistical significance at p-value < 0.05. Results: Cognitive impairment in LLD was associated with differential expression of 24 proteins related mainly to the regulation of immune-inflammatory activity, intracellular signaling, cell survival and protein and lipid homeostasis. Individuals with LLD+MCI also showed greater white matter hyperintensity burden compared with LLD+NC (P= 0.015), and no significant differences in gray matter volume or brain Aβ deposition. Conclusions: Cognitive impairment in LLD seems to be related to greater cerebrovascular disease along with abnormalities in immune-inflammatory control, cell survival, intracellular signaling, protein and lipid homeostasis, and clotting processes. These results suggest that individuals with LLD and cognitive impairment may be more vulnerable to accelerated brain aging and shed light on possible mediators of their elevated risk for progression to dementia.