Preprints.org · Oct 20, 2026

Proteomic Signatures of Vulnerability Across Late-Life Depression, Frailty, and Neurodegeneration

By Mollica A, Leccisotti I, Moretti MC et al.

Late-life depression (LLD) is increasingly recognized as a complex multisystem disorder associated with accelerated biological aging, impaired physiological resilience, frailty, and an increased risk of cognitive decline and dementia. Although growing evidence supports the close relationship between depression, frailty, and neurodegeneration, the molecular mechanisms underlying this continuum remain incompletely understood. In particular, conventional clinical and imaging biomarkers capture established disease but provide limited insight into the systemic biological processes that precede neurodegeneration. Proteomics has emerged as a powerful systems biology approach capable of characterizing the dynamic molecular networks involved in aging, neuropsychiatric disorders, and neurodegenerative diseases. Recent advances in high-throughput mass spectrometry have identified alterations in proteins associated with chronic inflammation, complement activation, mitochondrial dysfunction, oxidative stress, lipid metabolism, synaptic integrity, neurotrophic signaling, and cellular senescence across LLD, frailty, cognitive impairment, and Alzheimer's disease (AD). These convergent proteomic signatures suggest that these conditions may share common biological pathways reflecting progressive loss of physiological resilience rather than independent pathological entities. In this review, we examine the current evidence supporting shared proteomic mechanisms linking LLD, frailty, cognitive frailty (CF), and neurodegeneration. We discuss the potential integration of large-scale proteomic profiling with established AD biomarkers within the AT(N) framework to improve biological characterization, early risk stratification, and prediction of cognitive decline. Particular emphasis is placed on CF as a transitional and potentially modifiable phenotype in which systemic molecular dysregulation precedes overt neurodegeneration. By integrating evidence from geroscience, neuropsychiatry, and proteomics, we propose that proteomic profiling can redefine LLD and frailty as manifestations of a common biological vulnerability continuum. This systems-level perspective may facilitate the identification of individuals at high risk for dementia, support the development of multimodal biomarker panels, and advance precision neuropsychiatry through earlier diagnosis and personalized preventive interventions.

doi.org/10.20944/preprints202610.1843.v1Open accessMechanisms