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Proteomic Signatures of Vulnerability Across Late-Life Depression, Frailty, and Neurodegeneration
Mollica A, Leccisotti I, Moretti MC, Bonfitto I, Laurello R, Carapellese M, De Giorgi A, Altamura M et al.. Preprints.org, 2026-10-20
Topic: Genetics and APOE
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.
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APA 7th
Mollica, A., Leccisotti, I., Moretti, M. C., Bonfitto, I., Laurello, R., Carapellese, M., et al. (2026). Proteomic Signatures of Vulnerability Across Late-Life Depression, Frailty, and Neurodegeneration. Preprints.org. https://doi.org/10.20944/preprints202610.1843.v1
Vancouver
Mollica A, Leccisotti I, Moretti MC, Bonfitto I, Laurello R, Carapellese M, et al. Proteomic Signatures of Vulnerability Across Late-Life Depression, Frailty, and Neurodegeneration. Preprints.org. 2026. doi:10.20944/preprints202610.1843.v1.
BibTeX
@article{mollica2026-c402a472,
author = {Mollica, A. and Leccisotti, I. and Moretti, M. C. and Bonfitto, I. and Laurello, R. and Carapellese, M. and De Giorgi, A. and Altamura, M. and others},
title = {{Proteomic Signatures of Vulnerability Across Late-Life Depression, Frailty, and Neurodegeneration}},
journal = {Preprints.org},
year = {2026},
doi = {10.20944/preprints202610.1843.v1},
url = {https://doi.org/10.20944/preprints202610.1843.v1}
}
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Key findings
- 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.
- 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.
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Study details
- Evidence strengthLow
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 21 on the same rubric, but non-peer-reviewed sources are capped at 16, so it shows as 16. Scored zero for study design, sample size, effect reported, studied in people and randomized / blinded because the record does not state it. We have no data on times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record and multicenter collaboration, so those were left out: it earned 13 of the 62 points we could judge it on, which is 21 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 2 / 10 | Tier 4 — not a peer-reviewed journal (Preprints.org) |
| Journal's citation record | 0 / 4 | Not a journal article, so the journal's record does not count |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 4 / 10 | Preprint — not yet peer-reviewed. Hosted on a preprint server. |
| How recent | 5 / 5 | 2026 — within 1 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomized / blinded | 0 / 2 | No randomization or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multicenter collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 1 / 2 | Not in PubMed, but has a DOI |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 13 / 62 | Scored on 12 of 20 parts. We have no data for the rest, so they are left out: 13 of the 62 points we could judge it on is 21 out of 100. |
| Total | 21 / 100 | Capped to 16 because this is not a peer-reviewed article. |
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