Home › Research › Vascular contributions

Apoptosis protein markers in comorbid type 2 diabetes mellitus and depression; relationships with cognitive performance, incident dementia, and white matter hyperintensities

Sofia E. Perfetto, Myuri T. Ruthirakuhan, Yuen Yan Wong, Si Won Ryoo, Celine H.L. Huang, Fan Fan, Meghan J. Chenoweth, Sean M. Nestor et al.. Journal of Affective Disorders, 2026-08-05

This page is alzhub.org's plain-English summary of a published study, not the paper itself. It is generated from the record we hold for this study, sourced and linked below — check the original for the full text and methods.

50/100

✓ Peer-reviewed alzhub usefulness score 50 out of 100. Vascular contributions

Topic: Brain proteins, microglia and lab models

Plain-language summary

Type 2 diabetes mellitus (T2DM) and major depressive disorder (MDD) are reciprocal risk factors, and both elevate dementia risk. Dysregulation of programmed cell death is implicated in T2DM, MDD, and neurodegeneration, but proteomic markers of apoptosis have yet to be studied as dementia predictors in people with T2DM and/or MDD. This study examines apoptosis markers in comorbid T2DM and MDD, and their associations with cognitive, dementia, and neuroimaging outcomes. The retrospective sample (n = 15,765) consisted of UK Biobank participants (MDD only n = 1230; T2DM only n = 3644; comorbid T2DM + MDD n = 721). Individuals with T2DM + MDD comorbidity had poorer cognitive performance, and a higher 15-year dementia incidence (HR = 4.44, 95% CI = [3.23,6.11]). Among 60 apoptosis-related proteins identified by Kyoto Encyclopedia of Genes and Genomes pathway enrichment, 41 were significantly up-regulated in comorbid T2DM + MDD relative to controls, and 4 were higher in the comorbid group than both T2DM alone and MDD alone. Tumor necrosis factor ligand superfamily member 10 (TNFSF10), growth arrest and DNA damage-inducible protein GADD45 beta, tumor necrosis factor ligand superfamily member 6, and RAC-gamma serine/threonine-protein kinase were associated with dementia risk. Nine proteins (e.g. apoptosis-inducing factor 1, mitochondrial, caspase-2, mitogen-activated protein kinase kinase kinase 5, TNFSF10), were associated with white matter hyperintensity volumes in comorbid T2DM + MDD after FDR correction, but none were associated with cognitive performance, atrophy, or white matter microstructural changes. These findings identify peripheral apoptosis markers that were further elevated in comorbid T2DM + MDD compared to either alone, pointing to an important pathophysiological element underlying adverse outcomes in the context of mood and metabolic comorbidity.

What this study adds

Evidence grade: Low

The record lists 15,765 participants. In this large UK Biobank sample, people with both type 2 diabetes and depression had poorer cognitive performance and a higher 15-year dementia incidence, and several apoptosis-related proteins were linked to dementia risk. Reported effect size: HR = 4.44.

Taken from this record’s own fields, not from reading the paper. The grade is assigned from the abstract’s wording; what that means.

Cite this study APA, Vancouver, BibTeX · download .bib or .ris

APA 7th

Perfetto, S. E., Ruthirakuhan, M. T., Wong, Y. Y., Ryoo, S. W., Huang, C. H., Fan, F., et al. (2026). Apoptosis protein markers in comorbid type 2 diabetes mellitus and depression; relationships with cognitive performance, incident dementia, and white matter hyperintensities. Journal of Affective Disorders. https://doi.org/10.1016/j.jad.2026.122353

Vancouver

Perfetto SE, Ruthirakuhan MT, Wong YY, Ryoo SW, Huang CH, Fan F, et al. Apoptosis protein markers in comorbid type 2 diabetes mellitus and depression; relationships with cognitive performance, incident dementia, and white matter hyperintensities. Journal of Affective Disorders. 2026. doi:10.1016/j.jad.2026.122353. PMID: 42556583.

BibTeX

@article{perfetto2026-42556583,
  author  = {Perfetto, Sofia E. and Ruthirakuhan, Myuri T. and Wong, Yuen Yan and Ryoo, Si Won and Huang, Celine H.L. and Fan, Fan and Chenoweth, Meghan J. and Nestor, Sean M. and others},
  title   = {{Apoptosis protein markers in comorbid type 2 diabetes mellitus and depression; relationships with cognitive performance, incident dementia, and white matter hyperintensities}},
  journal = {Journal of Affective Disorders},
  year    = {2026},
  doi     = {10.1016/j.jad.2026.122353},
  pmid    = {42556583},
  url     = {https://doi.org/10.1016/j.jad.2026.122353}
}

Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.

How to read this study

Design: our record does not state a study design, so check the methods section of the original before weighing the result.
Size: the record lists 15,765 participants. Ask whether that is enough for the question, and who they were.
Effect: the record reports “HR = 4.44”. A statistically significant result can still be small in daily life.

What the evidence grade means here

This page is graded low. alzhub.org assigns the grade automatically from keywords in the abstract, not from reading the paper. Low means the abstract matched neither pattern. It is the default label, and it does not mean the work is poor; many sound lab and imaging papers land here. It can add at most 5 of the 100 points in the study score, and it is a label about design, not a verdict on whether the findings are true.

New to reading papers? Six questions to ask of any Alzheimer’s study · how we score.

Key findings

Among 60 apoptosis-related proteins identified by Kyoto Encyclopedia of Genes and Genomes pathway enrichment, 41 were significantly up-regulated in comorbid T2DM + MDD relative to controls, and 4 were higher in the comorbid group than both T2DM alone and MDD alone.
Tumor necrosis factor ligand superfamily member 10 (TNFSF10), growth arrest and DNA damage-inducible protein GADD45 beta, tumor necrosis factor ligand superfamily member 6, and RAC-gamma serine/threonine-protein kinase were associated with dementia risk.
Nine proteins (e.g. apoptosis-inducing factor 1, mitochondrial, caspase-2, mitogen-activated protein kinase kinase kinase 5, TNFSF10), were associated with white matter hyperintensity volumes in comorbid T2DM + MDD after FDR correction, but none were associated with cognitive performance, atrophy, or white matter microstructural changes.
These findings identify peripheral apoptosis markers that were further elevated in comorbid T2DM + MDD compared to either alone, pointing to an important pathophysiological element underlying adverse outcomes in the context of mood and metabolic comorbidity.

Why it matters

In this large UK Biobank sample, people with both type 2 diabetes and depression had poorer cognitive performance and a higher 15-year dementia incidence, and several apoptosis-related proteins were linked to dementia risk. The study identifies proteins that may help predict dementia in this group, but it does not test any treatment or show that changing these proteins affects dementia risk.

Study details

Participants15,765
Effect sizeHR = 4.44
Evidence strengthLow

How this study scored 50/100

Published in a peer-reviewed journal. Scored zero for study design and randomized / blinded because the record does not state it.

Component	Points	Why
Journal tier	7 / 10	Tier 3 — peer-reviewed journal (Journal of Affective Disorders)
Journal's citation record	3 / 4	Journal of Affective Disorders: journal h-index 306 (OpenAlex, 2026-10-29)
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	10 / 10	Peer-reviewed. Published as an article in a named peer-reviewed journal.
How recent	5 / 5	2026 — within 1 year(s) of the newest study here
Sample size	4 / 4	15,765 participants
Effect reported	3 / 3	Effect reported with a statistic (interval, p-value, ratio or similar)
Studied in people	3 / 3	Studied in people (participant count stated)
Randomized / blinded	0 / 2	No randomization or blinding stated — scores zero (not stated in the record — scored 0)
Times cited	1 / 7	Cited 1 times (OpenAlex, 2026-10-10)
Citations per year	0 / 5	0.5 citations a year over 2 year(s) since 2026
Impact for its field and year	3 / 6	Cited 4.7× the average for papers of its field and year (OpenAlex FWCI)
Cited by studies here	0 / 6	No other study in this library cites it
Still being cited	0 / 4	Cited 1 times in 2024–2026 (2026 still in progress; OpenAlex)
Senior author's track record	2 / 4	Last-listed author Walter Swardfager: h-index 47 (OpenAlex, whole career)
Institution's track record	2 / 3	University of Toronto: institution h-index 1,923 (OpenAlex)
Multicenter collaboration	2 / 3	OpenAlex lists 6 institution(s) in 3 countries
Indexed in PubMed	2 / 2	Indexed in PubMed (PMID 42556583)
Free to read	2 / 2	Free to read
Total	50 / 100	—

What each of these 20 components measures, and what this score is not →

Read the original

Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).

Studies in the library that share something with this one. The line above each title says what.

Studies this one cites

Referenced by this study and also in the alzhub library, so you can read them here.

Related studies in Vascular contributions from nearby years

Also tagged “precursor”

1,337 studies in the library carry the topic tag “precursor”; these are this study's neighbours in a fixed, alphabetical-by-hash tour of them, not the closest in content. All 1,337 tagged studies.

Studies sharing this one's topic tags

Similar studies

More on Vascular contributions

See all studies in Vascular contributions →