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Plasma lipidome dysregulation in frontotemporal dementia reveals shared, genotype‐specific, and severity‐linked alterations
Yohannes Abere Ambaw, Peter Alexander Ljubenkov, Shubham Singh, Abdi Hamed, Sebastian Boland, Adam L. Boxer, Tobias C. Walther, Robert V. Farese. Alzheimer s & Dementia, 2025-09-01
Topic: Brain proteins, microglia and lab models
FTD subjects exhibited increased plasma levels of gangliosides (GM3(d18:1_16:0), GM3(d18:1_24:1)), ceramide Cer(d18:1_23:0), and select polyunsaturated triacylglycerols. In contrast, phosphatidylethanolamine (PE(18:0_24:0) and sphingomyelin (SM(38:0) were reduced. Subtype-specific changes included elevated glucosylsphingosine (GlcSph(d18:1) in GRN carriers, reduced SM(34:1) in C9orf72, and decreased TG(16:0_18:1_20:3) in MAPT carriers. GM3(d18:1_16:0) was consistently elevated across all subtypes. Furthermore, the levels of these lipids correlated with disease severity. Our findings suggest that specific plasma lipid changes, notably several sphingolipids, may be useful biomarkers for FTD disease or progression. HIGHLIGHTS: Plasma lipidomics reveals both shared and mutation-specific lipid alterations in frontotemporal dementia (FTD). Glucosylsphingosine is specifically elevated in FTD caused by GRN mutations and correlates with disease severity. The ganglioside GM3(d18:1_16:0) is consistently elevated across GRN, MAPT, and C9orf72 variants and correlates with disease severity. Plasma sphingolipids emerge as promising biomarkers for FTD diagnosis, subtype differentiation, and disease monitoring.
Key findings
- FTD subjects exhibited increased plasma levels of gangliosides (GM3(d18:1_16:0), GM3(d18:1_24:1)), ceramide Cer(d18:1_23:0), and select polyunsaturated triacylglycerols.
- In contrast, phosphatidylethanolamine (PE(18:0_24:0) and sphingomyelin (SM(38:0) were reduced.
- Subtype-specific changes included elevated glucosylsphingosine (GlcSph(d18:1) in GRN carriers, reduced SM(34:1) in C9orf72, and decreased TG(16:0_18:1_20:3) in MAPT carriers.
- GM3(d18:1_16:0) was consistently elevated across all subtypes.
- Furthermore, the levels of these lipids correlated with disease severity.
Why it matters
This study found shared and mutation-specific plasma lipid changes in frontotemporal dementia, including consistently elevated ganglioside GM3(d18:1_16:0) across GRN, MAPT and C9orf72 variants, with lipid levels correlating with disease severity. The authors propose these sphingolipids as promising biomarkers for diagnosis, subtype differentiation and disease monitoring, not as a treatment, cure or prevention.
Study details
- Evidence strengthLow
How this study scored 43/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Alzheimer s & Dementia) |
| Journal's citation record | 2 / 4 | Alzheimer s & Dementia: journal h-index 228 (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 | 4 / 5 | 2025 — within 3 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) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 2 / 7 | Cited 6 times (OpenAlex, 2026-10-10) |
| Citations per year | 1 / 5 | 2.0 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 3 / 6 | Cited 3.8× 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 | 1 / 4 | Cited 6 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 4 / 4 | Last-listed author Robert V. Farese: h-index 110 (OpenAlex, whole career) |
| Institution's track record | 3 / 3 | Harvard University: institution h-index 3,235 (OpenAlex) |
| Multi-centre collaboration | 1 / 3 | OpenAlex lists 3 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 40922380) |
| Free to read | 2 / 2 | Free to read |
| Total | 43 / 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).
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
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 names 8 authors; APA and Vancouver show the first six, BibTeX and the downloads carry all of them. Check the citation against the original before you use it.
APA 7th
Ambaw, Y. A., Ljubenkov, P. A., Singh, S., Hamed, A., Boland, S., Boxer, A. L., et al. (2025). Plasma lipidome dysregulation in frontotemporal dementia reveals shared, genotype‐specific, and severity‐linked alterations. Alzheimer s & Dementia. https://doi.org/10.1002/alz.70631
Vancouver
Ambaw YA, Ljubenkov PA, Singh S, Hamed A, Boland S, Boxer AL, et al. Plasma lipidome dysregulation in frontotemporal dementia reveals shared, genotype‐specific, and severity‐linked alterations. Alzheimer s & Dementia. 2025. doi:10.1002/alz.70631. PMID: 40922380.
BibTeX
@article{ambaw2025-40922380,
author = {Ambaw, Yohannes Abere and Ljubenkov, Peter Alexander and Singh, Shubham and Hamed, Abdi and Boland, Sebastian and Boxer, Adam L. and Walther, Tobias C. and Farese, Robert V.},
title = {{Plasma lipidome dysregulation in frontotemporal dementia reveals shared, genotype‐specific, and severity‐linked alterations}},
journal = {Alzheimer s \& Dementia},
year = {2025},
doi = {10.1002/alz.70631},
pmid = {40922380},
url = {https://doi.org/10.1002/alz.70631}
}
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