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A novel Abeta isoform pattern in CSF reflects gamma-secretase inhibition in Alzheimer disease
Portelius E, Dean RA, Gustavsson MK, Andreasson U, Zetterberg H, Siemers E, Blennow K.. Alzheimer's research & therapy, 2010-03-29
Topic: Brain proteins, microglia and lab models
Introduction LY450139 (semagacestat) inhibits gamma-secretase, a key enzyme for generation of amyloid beta (Abeta), the peptide deposited in plaques in Alzheimer disease (AD). Previous data have shown that LY450139 lowers plasma Abeta, but has no clear effect on Abeta1-40 or Abeta1-42 levels in cerebrospinal fluid (CSF). By using targeted proteomics techniques, we recently identified several shorter Abeta isoforms, such as Abeta1-16, that in experimental settings increase during gamma-secretase inhibitor treatment, and thus may serve as sensitive biochemical indices of the treatment effect. Here, we test the hypothesis that these shorter Abeta isoforms may be biomarkers of gamma-secretase inhibitor treatment in clinical trials. Methods In a phase II clinical trial, 35 individuals with mild to moderate AD were randomized to placebo (n = 10) or LY450139 (100 mg (n = 15) or 140 mg (n = 10)) and underwent lumbar puncture at baseline and after 14 weeks of treatment. The CSF Abeta isoform pattern was analyzed with immunoprecipitation combined with MALDI-TOF mass spectrometry. Results The CSF levels of Abeta1-14, Abeta1-15, and Abeta1-16 showed a dose-dependent increase by 57% and 74%, 21% and 35%, and 30% and 67%, respectively in the 100-mg and 140-mg treatment groups. Abeta1-40 and Abeta1-42 were unaffected by treatment. Conclusions CSF Abeta1-14, Abeta1-15, and Abeta1-16 increase during gamma-secretase inhibitor treatment in AD, even at doses that do not affect Abeta1-42 or Abeta1-40, probably because of increased substrate availability of the C99 APP stub (APP beta-CTF) induced by gamma-secretase inhibition. These Abeta isoforms may be novel sensitive biomarkers to monitor the biochemical effect in clinical trials. Trial registration Clinical Trials.gov NCT00244322.
Key findings
- Previous data have shown that LY450139 lowers plasma Abeta, but has no clear effect on Abeta1-40 or Abeta1-42 levels in cerebrospinal fluid (CSF).
- Results The CSF levels of Abeta1-14, Abeta1-15, and Abeta1-16 showed a dose-dependent increase by 57% and 74%, 21% and 35%, and 30% and 67%, respectively in the 100-mg and 140-mg treatment groups.
Why it matters
In this phase II trial of 35 patients with mild to moderate Alzheimer's disease, the gamma-secretase inhibitor LY450139 (semagacestat) caused dose-dependent increases in shorter cerebrospinal fluid amyloid-beta isoforms (1-14, 1-15, and 1-16) but did not affect amyloid-beta 1-40 or 1-42. These shorter isoforms may serve as biomarkers of drug effect, but the study does not show any clinical benefit for treating Alzheimer's disease.
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Study details
- Participants35
- Evidence strengthHigh
How this study scored 51/100
Published in a peer-reviewed journal. Scored zero for study design and effect reported because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Alzheimer's research & therapy) |
| Journal's citation record | 1 / 4 | Alzheimer s Research & Therapy: journal h-index 146 (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 | 5 / 5 | Rated “high” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 1 / 5 | 2010 — within 20 year(s) of the newest study here |
| Sample size | 1 / 4 | 35 participants |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 3 / 3 | Studied in people (participant count stated) |
| Randomised / blinded | 1 / 2 | Randomised (as stated in the record) |
| Times cited | 4 / 7 | Cited 91 times (OpenAlex, 2026-10-10) |
| Citations per year | 2 / 5 | 5.1 citations a year over 18 year(s) since 2010 |
| Impact for its field and year | 3 / 6 | Cited 7.1× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 2 / 6 | Cited by 4 other studies in this library |
| Still being cited | 1 / 4 | Cited 3 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 4 / 4 | Last-listed author Kaj Blennow: h-index 220 (OpenAlex, whole career) |
| Institution's track record | 1 / 3 | University of Gothenburg: institution h-index 972 (OpenAlex) |
| Multi-centre collaboration | 1 / 3 | OpenAlex lists 2 institution(s) in 2 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 20350302) |
| Free to read | 2 / 2 | Free to read |
| Total | 51 / 100 | — |
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Read the original
- DOI: 10.1186/alzrt30
- PubMed: 20350302
- Original source →
- Free full text: Alzheimer s Research & Therapy →
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 7 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
Portelius, E., Dean, R. A., Gustavsson, M. K., Andreasson, U., Zetterberg, H., Siemers, E., et al. (2010). A novel Abeta isoform pattern in CSF reflects gamma-secretase inhibition in Alzheimer disease. Alzheimer's research & therapy. https://doi.org/10.1186/alzrt30
Vancouver
Portelius E, Dean RA, Gustavsson MK, Andreasson U, Zetterberg H, Siemers E, et al. A novel Abeta isoform pattern in CSF reflects gamma-secretase inhibition in Alzheimer disease. Alzheimer's research & therapy. 2010. doi:10.1186/alzrt30. PMID: 20350302.
BibTeX
@article{portelius2010-20350302,
author = {Portelius, E. and Dean, R. A. and Gustavsson, M. K. and Andreasson, U. and Zetterberg, H. and Siemers, E. and Blennow, K.},
title = {{A novel Abeta isoform pattern in CSF reflects gamma-secretase inhibition in Alzheimer disease}},
journal = {Alzheimer's research \& therapy},
year = {2010},
doi = {10.1186/alzrt30},
pmid = {20350302},
url = {https://doi.org/10.1186/alzrt30}
}
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