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Dysfunctionally phosphorylated type 1 insulin receptor substrate in neural-derived blood exosomes of preclinical Alzheimer's disease
Kapogiannis D, Boxer A, Schwartz JB, Abner EL, Biragyn A, Masharani U, Frassetto L, Petersen RC et al.. FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2014-10-23
Topic: Brain proteins, microglia and lab models
Insulin resistance causes diminished glucose uptake in similar regions of the brain in Alzheimer's disease (AD) and type 2 diabetes mellitus (DM2). Brain tissue studies suggested that insulin resistance is caused by low insulin receptor signaling attributable to its abnormal association with more phospho (P)-serine-type 1 insulin receptor substrate (IRS-1) and less P-tyrosine-IRS-1. Plasma exosomes enriched for neural sources by immunoabsorption were obtained once from 26 patients with AD, 20 patients with DM2, 16 patients with frontotemporal dementia (FTD), and matched case control subjects. At 2 time points, they were obtained from 22 others when cognitively normal and 1 to 10 yr later when diagnosed with AD. Mean exosomal levels of extracted P-serine 312-IRS-1 and P-pan-tyrosine-IRS-1 by ELISA and the ratio of P-serine 312-IRS-1 to P-pan-tyrosine-IRS-1 (insulin resistance factor, R) for AD and DM2 and P-serine 312-IRS-1 and R for FTD were significantly different from those for case control subjects. The levels of R for AD were significantly higher than those for DM2 or FTD. Stepwise discriminant modeling showed correct classification of 100% of patients with AD, 97.5% of patients with DM2, and 84% of patients with FTD. In longitudinal studies of 22 patients with AD, exosomal levels of P-serine 312-IRS-1, P-pan-tyrosine-IRS-1, and R were significantly different 1 to 10 yr before and at the time of diagnosis compared with control subjects. Insulin resistance reflected in R values from this blood test is higher for patients with AD, DM2, and FTD than case control subjects; higher for patients with AD than patients with DM2 or FTD; and accurately predicts development of AD up to 10 yr prior to clinical onset.
Key findings
- Brain tissue studies suggested that insulin resistance is caused by low insulin receptor signaling attributable to its abnormal association with more phospho (P)-serine-type 1 insulin receptor substrate (IRS-1) and less P-tyrosine-IRS-1.
- Mean exosomal levels of extracted P-serine 312-IRS-1 and P-pan-tyrosine-IRS-1 by ELISA and the ratio of P-serine 312-IRS-1 to P-pan-tyrosine-IRS-1 (insulin resistance factor, R) for AD and DM2 and P-serine 312-IRS-1 and R for FTD were significantly different from those for case control subjects.
- The levels of R for AD were significantly higher than those for DM2 or FTD.
- In longitudinal studies of 22 patients with AD, exosomal levels of P-serine 312-IRS-1, P-pan-tyrosine-IRS-1, and R were significantly different 1 to 10 yr before and at the time of diagnosis compared with control subjects.
Why it matters
This study found that levels of a dysfunctional insulin receptor substrate in neural-derived blood exosomes differed in Alzheimer's disease and could be detected 1 to 10 years before diagnosis in a small longitudinal group. It is a biomarker study for possible early detection, not a treatment, cure, or prevention.
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Study details
- Study designlongitudinal study
- Participants26
- Effect size97.5%
- Evidence strengthModerate
How this study scored 67/100
Published in a peer-reviewed journal, and it is a longitudinal study following the same people over time. Scored zero for randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (FASEB journal : official publication of the Federation of American Societies for Experimental Biology) |
| Journal's citation record | 3 / 4 | The FASEB Journal: journal h-index 401 (OpenAlex, 2026-10-29) |
| Study design | 7 / 12 | A longitudinal study following the same people over time |
| Strength of evidence | 3 / 5 | Rated “moderate” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 1 / 5 | 2015 — within 20 year(s) of the newest study here |
| Sample size | 1 / 4 | 26 participants |
| Effect reported | 2 / 3 | Effect reported as a number, without an interval or test |
| Studied in people | 3 / 3 | Studied in people (participant count stated) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 6 / 7 | Cited 348 times (OpenAlex, 2026-10-10) |
| Citations per year | 4 / 5 | 26.8 citations a year over 13 year(s) since 2015 |
| Impact for its field and year | 4 / 6 | Cited 14.4× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 3 / 6 | Cited by 10 other studies in this library |
| Still being cited | 3 / 4 | Cited 59 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 4 / 4 | Last-listed author Edward J. Goetzl: h-index 106 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | University of California, San Francisco: institution h-index 1,915 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 6 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 25342129) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 67 / 100 | — |
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Read the original
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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's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
APA 7th
Kapogiannis, D., Boxer, A., Schwartz, J. B., Abner, E. L., Biragyn, A., Masharani, U., et al. (2015). Dysfunctionally phosphorylated type 1 insulin receptor substrate in neural-derived blood exosomes of preclinical Alzheimer's disease. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. https://doi.org/10.1096/fj.14-262048
Vancouver
Kapogiannis D, Boxer A, Schwartz JB, Abner EL, Biragyn A, Masharani U, et al. Dysfunctionally phosphorylated type 1 insulin receptor substrate in neural-derived blood exosomes of preclinical Alzheimer's disease. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2015. doi:10.1096/fj.14-262048. PMID: 25342129.
BibTeX
@article{kapogiannis2015-25342129,
author = {Kapogiannis, D. and Boxer, A. and Schwartz, J. B. and Abner, E. L. and Biragyn, A. and Masharani, U. and Frassetto, L. and Petersen, R. C. and others},
title = {{Dysfunctionally phosphorylated type 1 insulin receptor substrate in neural-derived blood exosomes of preclinical Alzheimer's disease}},
journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology},
year = {2015},
doi = {10.1096/fj.14-262048},
pmid = {25342129},
url = {https://doi.org/10.1096/fj.14-262048}
}
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