Cerebrospinal fluid APOE levels: an endophenotype for genetic studies for Alzheimer's disease
Cruchaga C, Kauwe JS, Nowotny P, Bales K, Pickering EH, Mayo K, Bertelsen S, Hinrichs A et al.. Human molecular genetics, 2012-07-20
Topic: Genetics and APOE
The apolipoprotein E (APOE) genotype is the major genetic risk factor for Alzheimer's disease (AD). We have access to cerebrospinal fluid (CSF) and plasma APOE protein levels from 641 individuals and genome-wide genotyped data from 570 of these samples. The aim of this study was to test whether CSF or plasma APOE levels could be a useful endophenotype for AD and to identify genetic variants associated with APOE levels. We found that CSF (P = 8.15 × 10(-4)) but not plasma (P = 0.071) APOE protein levels are significantly associated with CSF Aβ(42) levels. We used Mendelian randomization and genetic variants as instrumental variables to confirm that the association of CSF APOE with CSF Aβ(42) levels and clinical dementia rating (CDR) is not because of a reverse causation or confounding effect. In addition the association of CSF APOE with Aβ(42) levels was independent of the APOE ε4 genotype, suggesting that APOE levels in CSF may be a useful endophenotype for AD. We performed a genome-wide association study to identify genetic variants associated with CSF APOE levels: the APOE ε4 genotype was the strongest single-genetic factor associated with CSF APOE protein levels (P = 6.9 × 10(-13)). In aggregate, the Illumina chip single nucleotide polymorphisms explain 72% of the variability in CSF APOE protein levels, whereas the APOE ε4 genotype alone explains 8% of the variability. No other genetic variant reached the genome-wide significance threshold, but nine additional variants exhibited a P-value <10(-6). Pathway mining analysis indicated that these nine additional loci are involved in lipid metabolism (P = 4.49 × 10(-9)).
Key findings
- The aim of this study was to test whether CSF or plasma APOE levels could be a useful endophenotype for AD and to identify genetic variants associated with APOE levels.
- We found that CSF (P = 8.15 × 10(-4)) but not plasma (P = 0.071) APOE protein levels are significantly associated with CSF Aβ(42) levels.
- In addition the association of CSF APOE with Aβ(42) levels was independent of the APOE ε4 genotype, suggesting that APOE levels in CSF may be a useful endophenotype for AD.
- We performed a genome-wide association study to identify genetic variants associated with CSF APOE levels: the APOE ε4 genotype was the strongest single-genetic factor associated with CSF APOE protein levels (P = 6.9 × 10(-13)).
- Pathway mining analysis indicated that these nine additional loci are involved in lipid metabolism (P = 4.49 × 10(-9)).
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Study details
- Participants641
- Evidence strengthLow
How this study scored 45/100
Published in a peer-reviewed journal. Scored zero for study design, effect reported and randomised / blinded because the record does not state it. We have no data on journal's citation record, 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 multi-centre collaboration, so those were left out: it earned 26 of the 58 points we could judge it on, which is 45 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Human molecular genetics) |
| Journal's citation record | — / 4 | No journal record from OpenAlex — left out of this score |
| 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 | 1 / 5 | 2012 — within 20 year(s) of the newest study here |
| Sample size | 2 / 4 | 641 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 | 0 / 2 | No randomisation 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 |
| Multi-centre collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 22821396) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 26 / 58 | Scored on 11 of 20 parts. We have no data for the rest, so they are left out: 26 of the 58 points we could judge it on is 45 out of 100. |
| Total | 45 / 100 | — |
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APA 7th
Cruchaga, C., Kauwe, J. S., Nowotny, P., Bales, K., Pickering, E. H., Mayo, K., et al. (2012). Cerebrospinal fluid APOE levels: an endophenotype for genetic studies for Alzheimer's disease. Human molecular genetics. https://doi.org/10.1093/hmg/dds296
Vancouver
Cruchaga C, Kauwe JS, Nowotny P, Bales K, Pickering EH, Mayo K, et al. Cerebrospinal fluid APOE levels: an endophenotype for genetic studies for Alzheimer's disease. Human molecular genetics. 2012. doi:10.1093/hmg/dds296. PMID: 22821396.
BibTeX
@article{cruchaga2012-22821396,
author = {Cruchaga, C. and Kauwe, J. S. and Nowotny, P. and Bales, K. and Pickering, E. H. and Mayo, K. and Bertelsen, S. and Hinrichs, A. and others},
title = {{Cerebrospinal fluid APOE levels: an endophenotype for genetic studies for Alzheimer's disease}},
journal = {Human molecular genetics},
year = {2012},
doi = {10.1093/hmg/dds296},
pmid = {22821396},
url = {https://doi.org/10.1093/hmg/dds296}
}