Immune response and endocytosis pathways are associated with the resilience against Alzheimer's disease
Tesi N, van der Lee SJ, Hulsman M, Jansen IE, Stringa N, van Schoor NM, Scheltens P, van der Flier WM et al.. Translational psychiatry, 2020-09-29
Topic: Amyloid, tau and blood-test diagnosis
Developing Alzheimer's disease (AD) is influenced by multiple genetic variants that are involved in five major AD-pathways. Per individual, these pathways may differentially contribute to the modification of the AD-risk. The pathways involved in the resilience against AD have thus far been poorly addressed. Here, we investigated to what extent each molecular mechanism associates with (i) the increased risk of AD and (ii) the resilience against AD until extreme old age, by comparing pathway-specific polygenic risk scores (pathway-PRS). We used 29 genetic variants associated with AD to develop pathway-PRS for five major pathways involved in AD. We developed an integrative framework that allows multiple genes to associate with a variant, and multiple pathways to associate with a gene. We studied pathway-PRS in the Amsterdam Dementia Cohort of well-phenotyped AD patients (N = 1895), Dutch population controls from the Longitudinal Aging Study Amsterdam (N = 1654) and our unique 100-plus Study cohort of cognitively healthy centenarians who avoided AD (N = 293). Last, we estimated the contribution of each pathway to the genetic risk of AD in the general population. All pathway-PRS significantly associated with increased AD-risk and (in the opposite direction) with resilience against AD (except for angiogenesis, p < 0.05). The pathway that contributed most to the overall modulation of AD-risk was β-amyloid metabolism (29.6%), which was driven mainly by APOE-variants. After excluding APOE variants, all pathway-PRS associated with increased AD-risk (except for angiogenesis, p < 0.05), while specifically immune response (p = 0.003) and endocytosis (p = 0.0003) associated with resilience against AD. Indeed, the variants in these latter two pathways became the main contributors to the overall modulation of genetic risk of AD (45.5% and 19.2%, respectively). The genetic variants associated with the resilience against AD indicate which pathways are involved with maintained cognitive functioning until extreme ages. Our work suggests that a favorable immune response and a maintained endocytosis pathway might be involved in general neuro-protection, which highlight the need to investigate these pathways, next to β-amyloid metabolism.
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APA 7th
Tesi, N., van der Lee, S. J., Hulsman, M., Jansen, I. E., Stringa, N., van Schoor, N. M., et al. (2020). Immune response and endocytosis pathways are associated with the resilience against Alzheimer's disease. Translational psychiatry. https://doi.org/10.1038/s41398-020-01018-7
Vancouver
Tesi N, van der Lee SJ, Hulsman M, Jansen IE, Stringa N, van Schoor NM, et al. Immune response and endocytosis pathways are associated with the resilience against Alzheimer's disease. Translational psychiatry. 2020. doi:10.1038/s41398-020-01018-7. PMID: 32994401.
BibTeX
@article{tesi2020-32994401,
author = {Tesi, N. and van der Lee, S. J. and Hulsman, M. and Jansen, I. E. and Stringa, N. and van Schoor, N. M. and Scheltens, P. and van der Flier, W. M. and others},
title = {{Immune response and endocytosis pathways are associated with the resilience against Alzheimer's disease}},
journal = {Translational psychiatry},
year = {2020},
doi = {10.1038/s41398-020-01018-7},
pmid = {32994401},
url = {https://doi.org/10.1038/s41398-020-01018-7}
}
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Key findings
- Here, we investigated to what extent each molecular mechanism associates with (i) the increased risk of AD and (ii) the resilience against AD until extreme old age, by comparing pathway-specific polygenic risk scores (pathway-PRS).
- We used 29 genetic variants associated with AD to develop pathway-PRS for five major pathways involved in AD.
- All pathway-PRS significantly associated with increased AD-risk and (in the opposite direction) with resilience against AD (except for angiogenesis, p < 0.05).
- The pathway that contributed most to the overall modulation of AD-risk was β-amyloid metabolism (29.6%), which was driven mainly by APOE-variants.
- After excluding APOE variants, all pathway-PRS associated with increased AD-risk (except for angiogenesis, p < 0.05), while specifically immune response (p = 0.003) and endocytosis (p = 0.0003) associated with resilience against AD.
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Study details
- Study designlongitudinal study
- Participants1,895
- Effect size29.6%; 45.5%; 19.2%
- Evidence strengthModerate
How this study scored 71/100
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. 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 41 of the 58 points we could judge it on, which is 71 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Translational psychiatry) |
| Journal's citation record | — / 4 | No journal record from OpenAlex — left out of this score |
| 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 | 2 / 5 | 2020 — within 10 year(s) of the newest study here |
| Sample size | 3 / 4 | 1,895 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 | — / 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 32994401) |
| Free to read | 2 / 2 | Free to read |
| Points | 41 / 58 | Scored on 11 of 20 parts. We have no data for the rest, so they are left out: 41 of the 58 points we could judge it on is 71 out of 100. |
| Total | 71 / 100 | — |
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