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Capillary angiopathy and aquaporin-4 after Aβ immunisation in Alzheimer’s disease – potential relevance to Amyloid-Related Imaging Abnormalities
Harrison CH, Sakai K, Johnston DA, Holmes C, Boche D, Nicoll JA.. medRxiv, 2022-12-08
Topic: Amyloid, tau and blood-test diagnosis
Aims Amyloid-related imaging abnormalities (ARIA) have hampered clinical trials and therapeutic use of amyloid-β (Aβ) immunotherapy for Alzheimer’s disease (AD), with the cause of the white matter oedema (ARIA-E) unknown. Aquaporin 4 (AQP4), present in astrocyte endfeet, controls water flow across the blood-brain barrier. Experimental studies suggest that as Aβ plaques are cleared following immunotherapy, capillary angiopathy (capCAA) increases, displacing astrocyte endfeet allowing influx of extracellular water (oedema). We sought neuropathological evidence for this mechanism in immunised AD patients. Methods Brains of 16 Alzheimer’s patients immunised against Aβ42 (iAD, AN1792, Elan Pharmaceuticals) and 28 unimmunized Alzheimer’s (cAD) cases were immunolabelled and quantified for Aβ42 and AQP4. Results CapCAA was 3.5 times higher in iAD (p=0.009). No difference between the groups was identified in the proportion of capillaries wrapped by AQP4 or AQP4 protein load. However, capCAA in iAD negatively correlated with AQP4 load (r = -0.498, p<0.001), suggesting disturbance of AQP4 in presence of capCAA. Conclusions After Aβ immunotherapy, capCAA was increased, likely reflecting the drainage of soluble Aβ towards the vasculature and providing a potential mechanism to disrupt AQP4-containing astrocyte endfeet, resulting in ARIA-E. We did not identify alterations in AQP4, potentially because of limitations in the timing of the post-mortem analysis. Given the recent licencing of Aβ immunotherapy, the field must prioritise obtaining neuropathological correlates of ARIA to explore its mechanisms further.
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APA 7th
Harrison, C. H., Sakai, K., Johnston, D. A., Holmes, C., Boche, D., & Nicoll, J. A. (2022). Capillary angiopathy and aquaporin-4 after Aβ immunisation in Alzheimer’s disease – potential relevance to Amyloid-Related Imaging Abnormalities. medRxiv. https://doi.org/10.1101/2022.12.08.22283144
Vancouver
Harrison CH, Sakai K, Johnston DA, Holmes C, Boche D, Nicoll JA. Capillary angiopathy and aquaporin-4 after Aβ immunisation in Alzheimer’s disease – potential relevance to Amyloid-Related Imaging Abnormalities. medRxiv. 2022. doi:10.1101/2022.12.08.22283144.
BibTeX
@article{harrison2022-b252d158,
author = {Harrison, C. H. and Sakai, K. and Johnston, D. A. and Holmes, C. and Boche, D. and Nicoll, J. A.},
title = {{Capillary angiopathy and aquaporin-4 after Aβ immunisation in Alzheimer’s disease – potential relevance to Amyloid-Related Imaging Abnormalities}},
journal = {medRxiv},
year = {2022},
doi = {10.1101/2022.12.08.22283144},
url = {https://doi.org/10.1101/2022.12.08.22283144}
}
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Key findings
- Experimental studies suggest that as Aβ plaques are cleared following immunotherapy, capillary angiopathy (capCAA) increases, displacing astrocyte endfeet allowing influx of extracellular water (oedema).
- Results CapCAA was 3.5 times higher in iAD (p=0.009).
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Study details
- Evidence strengthLow
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 18 on the same rubric, but non-peer-reviewed sources are capped at 16, so it shows as 16. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it. We have no data on 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 11 of the 62 points we could judge it on, which is 18 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 2 / 10 | Tier 4 — not a peer-reviewed journal (medRxiv) |
| Journal's citation record | 0 / 4 | Not a journal article, so the journal's record does not count |
| 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 | 4 / 10 | Preprint — not yet peer-reviewed. Hosted on a preprint server. |
| How recent | 3 / 5 | 2022 — within 6 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 | — / 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 | 1 / 2 | Not in PubMed, but has a DOI |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 11 / 62 | Scored on 12 of 20 parts. We have no data for the rest, so they are left out: 11 of the 62 points we could judge it on is 18 out of 100. |
| Total | 18 / 100 | Capped to 16 because this is not a peer-reviewed article. |
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