Capillary angiopathy and aquaporin 4 after Aβ immunisation in Alzheimers disease - potential relevance to Amyloid-Related Imaging Abnormalities

Abstract

Aims: Amyloid-related imaging abnormalities (ARIA) have hampered clinical trials and therapeutic use of amyloid-β (Aβ) immunotherapy for Alzheimers 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 Alzheimers patients immunised against Aβ42 (iAD, AN1792, Elan Pharmaceuticals) and 28 unimmunized Alzheimers (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.

Competing Interest Statement

JARN has been a consultant/advisor relating to Alzheimer immunisation programmes for Elan Pharmaceuticals, GlaxoSmithKline, Novartis, Roche, Janssen, Pfizer, Biogen and has received compensation from Biogen within the last 36 months. DB has been consultant/advisor to Biogen and has received compensation from Biogen within the past 36 months. The other authors declare that they have no conflict of interests.

Funding Statement

The study was funded by the Alzheimers Research UK (ART/PG2006/4, ART-EXT2010-1, ARUK-EG2015A-4) and the Medical Research Council UK (G501033). KS was supported by the SENSHIN Medical Research Foundation, KANAE foundation, and by the British Council Japan Association Scholarship.

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Ethics committee of Southampton and South West Hampshire Local Research Ethics Committees (Reference No: LRC 075/03/w) gave ethical approval for the iAD cases and NRES Committee South West Central Bristol, REC reference: 08/H0106/28 + 5 for the South West Dementia Brain bank AD cases.

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Data Availability

All data produced in the present study are available upon reasonable request to the authors.

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