Capillary angiopathy and aquaporin-4 after Aβ immunisation in Alzheimer’s disease – potential relevance to Amyloid-Related Imaging Abnormalities

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.