Capillary angiopathy and aquaporin 4 after AÎ² immunisation in Alzheimers disease - potential relevance to Amyloid-Related Imaging Abnormalities

Aims: Amyloid-related imaging abnormalities (ARIA) have hampered clinical trials and therapeutic use of amyloid-{beta} (A{beta}) 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 A{beta} 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 A{beta}42 (iAD, AN1792, Elan Pharmaceuticals) and 28 unimmunized Alzheimers (cAD) cases were immunolabelled and quantified for A{beta}42 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 A{beta} immunotherapy, capCAA was increased, likely reflecting the drainage of soluble A{beta} 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 A{beta} immunotherapy, the field must prioritise obtaining neuropathological correlates of ARIA to explore its mechanisms further.