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

AimsAmyloid-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. MethodsBrains 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. ResultsCapCAA 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. ConclusionsAfter 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.