AbstractBackgroundAmyloid‐related imaging abnormalities (ARIA) on MRI are frequently observed adverse advents in the context of anti‐Aβ immunotherapy trials in patients with Alzheimer’s disease (AD). The underlying histopathology and mechanisms of ARIA remain unknown, although coexisting Cerebral Amyloid Angiopathy (CAA) appears to be a risk factor.MethodTen cases were selected from the long‐term follow‐up study of patients who enrolled in the first clinical trial of active Aβ immunization for AD (AN1792; Elan Pharmaceuticals Inc) (iAD cases; mean age at death 81 years, mean survival time from first immunization 107 months). Eleven matched non‐immunized AD cases were used as “controls” (cAD cases; mean age at death 79 years). Formalin‐fixed coronal slabs from the occipital lobe were imaged on a 7T MRI scanner, including a T2*‐weighted gradient echo sequence (voxel size 200 µm3). Samples with and without ARIA were cut in serial sections and stained with Hematoxylin & Eosin (H&E), Perls’ Prussian blue (iron), Von Kossa (calcifications), and immunohistochemistry against Aβ (Dako; clone 6F/3D).ResultOn ex vivo MRI, ARIA were observed in 7/10 iAD cases (including one case with documented ARIA during life) compared to 1/11 cAD cases (p=0.004), in the form of cortical superficial siderosis, hypointense lining of the deeper cortical layers, and white matter rarefaction (arrows in Figure). Histopathologically, ARIA corresponded to intraneuronal, vascular, and extracellular iron depositions and calcifications (Figure). In iAD cases the degree of iron (p=0.0006) and calcium deposits (p<0.0001) was more severe compared to cAD cases. In contrast, Aβ plaque burden was less severe in iAD cases (p=0.0017), confirming the previously reported observation of Aβ plaque removal after immunotherapy. Although the degree of CAA was comparable between iAD and cAD cases, concentric splitting of the walls of leptomeningeal vessels (an advanced stage of CAA severity) was observed in iAD cases in areas with ARIA, but not in areas without ARIA (p=0.055).ConclusionThese findings suggest that ARIA in the context of anti‐Aβ immunotherapy may result in lasting neuropathological alterations (perhaps even in the absence of clinical symptoms) and that advanced CAA likely plays a role in the pathophysiology of ARIA.