title: Aβ immunotherapy for Alzheimer's disease: effects on apoE and cerebral vasculopathy.
abstract: Aβ immunotherapy for Alzheimer's disease (AD) results in the removal of Aβ plaques and increased cerebral amyloid angiopathy (CAA). In current clinical trials, amyloid-related imaging abnormalities (ARIAs), putatively due to exacerbation of CAA, are concerning side effects. We aimed to assess the role of the Aβ transporter apolipoprotein E (apoE) in the exacerbation of CAA and development of CAA-associated vasculopathy after Aβ immunotherapy. 12 Aβ42-immunized AD (iAD; AN1792, Elan Pharmaceuticals) cases were compared with 28 unimmunized AD (cAD) cases. Immunohistochemistry was quantified for Aβ42, apoE, apoE E4 and smooth muscle actin, and CAA-associated vasculopathy was analyzed. Aβ immunotherapy was associated with redistribution of apoE from cortical plaques to cerebral vessel walls, mirroring the altered distribution of Aβ42. Concentric vessel wall splitting was increased threefold in leptomeningeal vessels after immunotherapy (cAD 6.3 vs iAD 20.6 %, P < 0.001), but smooth muscle cell abnormalities did not differ. The findings suggest that apoE is involved in the removal of plaques and transport of Aβ to the cerebral vasculature induced by Aβ immunotherapy. Immunotherapy was not associated with CAA-related vascular smooth muscle damage, but was accompanied by increased splitting of the vessel wall, perhaps reflecting enhanced deposition and subsequent removal of Aβ. ARIA occurring in some current trials of Aβ immunotherapy may reflect an extreme form of these vascular changes.
authors.affiliation: Clinical Neurosciences, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: Kenji
authors.initials: K
authors.lastname: Sakai
authors.forename: Delphine
authors.initials: D
authors.lastname: Boche
authors.forename: Roxana
authors.initials: R
authors.lastname: Carare
authors.forename: David
authors.initials: D
authors.lastname: Johnston
authors.forename: Clive
authors.initials: C
authors.lastname: Holmes
authors.forename: Seth
authors.initials: S
authors.lastname: Love
authors.forename: James A R
authors.initials: JA
authors.lastname: Nicoll
mesh_terms: D000199:Actins / Q000378:metabolism; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism*; D001921:Brain / Q000098:blood supply / Q000473:pathology*; D016657:Cerebral Amyloid Angiopathy / Q000473:pathology / Q000503:physiopathology / Q000628:therapy; D002986:Clinical Trials as Topic; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007150:Immunohistochemistry; D007167:Immunotherapy / Q000379:methods*; D008297:Male; D008578:Meninges / Q000473:pathology / Q000503:physiopathology; D018613:Microscopy, Confocal; D009131:Muscle, Smooth, Vascular / Q000473:pathology / Q000503:physiopathology; D010446:Peptide Fragments / Q000378:metabolism; D058225:Plaque, Amyloid / Q000473:pathology / Q000503:physiopathology / Q000628:therapy
chemical_list: D000199:Actins; D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)