S.13.02 Immunotherapy in tauopathies

Abstract

Immunotherapy targeting Ab is currently in clinical trials for Alzheimer’s disease (AD). Two complications have been identified, leucoencephalopathy and cortical microhaemorrhages, both likely mediated by increased severity of cerebral amyloid angiopathy, accompanied by inflammation, as Ab plaques are cleared from the cortex. We have performed a long term neuropathological follow up of patients with a clinical diagnosis of mild to moderate AD (MMSE 15−25) who were actively immunised with Ab42 (Elan Pharmaceuticals). Of 80 patients in the study, 64 received Ab42 peptide and 16 the placebo. Post-mortem neuropathology confirmed the clinical diagnosis of AD in 12/16 (75%; 11 immunised, 1 placebo) and 4/16 (25%) had alternative neuropathological substrates for dementia: progressive supranuclear palsy, dementia with Lewy bodies, vascular dementia and frontotemporal dementia. All AD immunised patients showed variable histopathological evidence of mobilization and clearance of Ab plaques via microglia and/or the cerebral vasculature, implying an effect of the immunotherapy extending over many years [1,2]. 10/11 immunised AD patients had progressed to severe dementia (MMSE 10), by 6 years after immunization; one had died at 4 months [3]. The inclusion in a therapeutic trial for AD of patients with dementia due to other causes inevitably hampered the statistical power of the study. Many of the current clinical trials of immunotherapy include brain amyloid imaging (e.g. PIB-PET) and CSF Ab42 and phospho-tau to increase diagnostic accuracy, nevertheless post-mortem neuropathology follow up would provide additional valuable information.