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  1. James Nicoll
  1. University of Southampton, UK


Alzheimer's disease (AD) neuropathology is characterised by abnormal aggregation in the brain of amyloid-β (Ab) and hyperphosphorylated tau, associated with inflammation and loss of neurons and synapses. The amyloid cascade hypothesis places abnormal aggregation of Ab at an early point in the pathogenesis of the disease, upstream of tau aggregation, although how Ab and tau interact in disease pathogenesis is unclear. In numerous studies of transgenic mouse models of AD, Ab immunisation has resulted in Ab plaque removal with functional benefits. We have performed a long term clinical and neuropathological follow up of patients with AD who were actively immunised with Aβ42 (Elan Pharmaceuticals). A total of 80 patients were enrolled in the study which started in the year 2000:64 received Aβ42 peptide plus adjuvant and 16 received adjuvant alone. Post mortem neuropathology has identified substantial changes in the AD process in immunised patients including a lower Aβ load and a reduction in hyperphosphorylated tau, particularly in neuronal processes. In addition pathological “side-effects” were also observed, including: (i) altered microglial activation (ii) increased Aβ in the cerebral vasculature (cerebral amyloid angiopathy) and (iii) increased microhaemorrhages. In demonstrating that Ab immunisation can influence tau pathology, the findings provide support for the amyloid cascade hypothesis. However, the pathological “side effects” identified may be relevant to current immunotherapy trials, indicating that at least in a proportion of patients removing amyloid from the brain may have complications that need to be surmounted, for example by earlier intervention or use of immunotherapy as a preventative measure.

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