Alternative Aβ Immunotherapy Approaches for Alzheimer's Disease

In a seminal report in 1999, Schenk and colleagues demonstrated that vaccination of a mouse model of Alzheimer's disease (AD) with amyloid-β1-42 peptide (Aβ1-42) and adjuvant resulted in striking mitigation of AD-like pathology - giving rise to the field of AD immunotherapy. Later studies confirmed this result in other mouse models of AD and additionally showed cognitive improvement after Aβ vaccination. Based on these results, early developmental clinical trials ensued to immunize AD patients with Aβ1-42 plus adjuvant (so-called “active” Aβ immunotherapy; trade name AN-1792; Elan Pharmaceuticals, Dublin, Ireland). However, the phase IIa trial was halted after 6 % of patients developed aseptic meningoencephalitis. Despite occurrence of this adverse event, many individuals demonstrated high serum antibody titres to Aβ and histological evidence of clearance of the hallmark AD pathology, β-amyloid plaques. While raising justifiable safety concerns, these important results nonetheless demonstrated the feasibility of the active Aβ immunotherapy approach. This review focuses on alternative approaches to active Aβ vaccination that are currently in various stages of development - from pre-clinical studies in animal models to current clinical trials. Specifically, the focus is on those strategies that target inflammatory and immune aspects of AD, and can therefore be classified as immunotherapeutic in a broad sense.