Immunization for Alzheimer's disease

The recent termination of a Phase II clinical trial in which volunteers with Alzheimer's disease (AD) were vaccinated with Amyloid-β (Aβ)1-42, has cast doubt on the feasibility of this therapeutic approach. While the exact reasons for the cerebral inflammation in these patients is being determined, it is difficult to evaluate the cause of these adverse effects. The most likely reasons are Aβ1-42 toxicity and/or autoimmunity. Aβ vaccination approaches are based on the hypothesis that Aβ deposition and toxicity are central to the pathogenesis of AD. Therefore, it is counterintuitive to use the whole Aβ peptide for human vaccination. Aβ1-40/42 is a major plaque component that forms inflammatory/toxic fibrils as observed in many in vitro and in vivo studies. Furthermore, numerous studies have shown that Aβ1-40/42 bidirectionally crosses the blood–brain barrier (BBB) in experimental animals. Additionally, in vitro and in vivo studies indicate that minute amounts of Aβ1-42 may seed fibril/amyloid formation. The elderly, a target population for AD therapy, often have a poor immune response to vaccines, which enhances the gravity of these safety concerns. In these patients with an attenuated immune reaction, injected Aβ1-42 may initiate and/or enhance congophilic angiopathy, which eventually may result in reduced cerebral blood flow and/or intracerebral bleeding. Aβ1-42 may also cross the BBB and once within the brain parenchyma it may contribute to plaque formation and/or co-deposit on plaques. Together, these effects within blood vessels and/or brain parenchyma may actually enhance the progression of AD. Given the potential serious side effects of Aβ1-42 vaccination, it is safer to use immunogenic Aβ derivatives, which are less likely to be toxic. The main immunogenic epitopes of Aβ1-42 are contained within the first 30 amino acids of the peptide. Taking this into account, we have developed soluble antigenic Aβ derivatives, which are nonfibrillogenic and nontoxic in human cell culture. Our prototype peptide, K6Aβ1-30-NH2, diminishes amyloid burden to a similar extent as reported for Aβ1-42. Additionally, ramified IL-1β-positive microglia as well as phagocytes, associated with the Aβ plaques, were absent in the immunized mice, indicating reduced inflammation in these animals at the time point examined. Autoimmunity may be the culprit if follow-up studies reveal that the brain inflammation is related to antibody interactions with Aβ and/or amyloid precursor protein (APP). In such a scenario, any vaccination approach targeting Aβ can have similar consequences, although preventive treatment initiated prior to amyloid deposition may not result in these adverse reactions. T–cell-related autoimmunity may also be involved and can be expected to be less with Aβ derivatives not containing certain T-cell epitopes. An alternative to the active vaccination approach is passive immunization, which is associated with a lower risk of irreversible autoimmunity. This approach may also be used in patients with a muted immune response to the vaccine. However, in a chronic disease such as AD repeated antibody injections may lead to an anti-idiotype response and the resulting serum immune complexes can cause vasculitis and/or glomerulonephritis. Reduction of soluble Aβ within the peripheral system may be a critical part of the pathway that reduces cerebral plaque burden in Tg mice and ultimately in AD patients. Overall, the use of nontoxic Aβ derivatives and/or antibodies with very limited access into the CNS, such as IgM, may prove to have reduced side effects compared to Aβ1-40/42 and/or IgG-based immunization. Any therapeutic approach will be more effective when used prophylactically because of neuronal loss and increased amyloid burden in the later stages of AD. Reversal of clinical symptoms cannot be expected and early diagnosis of AD may be needed for effective therapy. Drug Dev. Res. 56:135–142, 2002. © 2002 Wiley-Liss, Inc.