AD Vaccine Alters Disease and Pathology in Humans

Abstracts & Commentary

Sources: Nicoll JA, et al. Nat Med. 2003;9(4):448-452; Hock C, et al. Neuron. 2003;38:547-554.

Two recent reports strongly suggest that Elan’s AN-1792 Alzheimer’s "vaccine," which was withdrawn from clinical trials after several Alzheimer’s disease (AD) patients developed severe brain inflammation, did in fact succeed in altering the course of AD in some cases.

Nicoll and colleagues from Southampton, UK, reported the postmortem findings from a 72-year-old woman with AD who developed brain inflammation after multiple injections with AN-1792 and died 12 months after her last injection. On postmortem analysis of the brain, large areas of the neocortex were found to have very few senile plaques, in contrast to the persistence of other elements of AD-associated pathology, such as neuropil threads, tangles, and amyloid angiopathy in the same areas. This pattern strongly resembles that observed in the brains of AD-model transgenic mice treated with AN-1792. Signs of a T-cell-mediated meningoencephalitis were also found. This is consistent with previous reports that the adverse inflammatory effects of AN-1792 are T-cell mediated, whereas the therapeutic effects are likely brought about by B cells. The findings suggest that immunotherapy can reduce the burden of amyloid-bearing plaques from the human brain.

In a study of a subset of patients involved in the Elan trial, investigators in Zurich found that 20 of 30 subjects injected at their site raised significant titers of anti-amyloid antibodies. Among those with a robust antibody response, the scores on tests of memory, general cognition, and daily function declined significantly less than in the subjects who failed to raise high titers of antibody. Benefits were seen in 2 of 3 patients who developed the meningoencephalitis transiently as a result of immunization. This study suggests that high titers of antibodies after immunization with AN-1792 can be associated with decreased progression of AD symptoms.

Commentary

Taken together, these 2 reports imply that a major landmark has been reached in the history of research on AD treatment. Although the data must be considered preliminary, there are strong indications that amyloid immunotherapy exerted a disease-modifying effect in humans, manifested by altered brain pathology, as well as a measurable symptomatic response in patients raising high antibody titers. Although injections of AN-1792 have been suspended, additional follow-up is being carried out on those already injected, and more information about treatment response should become available in the near future. Alternatives to AN-1792 that may be less prone to cause inflammatory side effects are under development, as are other methods of altering amyloid processing. These studies provide some of the first concrete evidence that a new generation of disease-modifying therapies for AD is on the way. — Norman R. Relkin

Dr. Relkin is Associate Professor of Clinical Neurology and Neuroscience, New York Presbyterian Hospital-Cornell Campus