According to a study published in The Lancet, immunization against the amyloid-β peptide clears amyloid plaques in the brain but fails to halt the progressive neurodegeneration that comes with Alzheimer’s disease.
The amyloid-β peptide accumulates in the brains of patients with Alzheimer’s disease, and this engenders plaque formation. Researchers have shown that after immunizing mice with full-length Aβ (Aβ42), there was a reduction in plaque and improvement in brain function. However, human trials have not yielded similar positive results. To test Aβ immunization’s long-term effects on the brain function of humans, Professor Clive Holmes (Memory Assessment and Research Centre, Moorgreen Hospital, Southampton, UK) and colleagues conducted a follow up study of a randomized, placebo controlled phase I trial.
In September 2000, 80 Alzheimer’s disease patients enrolled in a trial that tested the effects of immunisation with Aβ42 (the AN1792 vaccine). By September 2006, the follow-up study (focusing on long-term effects) had been completed. Of the 80, 64 patients received the vaccine and 16 received the placebo. Before the follow-up study, five patients from the placebo group and 15 patients from the vaccine group died. During the follow-up study, three patients from the placebo group and 19 from the vaccine group died. Nine of the deceased from the immunized group allowed the researchers to analyze them after death, and eight of nine were studied and found to have a lower Aβ load than the controls (2.0% vs. 5.1%). The researchers noted that the patients in the vaccine group had wide variations in Aβ load and degree of plaque removal. Additionally, they found that the degree of plaque removal was associated with the average antibody response measured during the study period. Of the eight in the immunization group who were analyzed after death, 7 were diagnosed with severe end-stage dementia before death. Ultimately, the researchers were unable to find enough evidence to suggest that the immunized group had improved survival or delayed sever dementia compared to the placebo group.
“Despite the evidence of disease modification, there is little evidence to suggest that there is any major effect on cognitive function. All but one of the individuals who died during the follow-up phase had clear end-stage dementia before death, including the two individuals with highest mean antibodies to Aβ and almost complete elimination of plaques. These findings imply that progressive neurodegeneration can occur in Alzheimer’s disease despite removal of plaques,” conclude the authors.
Dr. Peter St George-Hyslop (Department of Clinical Neurosciences, University of Cambridge, UK) and Dr. John C Morris (Centre for Research in Neurodegenerative Diseases and Toronto Western Hospital, University of Toronto) ask in an accompanying comment: “What are the next steps? Although the current study suggests that anti-Aβ vaccination – and perhaps other anti-Aβ therapies – may not completely cure symptomatic Alzheimer’s disease, removal of the initial motor for the disease might slow progression.”
Long-term effects of Aβ42 immunisation in Alzheimer’s disease: follow-up of a randomised, placebo-controlled phase I trial
C Holmes et al.
The Lancet (2008). 372[9634]: pp. 216 – 223.
Written by: Peter M Crosta