The article by Pfeifer et al. describes the exacerbation of cerebral hemorrhages seen in an aged APP-transgenic model following passive administration of anti-Aβ antibodies directed to amino acids 3-6. This particular transgenic mouse, called APP23, is described by the authors in a previous paper as a "spontaneous hemorrhagic stroke mouse model" (Winkler et al., 2001). At approximately 19 months of age onward, the mouse exhibits severe cerebral amyloid angiopathy (CAA), which is associated with recurrent hemorrhages as the mice age. Moderate to severe cerebral vascular amyloid also exists in approximately 26 percent of Alzheimer’s disease patients, as well, though the rate of hemorrhages is less than that seen in the APP23 mouse (approximately five percent of AD cases; see Greenberg et al., 1998).

When the authors gave 21-month-old APP23 mice a monoclonal antibody directed to Aβ3-6 once a week for five months, they saw that the rate of...  Read more

The article by Pfeifer et al. describes the exacerbation of cerebral hemorrhages seen in an aged APP-transgenic model following passive administration of anti-Aβ antibodies directed to amino acids 3-6. This particular transgenic mouse, called APP23, is described by the authors in a previous paper as a "spontaneous hemorrhagic stroke mouse model" (Winkler et al., 2001). At approximately 19 months of age onward, the mouse exhibits severe cerebral amyloid angiopathy (CAA), which is associated with recurrent hemorrhages as the mice age. Moderate to severe cerebral vascular amyloid also exists in approximately 26 percent of Alzheimer’s disease patients, as well, though the rate of hemorrhages is less than that seen in the APP23 mouse (approximately five percent of AD cases; see Greenberg et al., 1998).

When the authors gave 21-month-old APP23 mice a monoclonal antibody directed to Aβ3-6 once a week for five months, they saw that the rate of hemorrhages increased about twofold above baseline. The severity of the hemorrhages also increased approximately 30 percent above levels seen in the untreated group. No control antibody group was tested, and thus, we cannot be sure that the effect was specific for the particular anti-Aβ antibody monoclonal used.

As the authors correctly point out, these types of findings have not been seen in other APP-transgenic mouse models that have been actively or passively immunized with Aβ. Though other APP transgenes, such as the PDAPP mouse that we routinely have used in our studies, do show CAA, as well (Kimchi, 2001), the amount of this type of pathology is significantly less than that seen in the APP23 mice, and this might be the reason for the novelty of the new report.

Aβ immunotherapy for Alzheimer’s disease remains an important new approach for potential treatment of this devastating disease. Clinical progress with immunization of Aβ42 (AN 1792) recently suffered a setback when a subset of treated patients developed meningoencephalitis—a condition distinct from the hemorrhagic stroke described in the APP23 mouse. This recent finding, nevertheless, adds to a growing body of literature on the subject. As with all new preclinical observations, additional experiments will be required to understand whether these new findings, in this particular animal model, will have a clinical correlate in humans or not.

See response by Alexei Koudinov: Amyloid was never clearly implicated in Alzheimer's disease, so look at Aβ from a different angle. Koudinov AR. British Medical Journal (30 November 2002).

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