BACKGROUND: Anti-Abeta
immunotherapy in transgenic mice reduces both diffuse and compact
amyloid deposits, improves memory function and clears early-stage phospho-tau aggregates. As most
Alzheimer disease cases occur well past midlife, the current study examined adoptive transfer of anti-Abeta
antibodies to 19- and 23-month old APP-transgenic mice. METHODS: We investigated the effects of weekly anti-Abeta antibody treatment on radial-arm water-maze performance, parenchymal and vascular
amyloid loads, and the presence of microhemorrhage in the brain. 19-month-old mice were treated for 1, 2 or 3 months while 23-month-old mice were treated for 5 months. Only the 23-month-old mice were subject to radial-arm water-maze testing. RESULTS: After 3 months of weekly
injections, this passive immunization protocol completely reversed learning and
memory deficits in these mice, a benefit that was undiminished after 5 months of treatment. Dramatic reductions of diffuse Abeta immunostaining and parenchymal Congophilic
amyloid deposits were observed after five months, indicating that even well-established
amyloid deposits are susceptible to
immunotherapy. However,
cerebral amyloid angiopathy increased substantially with
immunotherapy, and some deposits were associated with microhemorrhage. Reanalysis of results collected from an earlier time-course study demonstrated that these increases in vascular deposits were dependent on the duration of
immunotherapy. CONCLUSIONS: The cognitive benefits of passive immunotherapy persist in spite of the presence of vascular
amyloid and small
hemorrhages. These data suggest that clinical trials evaluating such treatments will require precautions to minimize potential adverse events associated with microhemorrhage.