A two-year study with fibrillar β-amyloid (Aβ) immunization in aged canines:: Effects on cognitive function and brain Aβ

Aged canines ( dogs) accumulate human- type beta- amyloid ( A beta) in diffuse plaques in the brain with parallel declines in cognitive function. We hypothesized that reducing A beta in a therapeutic treatment study of aged dogs with preexisting A beta pathology and cognitive deficits would lead to cognitive improvements. To test this hypothesis, we immunized aged beagles ( 8.4 - 12.4 years) with fibrillar A beta(1-42) formulated with aluminum salt ( Alum) for 2.4 years ( 25 vaccinations). Cognitive testing during this time revealed no improvement in measures of learning, spatial attention, or spatial memory. After extended treatment ( 22 vaccinations), we observed maintenance of prefrontal- dependent reversal learning ability. In the brain, levels of soluble and insoluble A beta(1-40) and A beta(1-42) and the extent of diffuse plaque accumulation was significantly decreased in several cortical regions, with preferential reductions in the prefrontal cortex, which is associated with a maintenance of cognition. However, the amount of soluble oligomers remained unchanged. The extent of prefrontal A beta was correlated with frontal function and serum anti- A beta antibody titers. Thus, reducing total A beta maybe of limited therapeutic benefit to recovery of cognitive decline in a higher mammalian model of human brain aging and disease. Immunizing animals before extensive A beta deposition and cognitive decline to prevent oligomeric or fibrillar A beta formation may have a greater impact on cognition and also more directly evaluate the role of A beta on cognition in canines. Alternatively, clearing preexisting A beta from the brain in a treatment study may be more efficacious for cognition if combined with a second intervention that restores neuron health.