Anti-amyloid-beta immunization leads to amyloid clearance in patients with 
Alzheimer's disease, but the effect of vaccination on amyloid-beta-induced 
neuronal pathology has not been quantitatively examined. The objectives of this 
study were to address the effects of anti-amyloid-beta active immunization on 
neurite trajectories and the pathological hallmarks of Alzheimer's disease in 
the human hippocampus. Hippocampal sections from five patients with Alzheimer's 
disease enrolled in the AN1792 Phase 2a trial were compared with those from 13 
non-immunized Braak-stage and age-matched patients with Alzheimer's disease, and 
eight age-matched non-demented controls. Analyses included neurite curvature 
ratio as a quantitative measure of neuritic abnormalities, amyloid and tau 
loads, and a quantitative characterization of plaque-associated neuritic 
dystrophy and astrocytosis. Amyloid load and density of dense-core plaques were 
decreased in the immunized group compared to non-immunized patients (P < 0.01 
and P < 0.001, respectively). The curvature ratio in non-immunized patients with 
Alzheimer's disease was elevated compared to non-demented controls (P < 0.0001). 
In immunized patients, however, the curvature ratio was normalized when compared 
to non-immunized patients (P < 0.0001), and not different from non-demented 
controls. In the non-immunized patients, neurites close to dense-core plaques 
(within 50 microm) were more abnormal than those far from plaques (i.e. beyond 
50 microm) (P < 0.0001). By contrast, in the immunized group neurites close to 
and far from the remaining dense-core plaques did not differ, and both were 
straighter compared to the non-immunized patients (P < 0.0001). Compared to 
non-immunized patients, dense-core plaques remaining after immunization had 
similar degree of astrocytosis (P = 0.6060), more embedded dystrophic neurites 
(P < 0.0001) and were more likely to have mitochondrial accumulation (P < 
0.001). In addition, there was a significant decrease in the density of paired 
helical filament-1-positive neurons in the immunized group as compared to the 
non-immunized (P < 0.05), but not in the density of Alz50 or thioflavin-S 
positive tangles, suggesting a modest effect of anti-amyloid-beta immunization 
on tangle pathology. Clearance of amyloid plaques upon immunization with AN1792 
effectively improves a morphological measure of neurite abnormality in the 
hippocampus. This improvement is not just attributable to the decrease in plaque 
load, but also occurs within the halo of the remaining dense-core plaques. 
However, these remaining plaques still retain some of their toxic potential. 
Anti-amyloid-beta immunization might also ameliorate the hippocampal tau 
pathology through a decrease in tau phosphorylation. These data agree with 
preclinical animal studies and further demonstrate that human anti-amyloid-beta 
immunization does not merely clear amyloid from the Alzheimer's disease brain, 
but reduces some of the neuronal alterations that characterize Alzheimer's 
disease.