Post mortem examinations of AN-1792-vaccinated humans revealed this
therapy produced focal
senile plaque disruption. Despite the dispersal of substantial plaque material, vaccination did not constitute even a partial eradication of brain
amyloid as water soluble
amyloid-beta (
Abeta) 40/42 increased in the gray matter compared to sporadic
Alzheimer's disease (AD) patients and total brain Abeta levels were not decreased. Significant aspects of AD pathology were unaffected by vaccination with both vascular
amyloid and hyper-phosphorylated tau deposits appeared refractory to this
therapy. In addition, vaccination resulted in the consequential and drastic expansion of the white matter (WM)
amyloid pool to levels without precedent in sporadic AD patients. Although vaccination disrupted
amyloid plaques, this
therapy did not enhance long-term cognitive function or necessarily halt neurodegeneration. The intricate involvement of vascular pathology in AD evolution and the firm recalcitrance of vessel-associated
amyloid to antibody-mediated disruption suggest that immunization
therapies might be more effective if administered on a prophylactic basis before vascular impairment and well ahead of any clinically evident
cognitive decline.
Amyloid-beta is viewed as pathological based on the postmortem correlation of
senile plaques with an AD diagnosis. It remains uncertain which of the various forms of this
peptide is the most toxic and whether Abeta or
senile plaques themselves serve any desirable or protective functions. The long-term cognitive effects of chronic
immunotherapy producing a steadily accumulating and effectively permanent pool of disrupted Abeta
peptides within the human brain are unknown. In addition, the side effects of such
therapy provided on a chronic basis could extend far beyond the brain. Eagerly seeking new
therapies, critical knowledge gaps should prompt us to take a more wholistic perspective viewing Abeta and the
amyloid cascade as aspects of complex and many-faceted physiological processes that sometimes end in AD
dementia.