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-β (Aβ) 40/42 increased in the gray matter compared to sporadic Alzheimers disease (AD) patients and total brain Aβ levels were not decreased. Significant aspects of AD pathology were unaffected by vaccination with both vascular amyloid and hyperphosphorylated 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-β 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 Aβ 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 Aβ 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 Aβ and the amyloid cascade as aspects of complex and many-faceted physiological processes that sometimes end in AD dementia.
Longtine Center for Molecular Biology and Genetics, Sun Health Research Institute, Sun City AZ 85351, USA.