[Treatment strategy of Alzheimer's disease: pause in clinical trials of Abeta vaccine and next steps].

The important pathognomonic features of Alzheimer disease (AD) brain are the occurrence of abundant neurofibrillary tangles (NFTs) in neurons and presence of extracellular deposits of beta-amyloid (Abeta)- senile plaques. In the early 1980s, the NFTs were characterized, and cerebral amyloid was purified; further the amino acid sequences of the tau protein in the NFTs and of Abeta were identified. Immunohistochemical studies with antibodies to tau and Abeta revealed that extracellular accumulation of Abeta precedes that of tau in neurons. Molecular genetic studies revealed that abnormal gene mutations of familial AD accelerate Abeta production. On the basis of these findings, the amyloid cascade hypothesis that Abeta accumulation is the primary cause of neuronal degeneration and induces accumulation of tau in the AD brain was proposed and widely accepted. Thus, on the basis of this hypothesis, transgenic AD mice were treated with Abeta vaccine; the Abeta amyloid plaques were eliminated, and a dramatic improvement of the behavioral deficits was observed in the treated mice. The great success of preclinical studies promoted clinical trials of the Abeta vaccine in AD patients. However,the clinical trials were discontinued because of the occurrence of severe meningoencephalitis. Postmortem examination of the brains of the vaccinated patients with high titer of the anti- Abeta antibody in the serum revealed elimination of the Abeta plaques along with presence of cerebral inflammation. However, in autopsy-proven cases, assessment of the clinical and cognitive functions of the patients did not provide any evidence for improved survival or prolongation of the time to severe dementia. Thus, anti-Abeta antibody could eliminate the accumulated Abeta but could not rescue the degenerated neurons. Thus, the AD treatment strategy should be converted from repair and cure of AD to prevention. Anti-Abeta therapy must be started at the preclinical stage, and it is necessary to focus on tau and other proteins, mitochondria, glial cells, and other factors that influence the degeneration of neurons.