The exact mechanisms leading to Alzheimer's disease (AD) are largely unknown, 
limiting the identification of effective disease-modifying therapies. The two 
principal neuropathological hallmarks of AD are extracellular β-amyloid (Aβ), 
peptide deposition (senile plaques) and intracellular neurofibrillary tangles 
containing hyperphosphorylated tau protein. During the last decade, most of the 
efforts of the pharmaceutical industry were directed against the production and 
accumulation of Aβ. The most innovative of the pharmacological approaches was 
the stimulation of Aβ clearance from the brain of AD patients via the 
administration of Aβ antigens (active vaccination) or anti-Aβ antibodies 
(passive vaccination). Several active and passive anti-Aβ vaccines are under 
clinical investigation. Unfortunately, the first active vaccine (AN1792, 
consisting of preaggregate Aβ and an immune adjuvant, QS-21) was abandoned 
because it caused meningoencephalitis in approximately 6% of treated patients. 
Anti-Aβ monoclonal antibodies (bapineuzumab and solanezumab) are now being 
developed. The clinical results of the initial studies with bapineuzumab were 
equivocal in terms of cognitive benefit. The occurrence of vasogenic edema after 
bapineuzumab, and more rarely brain microhemorrhages (especially in Apo E ε4 
carriers), has raised concerns on the safety of these antibodies directed 
against the N-terminus of the Aβ peptide. Solanezumab, a humanized anti-Aβ 
monoclonal antibody directed against the midregion of the Aβ peptide, was shown 
to neutralize soluble Aβ species. Phase II studies showed a good safety profile 
of solanezumab, while studies on cerebrospinal and plasma biomarkers documented 
good signals of pharmacodynamic activity. Although some studies suggested that 
active immunization may be effective against tau in animal models of AD, very 
few studies regarding passive immunization against tau protein are currently 
available. The results of the large, ongoing Phase III trials with bapineuzumab 
and solanezumab will tell us if monoclonal anti-Aβ antibodies may slow down the 
rate of deterioration of AD. Based on the new diagnostic criteria of AD and on 
recent major failures of anti-Aβ drugs in mild-to-moderate AD patients, one 
could argue that clinical trials on potential disease-modifying drugs, including 
immunological approaches, should be performed in the early stages of AD.