In recent years, efforts have been directed to develop "disease-modifying" 
medications to treat Alzheimer's disease (AD), able to halt or slow the 
pathological process. Because the earlier the treatment starts, the greater is 
the possibility of efficacy, it is important to set up biomarkers for early 
diagnosis of functional brain abnormalities, before the clinical manifestation 
of the overt disease. Up to now, strategies to develop disease-modifying drugs 
have mainly targeted β amyloid (Aβ, accumulation, aggregation, clearance) and/or 
tau protein (phosphorylation and aggregation). Active and passive immunotherapy 
is the main strategy aimed at increasing Aβ clearance. Unfortunately several 
candidate diseasemodifying drugs have failed in phase III clinical trials 
conducted in mild to moderate AD. More recently, in phase III studies, 
bapineuzumab has been discontinued because it did not prove clinically effective 
(despite its significant effect on biomarkers), while solaneuzumab has been 
found effective in slowing AD progression. Several methological problems have 
been recently pointed out to explain the lack of clinical efficacy of novel 
disease-modifying drug-treatments; moreover, new insights in pathophysiology of 
AD give the premise to develop novel drug targeting. Clinical trials recently 
completed and/or still ongoing are discussed in the present review.