Drugs currently used for the treatment of Alzheimer's disease (AD) produce 
limited clinical benefits, and there is no disease-modifying therapy yet 
available. Compounds that inhibit or modulate γ-secretase, the pivotal enzyme 
that generates β-amyloid (Aβ), are potential therapeutics for AD. This article 
briefly reviews the profile of γ-secretase inhibitors and modulators that have 
reached the clinic. Studies in both transgenic and non-transgenic animal models 
of AD have indicated that γ-secretase inhibitors, administered by the oral 
route, are able to lower brain Aβ concentrations. However, scanty data are 
available on the effects of these compounds on brain Aβ deposition after 
prolonged administration. γ-Secretase inhibitors may cause abnormalities in the 
gastrointestinal tract, thymus, spleen, skin, and decrease in lymphocytes and 
alterations in hair color in experimental animals and in man, effects believed 
to be associated with the inhibition of the cleavage of Notch, a transmembrane 
receptor involved in regulating cell-fate decisions. Unfortunately, two large 
Phase III clinical trials of semagacestat in mild-to-moderate AD patients were 
prematurely interrupted because of the observation of a detrimental cognitive 
and functional effect of the drug. These detrimental effects were mainly 
ascribed to the inhibition of the processing of an unknown substrate of 
γ-secretase. It has been also hypothesized that the detrimental cognitive 
effects observed after semagacestat administration are due to the accumulation 
of the neurotoxic precursor of Aβ (the carboxy-terminal fragment of amyloid 
precursor protein, APP, or CTFβ) resulting from the block of the γ-secretase 
cleavage activity on APP. Some non-steroidal anti-inflammatory drugs and other 
small organic molecules have been found to modulate γ-secretase shifting its 
cleavage activity from longer to shorter Aβ species without affecting Notch 
cleavage. However, two large Phase III studies in mild AD patients with 
tarenflurbil, a putative γ-secretase modulator, were also completely negative. 
The failure of tarenflurbil was ascribed to low potency and brain penetration. 
New more selective γ-secretase inhibitors and more potent, more brain penetrant 
γ-secretase modulators are being developed with the hope of overcoming the 
previous setbacks. Further understanding of the reasons of the failures of these 
γ-secretase-based drugs in AD may be important for the future research on 
effective treatments for this devastating disease.