INTRODUCTION: LY450139 (semagacestat) inhibits gamma-secretase, a key enzyme for 
generation of amyloid beta (Abeta), the peptide deposited in plaques in 
Alzheimer disease (AD). Previous data have shown that LY450139 lowers plasma 
Abeta, but has no clear effect on Abeta1-40 or Abeta1-42 levels in cerebrospinal 
fluid (CSF). By using targeted proteomics techniques, we recently identified 
several shorter Abeta isoforms, such as Abeta1-16, that in experimental settings 
increase during gamma-secretase inhibitor treatment, and thus may serve as 
sensitive biochemical indices of the treatment effect. Here, we test the 
hypothesis that these shorter Abeta isoforms may be biomarkers of 
gamma-secretase inhibitor treatment in clinical trials.
METHODS: In a phase II clinical trial, 35 individuals with mild to moderate AD 
were randomized to placebo (n = 10) or LY450139 (100 mg (n = 15) or 140 mg (n = 
10)) and underwent lumbar puncture at baseline and after 14 weeks of treatment. 
The CSF Abeta isoform pattern was analyzed with immunoprecipitation combined 
with MALDI-TOF mass spectrometry.
RESULTS: The CSF levels of Abeta1-14, Abeta1-15, and Abeta1-16 showed a 
dose-dependent increase by 57% and 74%, 21% and 35%, and 30% and 67%, 
respectively in the 100-mg and 140-mg treatment groups. Abeta1-40 and Abeta1-42 
were unaffected by treatment.
CONCLUSIONS: CSF Abeta1-14, Abeta1-15, and Abeta1-16 increase during 
gamma-secretase inhibitor treatment in AD, even at doses that do not affect 
Abeta1-42 or Abeta1-40, probably because of increased substrate availability of 
the C99 APP stub (APP beta-CTF) induced by gamma-secretase inhibition. These 
Abeta isoforms may be novel sensitive biomarkers to monitor the biochemical 
effect in clinical trials.
TRIAL REGISTRATION: Clinical Trials.gov NCT00244322.