BACKGROUND: In a recent report, 76 weeks' treatment with a gamma-secretase 
inhibitor (semagacestat) was associated with poorer cognitive outcomes in 
Alzheimer's disease (AD).
OBJECTIVE: We sought to examine the effect of semagacestat treatment on 
neuropsychiatric symptoms (NPS).
METHODS: 1,537 participants with mild to moderate AD were randomized to 76 
weeks' treatment with placebo versus two doses of semagacestat. NPS were 
assessed with the Neuropsychiatric Inventory (NPI-Total and subdomains). 
Cognition was assessed with the Alzheimer's Disease Assessment Scale-Cognitive 
(first 11 items, ADAS11). Mixed-Model Repeated Measures was used to compare the 
effects of treatment assignment on change in NPI-total and subdomains over time. 
Survival analysis was used to assess the treatment effect on time to first 
worsening of NPS (NPI-Total ≥10 or NPI subdomain ≥4) for subjects with no or 
minor NPS at baseline.
RESULTS: Participants on high dose semagecestat (140 mg) had greater increase in 
NPI-Total and greater risk of incident first worsening in NPI-Total and in 
subdomains of aberrant motor behavior, appetite, depression/dysphoria, and 
sleep. ADAS11 increased more in participants whose NPI-Total increased.
CONCLUSION: In participants with mild to moderate AD, high dose semagacestat 
treatment was associated with greater severity and faster worsening of NPS in a 
pattern resembling an agitated depression. Increased NPS was associated with 
cognitive decline regardless of treatment assignment. These findings suggest 
that greater NPS may be the result of gamma-secretase treatment and emphasize 
the importance of monitoring NPS as potential adverse events in trials of novel 
treatments for AD.