Changes in neuropsychiatric inventory associated with semagacestat treatment of Alzheimer's disease

Paul B. Rosenberg, Krista L. Lanctot, Nathan Herrmann, Jacobo E. Mintzer, Anton P. Porsteinsson, Xiaoying Sun, Rema Raman

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


Background: In a recent report, 76 weeks treatment with a gamma-secretase inhibitor (semagacestat) was associated with poorer cognitive outcomes in Alzheimers 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 Alzheimers Disease Assessment Scale-Cognitive (first 11 items, ADAS11). Mixed-Model Repeated Measureswas 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.

Original languageEnglish (US)
Pages (from-to)373-381
Number of pages9
JournalJournal of Alzheimer's Disease
Issue number1
StatePublished - Aug 23 2016


  • Alzheimer's disease
  • Amyloid
  • Clinical trial
  • Depression
  • Neuropsychiatry

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Psychology
  • Geriatrics and Gerontology
  • Psychiatry and Mental health


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