title: Pharmacological Agents Targeting γ-Secretase Increase Risk of Cancer and Cognitive Decline in Alzheimer's Disease Patients: A Systematic Review and Meta-Analysis.
abstract: Drugs targeting γ-secretase in Alzheimer's disease (AD) have failed to demonstrate efficacy in clinical trials.
  
  
  
  To perform a meta-analysis of randomized controlled trials (RCTs) to evaluate the efficacy and safety of drugs targeting γ-secretase in AD.
  
  
  
  Ten trials were identified involving 5,227 patients using electronic databases and manual review of reference lists. RCTs of at least two weeks duration involving a drug targeting γ-secretase were eligible. The main outcomes examined were adverse events and cognitive measures (ADAS-cog, MMSE, ADCS-ADL, and CDR-sb). A sub-group analysis was performed, excluding the γ-secretase modulator tarenflurbil, to evaluate the safety and efficacy of γ-secretase inhibitors only.
  
  
  
  There was an increased risk of adverse events (Odds Ratio (OR) 1.38, 95% CI 1.09-1.73; p = 0.01), serious adverse events (OR 1.50, 95% CI 1.22-1.84; p < 0.001), and skin cancers (OR 4.77, 95% CI 2.83-8.06; p < 0.001). There was significantly increased risk of infections (OR 1.36, 95% CI 1.13-1.63; p < 0.001) in the subgroup analysis excluding tarenflurbil. Pooled results also revealed a worsening in ADAS-cog (difference in means 1.33, 95% CI 0.58-2.08; p < 0.001) and MMSE (difference in means -0.66, 95% CI -0.96 to 0.35; p < 0.001), but not ADCS-ADL or CDR-sb.
  
  
  
  The use of γ-secretase inhibitors is associated with significantly increased risk of serious adverse events including skin cancers, and worsening in cognitive indicators. This evidence indicates that γ-secretase may not be an appropriate target for clinical treatment of AD.
authors.affiliation: The Whiteley-Martin Research Centre, Discipline of Surgery, The University of Sydney, Nepean Hospital, Penrith, NSW, Australia.
authors.forename: Ross
authors.initials: R
authors.lastname: Penninkilampi
authors.affiliation: Department of Psychology, The Ohio State University, Columbus, OH, USA.
authors.forename: Holly M
authors.initials: HM
authors.lastname: Brothers
authors.affiliation: The Whiteley-Martin Research Centre, Discipline of Surgery, The University of Sydney, Nepean Hospital, Penrith, NSW, Australia.
authors.forename: Guy D
authors.initials: GD
authors.lastname: Eslick
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D014150:Antipsychotic Agents / Q000009:adverse effects*; D003072:Cognition Disorders / Q000139:chemically induced*; D016206:Databases, Bibliographic / Q000706:statistics & numerical data; D006801:Humans; D009369:Neoplasms / Q000139:chemically induced*; D016032:Randomized Controlled Trials as Topic
chemical_list: D014150:Antipsychotic Agents; D053829:Amyloid Precursor Protein Secretases
keywords: Alzheimer’s disease; amyloid beta-peptides; avagacestat; gamma-secretase; meta-analysis; semagacestat; tarenflurbil