title: Extended results of the Alzheimer's disease anti-inflammatory prevention trial.
abstract: BACKGROUND
  Epidemiologic evidence suggests that nonsteroidal anti-inflammatory drugs (NSAIDs) delay onset of Alzheimer's dementia (AD), but randomized trials show no benefit from NSAIDs in patients with symptomatic AD. The Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT) randomized 2,528 elderly persons to naproxen or celecoxib versus placebo for 2 years (standard deviation = 11 months) before treatments were terminated. During the treatment interval, 32 cases of AD revealed increased rates in both NSAID-assigned groups.
  
  
  METHODS
  We continued the double-masked ADAPT protocol for 2 additional years to investigate incidence of AD (primary outcome). We then collected cerebrospinal fluid (CSF) from 117 volunteer participants to assess their ratio of CSF tau to Aβ(1-42.)
  
  
  RESULTS
  Including 40 new events observed during follow-up of 2,071 randomized individuals (92% of participants at treatment cessation), there were 72 AD cases. Overall, NSAID-related harm was no longer evident, but secondary analyses showed that increased risk remained notable in the first 2.5 years of observations, especially in 54 persons enrolled with cognitive impairment--no dementia (CIND). These same analyses showed later reduction in AD incidence among asymptomatic enrollees who were given naproxen. CSF biomarker assays suggested that the latter result reflected reduced Alzheimer-type neurodegeneration.
  
  
  CONCLUSIONS
  These data suggest a revision of the original ADAPT hypothesis that NSAIDs reduce AD risk, as follows: NSAIDs have an adverse effect in later stages of AD pathogenesis, whereas asymptomatic individuals treated with conventional NSAIDs such as naproxen experience reduced AD incidence, but only after 2 to 3 years. Thus, treatment effects differ at various stages of disease. This hypothesis is consistent with data from both trials and epidemiological studies.
authors.affiliation: Centre for Studies on Prevention of Alzheimer's Disease, Douglas Mental Health University Institute Research Centre, Montreal, Quebec, Canada. john.breitner@mcgill.ca
authors.forename: John C
authors.initials: JC
authors.lastname: Breitner
authors.forename: Laura D
authors.initials: LD
authors.lastname: Baker
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Montine
authors.forename: Curtis L
authors.initials: CL
authors.lastname: Meinert
authors.forename: Constantine G
authors.initials: CG
authors.lastname: Lyketsos
authors.forename: Karen H
authors.initials: KH
authors.lastname: Ashe
authors.forename: Jason
authors.initials: J
authors.lastname: Brandt
authors.forename: Suzanne
authors.initials: S
authors.lastname: Craft
authors.forename: Denis E
authors.initials: DE
authors.lastname: Evans
authors.forename: Robert C
authors.initials: RC
authors.lastname: Green
authors.forename: M Saleem
authors.initials: MS
authors.lastname: Ismail
authors.forename: Barbara K
authors.initials: BK
authors.lastname: Martin
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Mullan
authors.forename: Marwan
authors.initials: M
authors.lastname: Sabbagh
authors.forename: Pierre N
authors.initials: PN
authors.lastname: Tariot
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid / Q000517:prevention & control*; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D000068579:Celecoxib; D016001:Confidence Intervals; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D009288:Naproxen / Q000627:therapeutic use*; D009483:Neuropsychological Tests; D010446:Peptide Fragments / Q000134:cerebrospinal fluid; D016016:Proportional Hazards Models; D011569:Psychiatric Status Rating Scales; D011720:Pyrazoles / Q000627:therapeutic use*; D013449:Sulfonamides / Q000627:therapeutic use*; D016875:tau Proteins / Q000134:cerebrospinal fluid
chemical_list: D016229:Amyloid beta-Peptides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D010446:Peptide Fragments; D011720:Pyrazoles; D013449:Sulfonamides; C075222:amyloid beta-protein (1-42); D016875:tau Proteins; D009288:Naproxen; D000068579:Celecoxib