title: The Alzheimer's prevention initiative composite cognitive test score: sample size estimates for the evaluation of preclinical Alzheimer's disease treatments in presenilin 1 E280A mutation carriers.
abstract: OBJECTIVE
  To identify a cognitive composite that is sensitive to tracking preclinical Alzheimer's disease decline to be used as a primary end point in treatment trials.
  
  
  METHODS
  We capitalized on longitudinal data collected from 1995 to 2010 from cognitively unimpaired presenilin 1 (PSEN1) E280A mutation carriers from the world's largest known early-onset autosomal dominant Alzheimer's disease kindred to identify a composite cognitive test with the greatest statistical power to track preclinical Alzheimer's disease decline and estimate the number of carriers age 30 years and older needed to detect a treatment effect in the Alzheimer's Prevention Initiative's (API) preclinical Alzheimer's disease treatment trial. The mean-to-standard-deviation ratios (MSDRs) of change over time were calculated in a search for the optimal combination of 1 to 7 cognitive tests/subtests drawn from the neuropsychological test battery in cognitively unimpaired mutation carriers during a 2- and 5-year follow-up period (n = 78 and 57), using data from noncarriers (n = 31 and 56) during the same time period to correct for aging and practice effects. Combinations that performed well were then evaluated for robustness across follow-up years, occurrence of selected items within top-performing combinations, and representation of relevant cognitive domains.
  
  
  RESULTS
  The optimal test combination included Consortium to Establish a Registry for Alzheimer's Disease (CERAD) Word List Recall, CERAD Boston Naming Test (high frequency items), Mini-Mental State Examination (MMSE) Orientation to Time, CERAD Constructional Praxis, and Raven's Progressive Matrices (Set A), with an MSDR of 1.62. This composite is more sensitive than using either the CERAD Word List Recall (MSDR = 0.38) or the entire CERAD-Col battery (MSDR = 0.76). A sample size of 75 cognitively normal PSEN1 E280A mutation carriers aged 30 years and older per treatment arm allows for a detectable treatment effect of 29% in a 60-month trial (80% power, P = .05).
  
  
  CONCLUSIONS
  We have identified a composite cognitive test score representing multiple cognitive domains that, compared to the most sensitive single test item, has improved power to track preclinical Alzheimer's disease decline in autosomal dominant Alzheimer's disease mutation carriers and to evaluate preclinical Alzheimer's disease treatments. This API composite cognitive test score will be used as the primary end point in the first API trial in cognitively unimpaired autosomal dominant Alzheimer's disease carriers within 15 years of their estimated age at clinical onset. We have independently confirmed our findings in a separate cohort of cognitively healthy older adults who progressed to the clinical stages of late-onset Alzheimer's disease, described in a separate report, and continue to refine the composite in independent cohorts and compared with other analytic approaches.
authors.affiliation: Banner Alzheimer's Institute, 901 E Willetta St, Phoenix, AZ 85006 Napatkamon.Ayutyanont@bannerhealth.com.
authors.forename: Napatkamon
authors.initials: N
authors.lastname: Ayutyanont
authors.forename: Jessica B S
authors.initials: JB
authors.lastname: Langbaum
authors.forename: Suzanne B
authors.initials: SB
authors.lastname: Hendrix
authors.forename: Kewei
authors.initials: K
authors.lastname: Chen
authors.forename: Adam S
authors.initials: AS
authors.lastname: Fleisher
authors.forename: Michel
authors.initials: M
authors.lastname: Friesenhahn
authors.forename: Michael
authors.initials: M
authors.lastname: Ward
authors.forename: Camilo
authors.initials: C
authors.lastname: Aguirre
authors.forename: Natalia
authors.initials: N
authors.lastname: Acosta-Baena
authors.forename: Lucìa
authors.initials: L
authors.lastname: Madrigal
authors.forename: Claudia
authors.initials: C
authors.lastname: Muñoz
authors.forename: Victoria
authors.initials: V
authors.lastname: Tirado
authors.forename: Sonia
authors.initials: S
authors.lastname: Moreno
authors.forename: Pierre N
authors.initials: PN
authors.lastname: Tariot
authors.forename: Francisco
authors.initials: F
authors.lastname: Lopera
authors.forename: Eric M
authors.initials: EM
authors.lastname: Reiman
mesh_terms: D000328:Adult; D000483:Alleles; D000544:Alzheimer Disease / Q000175:diagnosis / Q000235:genetics* / Q000517:prevention & control* / Q000523:psychology; D002869:Chromosome Aberrations; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D018450:Disease Progression; D005799:Genes, Dominant / Q000235:genetics*; D006580:Genetic Carrier Screening; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D008137:Longitudinal Studies; D008875:Middle Aged; D009483:Neuropsychological Tests / Q000706:statistics & numerical data*; D053764:Presenilin-1 / Q000235:genetics*; D011594:Psychometrics / Q000706:statistics & numerical data; D015203:Reproducibility of Results
chemical_list: C508853:PSEN1 protein, human; D053764:Presenilin-1