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

Objective— There is a need to identify a cognitive composite that is sensitive to tracking preclinical AD decline to be used as a primary endpoint in treatment trials. Method— 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 AD (ADAD) kindred to identify a composite cognitive test with the greatest statistical power to track preclinical AD decline and estimate the number of carriers age 30 and older needed to detect a treatment effect in the Alzheimer’s Prevention Initiative’s (API) preclinical AD treatment trial. The mean-to-standard-deviation ratios (MSDRs) of change over time were calculated in a search for the optimal combination of one to seven cognitive tests/sub-tests drawn from the neuropsychological test battery in cognitively unimpaired mutation carriers during a two and five year follow-up period, using data from non-carriers 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— This optimal test combination included CERAD Word List Recall, CERAD Boston Naming Test (high frequency items), MMSE Orientation to Time, CERAD Constructional Praxis and Ravens 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 age 30 and older per treatment arm allows for a detectable treatment effect of 29% in a 60-month trial (80% power, p=0.05). Conclusions— We have identified a composite cognitive test score representing multiple cognitive domains that has improved power compared to the most sensitive single test item to track preclinical AD decline in ADAD mutation carriers and evaluate preclinical AD treatments. This API composite cognitive test score will be used as the primary endpoint in the first API trial in cognitively unimpaired ADAD 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 AD, described in a separate report, and continue to refine the composite in independent cohorts and compared with other analytical approaches.

• Autores: Lopera Restrepo, Francisco Javier; Napatkamon Ayutyanont; Langbaum, Jessica B.; Hendrix, Suzanne B.; Fleisher, Adam S.; Friesenhahn, Michel; Ward, Michael; Aguirre Acevedo, Daniel Camilo; Acosta Baena, Natalia; Madrigal Zapata, Lucía del Socorro; Muñoz, Claudia; Tirado Pérez, Victoria Claudia; Moreno Masmela, Sonia; Chen, Kewei; Tariot, Pierre N.; Reiman, Eric M.
• Tipo de recurso: Article of investigation
• Fecha de publicación: 2014
• Institución: Universidad de Antioquia
• Repositorio: Repositorio UdeA
• Idioma: eng
• OAI Identifier: oai:bibliotecadigital.udea.edu.co:10495/47901
• Acceso en línea: https://hdl.handle.net/10495/47901
• Palabra clave: 610 - Medicina y salud; Enfermedad de Alzheimer; Alzheimer Disease; Aberraciones Cromosómicas; Chromosome Aberrations; Análisis Mutacional de ADN; DNA Mutational Analysis; Progresión de la Enfermedad; Disease Progression; Genes Dominantes; Genes, Dominant; Tamización de Portadores Genéticos; Genetic Carrier Screening; Predisposición Genética a la Enfermedad; Genetic Predisposition to Disease; Presenilina-1; Presenilin-1; https://id.nlm.nih.gov/mesh/D000544; https://id.nlm.nih.gov/mesh/D002869; https://id.nlm.nih.gov/mesh/D004252; https://id.nlm.nih.gov/mesh/D018450; https://id.nlm.nih.gov/mesh/D005799; https://id.nlm.nih.gov/mesh/D006580; https://id.nlm.nih.gov/mesh/D020022; https://id.nlm.nih.gov/mesh/D053764; ODS 3: Salud y bienestar. Garantizar una vida sana y promover el bienestar de todos a todas las edades
• Rights: openAccess
• License: http://purl.org/coar/access_right/c_abf2