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 mut...
| Authors: | ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; |
|---|---|
| Format: | Article |
| Status: | Accepted version |
| Publication date: | 2014 |
| Country: | Colombia |
| Institution: | Universidad de Antioquia |
| Repository: | Repositorio UdeA |
| Language: | English |
| OAI Identifier: | oai:bibliotecadigital.udea.edu.co:10495/47901 |
| Online Access: | https://hdl.handle.net/10495/47901 |
| Access Level: | Open access |
| Keyword: | 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 |
| Summary: | 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. |
|---|