Optimal age and outcome measures for Alzheimer's disease prevention trials in people with Down syndrome.

Rosalyn Hithersay,Andre Strydom,Ben Carter,R Asaad Baksh,Carla M Startin,Peter Wijeratne,Sarah Hamburg

doi:10.1002/alz.12222

Abstract

People with Down syndrome (DS) typically develop Alzheimer's disease (AD) neuropathology before age 40, but a lack of outcome measures and longitudinal data have impeded their inclusion in randomized controlled trials (RCTs). Cohort study. Event-based and dose-response Emax models were fitted to longitudinal cognitive data, to stage AD and determine the earliest ages of decline. Results informed sample size estimations for hypothetical RCTs of disease-modifying treatments that reduced decline by 35% or 75%. Seventy-five percent of participants progressed or remained stable in the AD staging model; effect sizes varied by age group and tests. Varied treatment effects could be detected with 50-200 people per arm when using sensitive cognitive outcome measures and targeting recruitment to ages 36 to 45 years. Efficient RCTs of AD preventative treatments can be conducted in the DS population using sensitive outcome measures to monitor early decline. Dose-response models could help tailor future RCTs.

Highlights

People with Down syndrome (DS) typically develop Alzheimer’s disease (AD) neuropathology before age 40, but a lack of outcome measures and longitudinal data have impeded their inclusion in randomized controlled trials (RCTs)
Interpretation: This study shows that existing cognitive tools can be used to detect early cognitive decline in adults with DS, and provides approaches for determining optimal age bands and outcome measures for clinical trials
In keeping with the European Medicines Agency guidance highlighting the need to identify subscales and items that are sensitive during early stages of symptomatic AD,[11] we aimed to use longitudinal data from a DS cohort study to: 1. Validate a dementia staging model with new data in order to identify the earliest stages of AD-related cognitive decline and cognitive tests associated with these changes

Summary

Introduction

People with Down syndrome (DS) typically develop Alzheimer’s disease (AD) neuropathology before age 40, but a lack of outcome measures and longitudinal data have impeded their inclusion in randomized controlled trials (RCTs). Event-based and dose-response Emax models were fitted to longitudinal cognitive data, to stage AD and determine the earliest ages of decline. Varied treatment effects could be detected with 50-200 people per arm when using sensitive cognitive outcome measures and targeting recruitment to ages 36 to 45 years. Discussion: Efficient RCTs of AD preventative treatments can be conducted in the DS population using sensitive outcome measures to monitor early decline. Dose-response models could help tailor future RCTs. Trisomy 21 (“Down syndrome”; DS) is the most common genetic driver of early-onset Alzheimer’s disease (AD),[1] present in approximately. Aside from being a missed scientific opportunity, this exclusion limits access to health care that is appropriate and targeted to this population’s needs

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