Post Hoc Analyses of ApoE Genotype-Defined Subgroups in Clinical Trials

Journal of Alzheimer's Disease : JAD
Richard E KennedyLon S Schneider

Abstract

Many post hoc analyses of clinical trials in Alzheimer's disease (AD) and mild cognitive impairment (MCI) are in small Phase 2 trials. Subject heterogeneity may lead to statistically significant post hoc results that cannot be replicated in larger follow-up studies. We investigated the extent of this problem using simulation studies mimicking current trial methods with post hoc analyses based on ApoE4 carrier status. We used a meta-database of 24 studies, including 3,574 subjects with mild AD and 1,171 subjects with MCI/prodromal AD, to simulate clinical trial scenarios. Post hoc analyses examined if rates of progression on the Alzheimer's Disease Assessment Scale-cognitive (ADAS-cog) differed between ApoE4 carriers and non-carriers. Across studies, ApoE4 carriers were younger and had lower baseline scores, greater rates of progression, and greater variability on the ADAS-cog. Up to 18% of post hoc analyses for 18-month trials in AD showed greater rates of progression for ApoE4 non-carriers that were statistically significant but unlikely to be confirmed in follow-up studies. The frequency of erroneous conclusions dropped below 3% with trials of 100 subjects per arm. In MCI, rates of statistically significant differences with g...Continue Reading

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Citations

Sep 22, 2019·Scientific Reports·Charles K FisherUNKNOWN Abbott, Alliance for Aging Research, Alzheimer’s Association, Alzheimer’s Foundation of America, AstraZeneca Pharmaceuticals
Apr 30, 2020·Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics·Somin KwonEliezer Masliah
Jun 17, 2020·Journal of Alzheimer's Disease : JAD·Mackenzie E FowlerUNKNOWN Alzheimer’s Disease Neuroimaging Initiative
Jun 10, 2017·Journal of Alzheimer's Disease : JAD·Heather M WilkinsRussell H Swerdlow

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