Potential utility of using both APOEε4 and Aβ positivity to enrich clinical trials of tau‐targeting therapies

Background The use of enrichment strategies is crucial for selecting individuals with the highest probability of Alzheimer’s disease (AD)‐related progression in typical clinical trial time frames. Although both amyloid‐ß (Aß) pathology and the apolipoprotein E e4 (APOEe4) genotype have been shown to accelerate tau accumulation, it is still not clear whether assessing both APOEe4 genotype and Aß positivity is useful to enrich tau‐targeting trials using tau positron emission tomography (PET) as outcome. Here, we investigated the implications of considering APOEe4 carriership for population enrichment in trials testing drug effects on tau tangle deposition in cognitively impaired (CI) individuals across the AD continuum. Method We studied 29 Aß positive CI individuals (16 with mild cognitive impairment [MCI] and 13 with AD dementia) from the McGill Translational Biomarkers in Aging and Dementia (TRIAD) cohort. Study participants underwent clinical assessments, APOE genotyping, magnetic resonance imaging, PET for Aß ([18F]AZD4694) and tau ([18F]MK6240) at baseline, as well as a follow‐up tau‐PET scan (mean follow‐up, 2.2 years). Aß positivity was determined as global [18F]AZD4694 SUVR = 1.55. Result No demographic differences were observed between APOEe4 carriers and noncarriers (Table 1). Regression analysis revealed that APOEe4 carriers had higher tau‐PET SUVR increase in temporal regions compared to APOEe4 noncarriers (Figure 1). The use of Aß positivity alone for population enrichment of a clinical trial focusing on CI individuals would require a sample size of 436 individuals per study arm to test a 25% drug effect on tau‐PET accumulation (Figure 2). A similar clinical trial with a population enrichment strategy using Aß positivity plus APOEe4 carriership would require a sample size of as few as 158 individuals per study arm (reduction of 64% in relation to using only Aß positivity) to test the same drug effect (Figure 2). Conclusion Our results reveal that APOEe4 carriership is associated with increased tau tangle accumulation in CI individuals who are Aß positive. Clinical trials testing drug effects on tangle deposition may benefit from assessing both APOEe4 carriership and Aß positivity statuses as enrollment criteria to select individuals at higher risk of fast tau accumulation, resulting in a more cost‐effective trial.