<i>APOE</i> ε4 genotyping for populational enrichment of tau‐targeting clinical trials in cognitively impaired individuals

Abstract Background The accumulation of tau tangle deposits is a potential target for clinical trials in Alzheimer's disease (AD). It is known that amyloid‐β (Aβ) pathology and the apolipoprotein E ε4 ( APOE ε4) allele accelerate tau pathology; yet, it is unclear whether assessing both variables could lead to more cost‐effective tau‐targeting trials using tau positron emission tomography (PET) as outcome. Here, we investigated the potential utility of considering APOE ε4 carriership for population enrichment in AD trials testing drug effects on tau tangle deposition in cognitively impaired (CI) individuals. Method Data was retrieved from the ADNI cohort. We selected CI participants with available clinical assessments, APOE genotyping, Aβ PET ([ 18 F]Florbetapir or [ 18 F]Florbetaben) and tau PET ([ 18 F]Flortaucipir) at baseline and a 2‐year follow‐up. Patients with global [ 18 F]Florbetapir SUVR >1.11 or [ 18 F]Florbetaben SUVR >1.08 were considered Aβ positive (Aβ+). We calculated required sample size and total costs for a hypothetical clinical trial testing a 25% drug effect on reducing tau PET accumulation in the medial temporal lobe (MTL) and neocortex (NEO) with 80% power at alpha level 0.05. Result We studied 78 CI individuals over a mean (SD) of 2.16 (0.31) years of follow up (Table 1). Figure 1 displays enrichment strategies based on the use of Aβ positivity alone or APOE ε4 carriership associated with Aβ positivity for the selection of patients for a hypothetical tau‐targeting trial in CI individuals. The addition of APOE ε4 carriership to Aβ positivity in the population enrichment strategy would notably reduce the required sample sizes (tau PET MTL = 53% and tau PET NEO = 41%), as well as trial costs (tau PET MTL = 55% and tau PET NEO = 44%), compared to using Aβ positivity alone (Figure 2). Conclusion Our results support that using APOE ε4 genotype together with Aβ positivity for population enrichment to select individuals at higher risk of fast tau accumulation could potentially reduce required sample sizes and costs for tau‐targeting trials focusing on CI individuals. Hence, this may be a cost‐effective strategy.

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