# APOEε4 genotyping for populational enrichment of tau‐targeting clinical trials in cognitively impaired individuals

## TL;DR

This study shows that combining APOEε4 genotyping with amyloid-beta PET scans can reduce sample sizes and costs in clinical trials targeting tau accumulation in Alzheimer's disease.

## Contribution

The study demonstrates that combining APOEε4 carriership with Aβ positivity improves population enrichment for tau-targeting trials.

## Key findings

- Combining APOEε4 and Aβ positivity reduces required sample sizes by 53% in the medial temporal lobe and 41% in the neocortex.
- This strategy also reduces trial costs by 55% in the medial temporal lobe and 44% in the neocortex compared to using Aβ positivity alone.

## Abstract

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 (APOEε4) 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 APOEε4 carriership for population enrichment in AD trials testing drug effects on tau tangle deposition in cognitively impaired (CI) individuals.

Data was retrieved from the ADNI cohort. We selected CI participants with available clinical assessments, APOE genotyping, Aβ PET ([18F]Florbetapir or [18F]Florbetaben) and tau PET ([18F]Flortaucipir) at baseline and a 2‐year follow‐up. Patients with global [18F]Florbetapir SUVR >1.11 or [18F]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.

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 APOEε4 carriership associated with Aβ positivity for the selection of patients for a hypothetical tau‐targeting trial in CI individuals. The addition of APOEε4 carriership to Aβ positivity in the population enrichment strategy would notably reduce the required sample sizes (tau PETMTL = 53% and tau PETNEO = 41%), as well as trial costs (tau PETMTL = 55% and tau PETNEO = 44%), compared to using Aβ positivity alone (Figure 2).

Our results support that using APOEε4 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.