Population enrichment strategy using APOEε4 genotype in tau‐targeting trials for preclinical Alzheimer's disease

TL;DR

This study shows that combining APOEε4 genotype with amyloid-beta status can make Alzheimer's disease trials more efficient by reducing the number of participants needed and lowering costs.

Contribution

The novelty is demonstrating that using APOEε4 genotyping alongside amyloid-beta positivity improves participant selection for tau-targeting Alzheimer's trials.

Findings

Combining APOEε4 and amyloid-beta status reduces sample size by 28% and costs by 34% for medial temporal lobe tau trials.

The same strategy reduces sample size by 24% and costs by 36% for neocortex tau trials.

Abstract

Trials in preclinical Alzheimer's disease (AD) are becoming increasingly important, as AD pathological changes appear decades before dementia onset. Amyloid‐beta (Aβ) pathology and the apolipoprotein E ε4 (APOEε4) carriership jointly accelerate tau tangle accumulation. However, the utility of assessing both variables to enhance participant selection for AD trials using tau positron emission tomography (PET) as outcome has not yet been explored. Here, we investigated the implications of considering APOEε4 status for participant selection in tau‐targeting trials for preclinical AD.

We analyzed 96 cognitively unimpaired (CU) individuals (aged 57‐90 years) from the ADNI cohort that underwent clinical assessments, APOE genotyping, PET for Aβ ([18F]Florbetapir or [18F]Florbetaben) and tau ([18F]Flortaucipir) at baseline, along with a 2‐year follow‐up. Aβ positivity was determined as global [18F]Florbetapir SUVR >1.11 or [18F]Florbetaben SUVR >1.08. We calculated the sample size required for a hypothetical clinical trial testing a 25% drug effect, with 80% power at alpha level 0.05, to reduce tau‐PET accumulation in the medial temporal lobe (MTL) and neocortex (NEO), along with the total trial costs.

Table 1 reports the demographic information of the study population. Figure 1 shows enrichment strategies for the selection of participants in a clinical trial aiming at tau PET reduction in CU individuals. In comparison to using only Aβ positivity, the use of APOEε4 genotyping together with Aβ positivity for population enrichment would reduce the sample size and total costs, respectively, by 28% and 34% in trials targeting tau PETMTL, and by 24% and 36%, respectively, in trials targeting tau PETNEO (Figure 2).

Our findings suggest that combining APOEε4 status with Aβ positivity may be a cost‐effective strategy for enriching participant selection in AD tau‐targeting trials focusing on asymptomatic individuals, reducing required sample sizes and trial costs.

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