# Utility of APOE testing for reducing ARIA under probabilistic stopping rates to treat with anti-amyloid therapy for ε4-homozygote patients: A simulation study

## TL;DR

This study uses simulations to evaluate how APOE testing can help reduce ARIA risks in anti-amyloid treatments for ε4-homozygote patients.

## Contribution

The study introduces a Bayesian simulation framework to quantify the utility of APOE testing in mitigating ARIA under varying treatment discontinuation probabilities.

## Key findings

- NNTs to prevent ARIA events increase as treatment discontinuation probability decreases.
- Even with universal discontinuation policies, APOE testing only moderately reduces total ARIA events.
- APOE testing's main benefit is in supporting decision-making rather than significantly improving safety.

## Abstract

APOE ε4/ε4 genotype increases the risk of Amyloid-Related Imaging Abnormalities (ARIA) from anti-amyloid antibody treatment (AAT). While guidelines recommend testing, its practical utility depends on the resulting probability (p) that treatment is actually withheld for ε4-homozygotes, which varies significantly across clinical settings.

To quantify the Number Needed to Test (NNT) to prevent one ARIA event as a function of p of withholding AAT in ε4/ε4 patients.

A Bayesian simulation study using a Beta-Binomial model to analyze genotype-stratified contingency tables.

Data were derived from two published, phase 3 clinical trials: Clarity-AD (lecanemab) and TRAILBLAZER-ALZ 2 (donanemab).

Aggregate data from source trials.

Simulation of varying treatment discontinuation probability p from 0 (none) to 1 (universal for ε4-homozygotes).

NNT to prevent one ARIA event (any ARIA-E, any ARIA-H, and symptomatic ARIA-E) and the fractional reduction in total ARIA events as a function of p.

NNTs increased (worsened) significantly as p decreased. Under the most conservative policy (p = 1), the median NNT to prevent one any ARIA-E event was 20–30 (lecanemab) and 15–25 (donanemab), yet this only reduced total ARIA events by 10–30%. The NNT to prevent one symptomatic ARIA-E (lecanemab) was substantially higher, at 70–90 (at p = 1).

The direct safety impact of APOE testing for ARIA mitigation is limited, even under universal discontinuation policies. Its primary value lies in supporting shared decision-making and operational planning rather than as a standalone safety lever.