Neurology News

APOE Carriers Show Higher Risk for Amyloid-Related Imaging Abnormalities

Apolipoprotein E (APOE) genotypes are associated with the risk for amyloid-related imaging abnormalities (ARIA), according to the results of a genome-wide association study (GWAS) published in Neurology.

Previous trials of anti-amyloid monoclonal antibodies have reported an association between APOE e4 carriage and drug-induced ARIA risk, however, no studies have evaluated the rest of the human genome for risk alleles.

Researchers sourced data for this GWAS from the phase 3 ENGAGE (ClinicalTrials.gov Identifier: NCT02477800) and EMERGE (ClinicalTrials.gov Identifier: NCT02484547) trials that assessed aducanumab among patients with mild cognitive impairment (MCI) associated with Alzheimer disease (AD). In this study, the subset of individuals (n=1691; mean age, 70.3; 51% women) who received ³1 dose of aducanumab, had ³1 post-baseline magnetic resonance image (MRI), and had genotyping array data were assessed for ARIA risk. Among the study population, 50% had APOE e3/e4 genotype.

[W]e identified a robust association between genetic variants at the APOE locus and risk of developing aducanumab-related ARIA-E and ARIA-H, with no additional associations observed beyond this region.

The most significant association with ARIA risk was located in the APOE region. When conditioning on APOE, no additional variants reached genome-wide significance.

The association between ARIA and APOE was dose-dependent. Risk for ARIA with edema or sulcal effusion (ARIA-E) was associated with APOE e3/e4 (odds ratio [OR], 1.74; P =.0002), APOE e2/e4 (OR, 2.60; P =.01), and APOE e4/e4 (OR, 4.28; P =6.2E-17).

For ARIA with hemorrhage (ARIA-H), significant associations were observed for APOE e3/e4 for ARIA-H with microhemorrhage (OR, 1.46; P =.03) or with superficial siderosis (OR, 3.14; P =3.2E-6) and APOE e4/e4 for ARIA-H with microhemorrhage (OR, 4.58; P =2.9E-14) or with superficial siderosis (OR, 7.84; P =7.8E-15).

Stratified by ARIA severity, compared with control individuals, APOE e3/e4 was associated with risk for:

  • mild (relative risk [RR], 1.55; P =.02) and moderate (RR, 1.53; P =.005) ARIA-E;
  • mild (RR, 2.68; P =.0002) and severe (RR, 4.18; P =.01) ARIA-H with superficial siderosis;
  • APOE e4/e4 with mild (RR, 2.44; P =1.37E-5), moderate (RR, 2.77; P =2.89E-11), and severe (RR, 3.58; P =2.72E-5) ARIA-E;
  • mild (RR, 2.32; P =1.83E-7), moderate (RR, 3.70; P =.001), and severe (RR, 4.79; P =2.38E-6) ARIA-H with microhemorrhage; and
  • mild (RR, 3.57; P =6.76E-6), moderate (RR, 4.76; P =4.05E-6), and severe (RR, 7.32; P =2.06E-5) ARIA-H with superficial siderosis.

Stratified by symptomatic status, relative to control individuals, APOE e3/e4 was associated with:

  • symptomatic (RR, 1.59; P =.03) and asymptomatic (RR, 1.53; P =.001) ARIA-E;
  • asymptomatic ARIA-H with microhemorrhage (RR, 1.38; P =.03);
  • symptomatic (RR, 3.48; P =.04) and asymptomatic (RR, 2.51; P =2.1E-5) ARIA-H with superficial siderosis;
  • APOE e4/e4 with symptomatic (RR, 2.56; P =3.8E-5) and asymptomatic (RR, 2.90; P =2.2E-15) ARIA-E;
  • asymptomatic (RR, 3.55; P =8.3E-5) and symptomatic (RR, 2.72; P =1.7E-11) ARIA-H with microhemorrhage; and
  • symptomatic (RR, 5.14; P =.004) and asymptomatic (RR, 4.69; P =1.2E-13) ARIA-H with superficial siderosis.

Risk for ARIA-E combined with ARIA-H microhemorrhage was associated with

  • APOE e3/e4 (OR, 1.66; P =.02) and e4/e4 (OR, 5.55; P =2.16E-13) and
  • combined with ARIA-H with superficial siderosis with APOE e3/e4 (OR, 3.45; P =6.42E-6) and e4/e4 (OR, 8.90; P =6.75E-14).

“[W]e identified a robust association between genetic variants at the APOE locus and risk of developing aducanumab-related ARIA-E and ARIA-H, with no additional associations observed beyond this region.”

Disclosures: This research was supported by Biogen. Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.

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