Work

ABCA1 rare variants interact with APOE isoforms to confer Alzheimer’s Disease risk

Year: 2024

Type: article

Abstract: BACKGROUND: Several lines of evidence now suggest that ABCA1 plays a role in Alzheimer's disease (AD). Rare variants on ABCA1 increased AD risk in a large genetic study, and mouse models suggest that increasing ABCA1 activity can reverse signs of AD pathology. While there is growing consensus that ABCA1 and ApoE directly interact, it is unclear how APOE genotype affects this interaction in the context of neurodegeneration. METHOD: We conducted burden tests of rare variants (MAF < 1%) on ABCA1 either causing loss of function or having a REVEL score above 0.75 in European-ancestry participants from ADSP whole-genome (WGS), whole-exome (WES) sequencing, and UK Biobank WES datasets. All analyses were adjusted for sex, PCs 1-4, and sequencing platform. Stratifying by APOE genotype, we tested the association between ABCA1 variant carrier status and AD using logistic regression, then meta-analyzed the results with fixed-effect inverse-weighted variance. To test directly for an APOE interaction with ABCA1, we analyzed all APOE genotypes together adding interaction terms ε2*ABCA1 and ε4*ABCA1, and additionally adjusted for APOE ε2/ε4 dosages. RESULT: Carrying an ABCA1 variant was associated with increased AD risk in APOE ε2/ε3 and ε3/ε3 cohorts. In contrast, the association was not significant in ε3/ε4 or ε4/ε4 (Fig. 1). Models including cross-terms in the whole-APOE cohort supported an interaction between ABCA1 variants and APOE ε4 dosage diminishing risk compared to having an ABCA1 variant by itself (Table 1). Analysis of missense variants by themselves showed a significant protective effect for extracellular domain mutations in ε3/ε4, whereas they increased risk in ε3/ε3 and showed no effect in ε2/ε3 (Fig. 2). Conversely, ε2/ε3 saw a risk-increasing association only with nucleotide-binding domain mutations. CONCLUSION: ABCA1 rare variants are associated with AD risk and the effect size appears to be modulated by APOE genotype, showing significant interaction with ε4 dosage. This suggests an interplay between ABCA1 and different ApoE isoforms in contributing to AD, highlighting a potential pathogenic mechanism. Further, as extracellular domain mutations show diverging impacts on AD risk depending on APOE genotype, this domain may play a critical role in the pathogenic interaction between ABCA1 and ApoE.

Source: Alzheimer s & Dementia

DOI: 10.1002/alz.092053

Authors: Andrés Peña‐Tauber, Ricardo Hernandez Arriaza, Yann Le Guen, Chaitan Khosla, Michael D Greicius

Institutions: Stanford Medicine, Stanford University

Language: English

Topic: Alzheimer's disease research and treatments

Subfield: Physiology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $4,000