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Inter- and intra-chromosomal modulators of the APOE ɛ2 and ɛ4 effects on the Alzheimer's disease risk.

Publication ,  Journal Article
Nazarian, A; Philipp, I; Culminskaya, I; He, L; Kulminski, AM
Published in: GeroScience
February 2023

The mechanisms of incomplete penetrance of risk-modifying impacts of apolipoprotein E (APOE) ε2 and ε4 alleles on Alzheimer's disease (AD) have not been fully understood. We performed genome-wide analysis of differences in linkage disequilibrium (LD) patterns between 6,136 AD-affected and 10,555 AD-unaffected subjects from five independent studies to explore whether the association of the APOE ε2 allele (encoded by rs7412 polymorphism) and ε4 allele (encoded by rs429358 polymorphism) with AD was modulated by autosomal polymorphisms. The LD analysis identified 24 (mostly inter-chromosomal) and 57 (primarily intra-chromosomal) autosomal polymorphisms with significant differences in LD with either rs7412 or rs429358, respectively, between AD-affected and AD-unaffected subjects, indicating their potential modulatory roles. Our Cox regression analysis showed that minor alleles of four inter-chromosomal and ten intra-chromosomal polymorphisms exerted significant modulating effects on the ε2- and ε4-associated AD risks, respectively, and identified ε2-independent (rs2884183 polymorphism, 11q22.3) and ε4-independent (rs483082 polymorphism, 19q13.32) associations with AD. Our functional analysis highlighted ε2- and/or ε4-linked processes affecting the lipid and lipoprotein metabolism and cell junction organization which may contribute to AD pathogenesis. These findings provide insights into the ε2- and ε4-associated mechanisms of AD pathogenesis, underlying their incomplete penetrance.

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Published In

GeroScience

DOI

EISSN

2509-2723

ISSN

2509-2715

Publication Date

February 2023

Volume

45

Issue

1

Start / End Page

233 / 247

Related Subject Headings

  • Humans
  • Genotype
  • Apolipoproteins E
  • Apolipoprotein E2
  • Alzheimer Disease
  • 3202 Clinical sciences
  • 3105 Genetics
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Nazarian, A., Philipp, I., Culminskaya, I., He, L., & Kulminski, A. M. (2023). Inter- and intra-chromosomal modulators of the APOE ɛ2 and ɛ4 effects on the Alzheimer's disease risk. GeroScience, 45(1), 233–247. https://doi.org/10.1007/s11357-022-00617-0
Nazarian, Alireza, Ian Philipp, Irina Culminskaya, Liang He, and Alexander M. Kulminski. “Inter- and intra-chromosomal modulators of the APOE ɛ2 and ɛ4 effects on the Alzheimer's disease risk.GeroScience 45, no. 1 (February 2023): 233–47. https://doi.org/10.1007/s11357-022-00617-0.
Nazarian A, Philipp I, Culminskaya I, He L, Kulminski AM. Inter- and intra-chromosomal modulators of the APOE ɛ2 and ɛ4 effects on the Alzheimer's disease risk. GeroScience. 2023 Feb;45(1):233–47.
Nazarian, Alireza, et al. “Inter- and intra-chromosomal modulators of the APOE ɛ2 and ɛ4 effects on the Alzheimer's disease risk.GeroScience, vol. 45, no. 1, Feb. 2023, pp. 233–47. Epmc, doi:10.1007/s11357-022-00617-0.
Nazarian A, Philipp I, Culminskaya I, He L, Kulminski AM. Inter- and intra-chromosomal modulators of the APOE ɛ2 and ɛ4 effects on the Alzheimer's disease risk. GeroScience. 2023 Feb;45(1):233–247.

Published In

GeroScience

DOI

EISSN

2509-2723

ISSN

2509-2715

Publication Date

February 2023

Volume

45

Issue

1

Start / End Page

233 / 247

Related Subject Headings

  • Humans
  • Genotype
  • Apolipoproteins E
  • Apolipoprotein E2
  • Alzheimer Disease
  • 3202 Clinical sciences
  • 3105 Genetics