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APOE, TOMM40, and sex interactions on neural network connectivity

Li T 1 , Pappas C 2 , Le ST 2 , Wang Q 2 , Klinedinst BS 3 , Larsen BA 4 Show all authors , Pollpeter A 2 , Lee LY 5 , Lutz MW 6 , Gottschalk WK 6 , Swerdlow RH 7 , Nho K 8 , Willette AA 9

Affiliations 

  • 1 Department of Food Science and Human Nutrition, Iowa State University, Ames, IA, USA; Graduate Genetics and Genomics Program, Iowa State University, Ames, IA, USA. Electronic address: tianqili@iastate.edu
  • 2 Department of Food Science and Human Nutrition, Iowa State University, Ames, IA, USA
  • 3 Department of Food Science and Human Nutrition, Iowa State University, Ames, IA, USA; Graduate Neuroscience Program, Iowa State University, Ames, IA, USA
  • 4 Department of Biomedical Sciences, Iowa State University, Ames, IA, USA; Graduate Neuroscience Program, Iowa State University, Ames, IA, USA
  • 5 Department of Medicine, University of Malaya, Kuala Lumpur, Malaysia
  • 6 Department of Neurology, Duke University, Durham, NC
  • 7 Department of Neurology, University of Kansas, Kansas City, KS
  • 8 Department of Radiology and Imaging Sciences, Indiana University, Indianapolis, IN, USA
  • 9 Department of Food Science and Human Nutrition, Iowa State University, Ames, IA, USA; Department of Biomedical Sciences, Iowa State University, Ames, IA, USA; Department of Psychology, Iowa State University, Ames, IA, USA; Department of Neurology, University of Iowa, Iowa City, IA, USA. Electronic address: Awillett@iastate.edu
Neurobiol Aging, 2022 Jan;109:158-165.
PMID: 34740077 DOI: 10.1016/j.neurobiolaging.2021.09.020

Abstract

The Apolipoprotein E ε4 (APOE ε4) haplotype is the strongest genetic risk factor for late-onset Alzheimer's disease (AD). The Translocase of Outer Mitochondrial Membrane-40 (TOMM40) gene maintains cellular bioenergetics, which is disrupted in AD. TOMM40 rs2075650 ('650) G versus A carriage is consistently related to neural and cognitive outcomes, but it is unclear if and how it interacts with APOE. We examined 21 orthogonal neural networks among 8,222 middle-aged to aged participants in the UK Biobank cohort. ANOVA and multiple linear regression tested main effects and interactions with APOE and TOMM40 '650 genotypes, and if age and sex acted as moderators. APOE ε4 was associated with less strength in multiple networks, while '650 G versus A carriage was related to more language comprehension network strength. In APOE ε4 carriers, '650 G-carriage led to less network strength with increasing age, while in non-G-carriers this was only seen in women but not men. TOMM40 may shift what happens to network activity in aging APOE ε4 carriers depending on sex.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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