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Cited by 7Alzheimer's disease research and treatmentsMetabolomics and Mass Spectrometry StudiesDementia and Cognitive Impairment Research

APOE genotype influences on the brain metabolome of aging mice - role for mitochondrial energetics in mechanisms of resilience in APOE2 genotype

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Borkowski, Kamil, Liang, Nuanyi, Zhao, Na, Arnold, Matthias, Huynh, Kevin, Karu, Naama, Mahmoudiandehkordi, Siamak, Kueider-Paisley, Alexandra +4 more·2025·Molecular Neurodegeneration
DOI 10.1186/s13024-025-00888-zPMC PMC12403941

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Abstract

Alzheimer’s disease (AD) risk and progression are significantly influenced by APOE genotype with APOE4 increasing and APOE2 decreasing susceptibility compared to APOE3. While the effect of those genotypes was extensively studied on blood metabolome, less is known about their impact in the brain. Here we investigated the impacts of APOE genotypes and aging on brain metabolic profiles across the lifespan, using human APOE-targeted replacement mice. Biocrates P180 targeted metabolomics platform was used to measure a broad range of metabolites probing various metabolic processes. In all genotypes investigated we report changes in acylcarnitines, biogenic amines, amino acids, phospholipids and sphingomyelins during aging. The decreased ratio of medium to long-chain acylcarnitine suggests a reduced level of fatty acid β-oxidation and thus the possibility of mitochondrial dysfunction as these animals age. Additionally, aging APOE2/2 mice had altered branch-chain amino acids (BCAA) profile and increased their downstream metabolite C5 acylcarnitine, indicating increased branched-chain amino acid utilization in TCA cycle and better energetic profile endowed by this protective genotype. We compared these results with human dorsolateral prefrontal cortex metabolomic data from the Religious Orders Study/Memory and Aging Project, and we found that the carriers of APOE2/3 genotype had lower markers of impaired BCAA katabolism, including tiglyl carnitine, methylmalonate and 3-methylglutaconate. In summary, these results suggest a potential involvement of the APOE2 genotype in BCAA utilization in the TCA cycle and nominate these humanized APOE mouse models for further study of APOE in AD, brain aging, and brain BCAA utilization for energy. We have previously shown lower plasma BCAA to be associated with incident dementia, and their higher levels in brain with AD pathology and cognitive impairment. Those findings together with our current results could potentially explain the AD-protective effect of APOE2 genotype by enabling higher utilization of BCAA for energy during the decline of fatty acid β-oxidation.

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  • Increases in 3- and 4-hydroxyphenylacetic acid in 4s2M are consistent with alterations in aromatic amino acid-related metabolic flux; such metabolites can arise from tyrosine and monoamine pathways and may reflect systemic metabolic influences rather than direct energetic pathway remodeling.

    “In contrast, increases in 3- and 4-hydroxyphenylacetic acid in 4s2M are consistent with alterations in aromatic amino acid–related metabolic flux; such metabolites can arise from tyrosine and monoamine pathways and may reflect systemic metabolic influences rather than direct energetic pathway remodeling”

    From Older adult APOE4 mice exhibit modest immunometabolic adaptation following microglial APOE2 replacement (2027) · cites this paper as Borkowski et al., 2025

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Cited by

Sorted by citations

Authors
Borkowski, K., Liang, N., Zhao, N., Arnold, M., Huynh, K., Karu, N., Mahmoudiandehkordi, S., Kueider-Paisley, A., Kanekiyo, T., Bu, G., Kaddurah-Daouk, R., & the Alzheimer’s Disease Metabolomics Consortium
Affiliations
  • University of California, Davis (US)
  • Mayo Clinic (US)
  • Duke University (US)
  • The University of Melbourne (AU)
  • Hong Kong University of Science and Technology (HK)
Corresponding author
Borkowski, Kamil
ORCID
Venue
Molecular Neurodegeneration
Publisher
Springer Science and Business Media LLC
Published
2025-09-02
Volume
20
Issue
1
Pages
97-97
ISSN
1750-1326 (ISSN-L)
DOI
10.1186/s13024-025-00888-z
PMC
PMC12403941
OpenAlex
W4413934740
Cited by
7
References
6
Citations by year
2026: 6 · 2025: 1
FWCI
3.93
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Neurodegeneration (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed Central (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Minerva Access (University of Melbourne) (submittedVersion, cc-by)
  • Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
Funders
National Institute on Aging (R01AG069901, RF1AG051504, R01AG081322)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolomics and Mass Spectrometry Studies
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
APOE genotype, APOE2, APOE ε4, brain metabolome, brain aging, Alzheimer's disease, mitochondrial dysfunction, fatty acid beta-oxidation, acylcarnitines, branched-chain amino acids, TCA cycle, brain energy metabolism, dorsolateral prefrontal cortex, phospholipids, sphingomyelin, biogenic amines

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