Cited by 310Alzheimer's disease research and treatmentsFatty Acid Research and HealthDementia and Cognitive Impairment Research

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Association between fatty acid metabolism in the brain and Alzheimer disease neuropathology and cognitive performance: A nontargeted metabolomic study

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Snowden, Stuart G., Ebshiana, Amera A., Hye, Abdul, An, Yang, Pletnikova, Olga, O’Brien, Richard, Troncoso, John, Legido-Quigley, Cristina, Thambisetty, Madhav·2017·PLOS Medicine

DOI 10.1371/journal.pmed.1002266PMC PMC5360226

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Abstract

BACKGROUND: The metabolic basis of Alzheimer disease (AD) pathology and expression of AD symptoms is poorly understood. Omega-3 and -6 fatty acids have previously been linked to both protective and pathogenic effects in AD. However, to date little is known about how the abundance of these species is affected by differing levels of disease pathology in the brain. METHODS AND FINDINGS: We performed metabolic profiling on brain tissue samples from 43 individuals ranging in age from 57 to 95 y old who were stratified into three groups: AD (N = 14), controls (N = 14) and "asymptomatic Alzheimer's disease" (ASYMAD), i.e., individuals with significant AD neuropathology at death but without evidence for cognitive impairment during life (N = 15) from the autopsy sample of the Baltimore Longitudinal Study of Aging (BLSA). We measured 4,897 metabolite features in regions both vulnerable in the middle frontal and inferior temporal gyri (MFG and ITG) and resistant (cerebellum) to classical AD pathology. The levels of six unsaturated fatty acids (UFAs) in whole brain were compared in controls versus AD, and the differences were as follows: linoleic acid (p = 8.8 x 10-8, FC = 0.52, q = 1.03 x 10-6), linolenic acid (p = 2.5 x 10-4, FC = 0.84, q = 4.03 x 10-4), docosahexaenoic acid (p = 1.7 x 10-7, FC = 1.45, q = 1.24 x 10-6), eicosapentaenoic acid (p = 4.4 x 10-4, FC = 0.16, q = 6.48 x 10-4), oleic acid (p = 3.3 x 10-7, FC = 0.34, q = 1.46 x 10-6), and arachidonic acid (p = 2.98 x 10-5, FC = 0.75, q = 7.95 x 10-5). These fatty acids were strongly associated with AD when comparing the groups in the MFG and ITG, respectively: linoleic acid (p < 0.0001, p = 0.0006), linolenic acid (p < 0.0001, p = 0.002), docosahexaenoic acid (p < 0.0001, p = 0.0024), eicosapentaenoic acid (p = 0.0002, p = 0.0008), oleic acid (p < 0.0001, p = 0.0003), and arachidonic acid (p = 0.0001, p = 0.001). Significant associations were also observed between the abundance of these UFAs with neuritic plaque and neurofibrillary tangle burden as well as domain-specific cognitive performance assessed during life. Based on the regional pattern of differences in brain tissue levels of these metabolites, we propose that alterations in UFA metabolism represent both global metabolic perturbations in AD as well as those related to specific features of AD pathology. Within the middle frontal gyrus, decrements in linoleic acid, linolenic acid, and arachidonic acid (control>ASYMAD>AD) and increases in docosahexanoic acid (AD>ASYMAD>control) may represent regionally specific threshold levels of these metabolites beyond which the accumulation of AD pathology triggers the expression of clinical symptoms. The main limitation of this study is the relatively small sample size. There are few cohorts with extensive longitudinal cognitive assessments during life and detailed neuropathological assessments at death, such as the BLSA. CONCLUSIONS: The findings of this study suggest that unsaturated fatty acid metabolism is significantly dysregulated in the brains of patients with varying degrees of Alzheimer pathology.

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Fig 1 Boxplots showing the effect of disease status on the abundance of six UFAs in the CB, ITG, and MFG. Dysregulation of six UFAs shown by boxplots of three disease statuses separated by brain region A) arachidonic acid (AA), B) oleic acid (OLA), C) eicosapentaenoic acid (EPA), D) linolenic acid (LNA), E) linoleic acid (LA), F) docosahexaenoic acid (DHA). AS, asymptomatic Alzheimer; CN, control; DM, Dementia/Alzheimer.CC0 · PubMed Central

Fig 2 Forest plot showing the relationship of the abundance of six UFAs in the MFG and five measures of cognitive performance. A) Association between UFA levels and longitudinal cognitive performance. B) Association between UFA levels and cognitive performance at the last visit prior to death. AA, arachidonic acid; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; LA, linoleic acid; LNA, linolenic acid; OLA, oleic acid; STD, Standard.CC0 · PubMed Central

Fig 3 Overview of omega-3 and omega-6 UFA metabolism showing the potential association between the measured UFAs. Metabolites highlighted in red have been associated with increased risk of disease pathology, with metabolites highlighted in green have been associated with decreased risk of disease pathology. COX, cyclooxygenase; CYP450, cytochrome P450; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; LCD, lineoyl-CoA desaturase; LOX, lipoxygenase; PLA2, phospholipase A2.CC0 · PubMed Central

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Authors: Snowden, S. G., Ebshiana, A. A., Hye, A., An, Y., Pletnikova, O., O’Brien, R., Troncoso, J., Legido-Quigley, C., & Thambisetty, M.
Affiliations: King's College London (GB)
National Institute on Aging (US)
Duke University (US)
Johns Hopkins University (US)
Corresponding author: Thambisetty, Madhav
ORCID: Snowden, Stuart G.
Hye, Abdul
An, Yang
O’Brien, Richard
Thambisetty, Madhav
Venue: PLOS Medicine
Publisher: Public Library of Science (PLoS)
Published: 2017-03-21
Volume: 14
Issue: 3
Pages: e1002266
ISSN: 1549-1277 (ISSN-L)
1549-1676
DOI: 10.1371/journal.pmed.1002266
PMC: PMC5360226
OpenAlex: W2600991905
Cited by: 309
References: 68
Citations by year: 2026: 21 · 2025: 39 · 2024: 33 · 2023: 32 · 2022: 30 · 2021: 42 · 2020: 42 · 2019: 35 · 2018: 22 · 2017: 12
FWCI: 22.47
Type: journal article
Language: en
Open access: gold
doi.org
Licence: public-domain
creativecommons.org/publicdomain/zero/1.0/ (vor)
Locations: PLoS Medicine (publishedVersion, public-domain)
PubMed Central (publishedVersion, public-domain)
PubMed (publishedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Figshare (submittedVersion, cc-by)
Research Portal (King's College London) (submittedVersion, public-domain)
Funders: Innovative Medicines Initiative. (European Medical Information Framework grant agreement no. 115372)
Innovative Medicines Initiative (European Medical Information Framework grant agreement no. 115372)
libyan cultural attache (7922)
Intramural Research Program of the NIH, National Institute on Aging
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
Health Sciences › Nursing › Nutrition and Dietetics › Fatty Acid Research and Health
Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords: Alzheimer's disease, brain fatty acid metabolism, unsaturated fatty acids, omega-3 fatty acids, omega-6 fatty acids, docosahexaenoic acid, eicosapentaenoic acid, linoleic acid, arachidonic acid, linolenic acid, oleic acid, Alzheimer's disease pathology, cognitive performance, middle frontal gyrus, inferior temporal gyrus, cerebellum
MeSH terms: Aged, Aged, 80 and over, Alzheimer Disease, Brain, Cognition, Fatty Acids, Female, Humans, Longitudinal Studies, Male, Middle Aged, Baltimore, Metabolome, Cognitive Dysfunction

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Association between fatty acid metabolism in the brain and Alzheimer disease neuropathology and cognitive performance: A nontargeted metabolomic study

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