Metabolites Associated with Early Cognitive Changes Implicated in Alzheimer’s Disease
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Abstract
Background: Understanding metabolic mechanisms associated with cognitive changes preceding an Alzheimer’s disease (AD) diagnosis could advance our understanding of AD progression and inform preventive methods. Objective: We investigated the metabolomics of the early changes in executive function and delayed recall, the earliest aspects of cognitive function to change in the course of AD development, in order to better understand mechanisms that could contribute to early stages and progression of this disease. Methods: This investigation used longitudinal plasma samples from the Wisconsin Registry for Alzheimer’s Prevention (WRAP), a cohort of participants who were dementia free at enrollment and enriched with a parental history of AD. Metabolomic profiles were quantified for 2,324 fasting plasma samples among 1,200 participants, each with up to three study visits, which occurred every two years. Metabolites were individually tested for association with executive function and delayed recall trajectories across age. Results: Of 1,097 metabolites tested, levels of seven were associated with executive function trajectories, including an amino acid cysteine S-sulfate and three fatty acids, including erucate (22 : 1n9), while none were associated with delayed recall trajectories. Replication was attempted for four of these metabolites that were present in the Vietnam Era Twin Study of Aging (VETSA). Although none reached statistical significance, three of these associations showed consistent effectdirections. Conclusion: Our results suggest potential metabolomic mechanisms that could contribute to the earliest signs of cognitive decline. In particular, fatty acids may be associated with cognition in a manner that is more complex than previously suspected.
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Metabolomic biomarkers such as reduced docosahexaenoic acid (DHA) and elevated homocysteine have demonstrated clinical utility.
“Despite variability introduced by diet and comorbid conditions, metabolomic biomarkers such as reduced docosahexaenoic acid (DHA) and elevated homocysteine have demonstrated clinical utility133,194, 195, 196, 197, 198, 199.”
From Artificial intelligence-driven multi-omics approaches in Alzheimer's disease: Progress, challenges, and future directions (2025) · cites this paper as [194]
The Discussion reports exploratory associations between other plasma metabolites and cognitive trajectories, and describes findings on omega-3 fatty acids as mixed. Searches for DHA, homocysteine, and clinical utility found no passage in our copy establishing that either named metabolite has demonstrated clinical utility. The Discussion has no page number in the indexed copy. (LLM, conf=0.76)
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- Authors
- Darst, B. F., Huo, Z., Jonaitis, E. M., Koscik, R. L., Clark, L. R., Lu, Q., Kremen, W. S., Franz, C. E., Rana, B., Lyons, M. J., Hogan, K. J., Zhao, J., Johnson, S. C., & Engelman, C. D.
- Affiliations
- University of Wisconsin–Madison (US)
- University of Florida (US)
- University of California San Diego (US)
- Boston University (US)
- Corresponding author
- Darst, Burcu F.
- ORCID
- Venue
- Journal of Alzheimer’s Disease
- Publisher
- SAGE Publications
- Published
- 2021-02-02
- Volume
- 79
- Issue
- 3
- Pages
- 1041-1054
- ISSN
- 1387-2877 (ISSN-L)
- 1875-8908
- PMC
- PMC8054536
- OpenAlex
- W3119123056
- Cited by
- 16
- References
- 58
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 4 · 2023: 1 · 2022: 2 · 2021: 1 · 2020: 1
- FWCI
- 1.44
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- Journal of Alzheimer s Disease (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Helen Bader Foundation
- Northwestern Mutual Foundation
- Extendicare Foundation
- Northwestern University
- National Institutes of Health (UL1TR000427, NLM5T15LM007359)
- National Institute on Aging (R01AG059329, R01AG054047, R01AG022381, R01AG062483, R01AG050595, R01AG027161, P30AG062715)
- National Institute of Mental Health (R01MH097018)
- U.S. National Library of Medicine (T15LM007359)
- National Center for Advancing Translational Sciences
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R24HD047873, P2CHD047873)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolomics and Mass Spectrometry Studies
- Keywords
- Alzheimer's disease, early cognitive decline
- MeSH terms
- Adult, Aged, Aged, 80 and over, Alzheimer Disease, Cysteine, Fatty Acids, Female, Humans, Longitudinal Studies, Male, Middle Aged, Prospective Studies, Mental Recall, Disease Progression, Metabolic Networks and Pathways, Metabolomics, Executive Function, Mendelian Randomization Analysis, Cognitive Dysfunction
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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