Branched-Chain Amino Acids Are Linked with Alzheimer’s Disease-Related Pathology and Cognitive Deficits
Open accessAbstract
Alzheimer’s disease (AD) is an irreversible neurodegenerative disorder with a complex pathophysiology. Type 2 diabetes (T2D) is a strong risk factor for AD that shares similar abnormal features including metabolic dysregulation and brain pathology such as amyloid and/or Tau deposits. Emerging evidence suggests that circulating branched-chain amino acids (BCAAs) are associated with T2D. While excess BCAAs are shown to be harmful to neurons, its connection to AD is poorly understood. Here we show that individuals with AD have elevated circulating BCAAs and their metabolites compared to healthy individuals, and that a BCAA metabolite is correlated with the severity of dementia. APPSwe mouse model of AD also displayed higher plasma BCAAs compared to controls. In pursuit of understanding a potential causality, BCAA supplementation to HT-22 neurons was found to reduce genes critical for neuronal health while increasing phosphorylated Tau. Moreover, restricting BCAAs from diet delayed cognitive decline and lowered AD-related pathology in the cortex and hippocampus in APP/PS1 mice. BCAA restriction for two months was sufficient to correct glycemic control and increased/restored dopamine that were severely reduced in APP/PS1 controls. Treating 5xFAD mice that show early brain pathology with a BCAA-lowering compound recapitulated the beneficial effects of BCAA restriction on brain pathology and neurotransmitters including norepinephrine and serotonin. Collectively, this study reveals a positive association between circulating BCAAs and AD. Our findings suggest that BCAAs impair neuronal functions whereas BCAA-lowering alleviates AD-related pathology and cognitive decline, thus establishing a potential causal link between BCAAs and AD progression.
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Evidence suggests that branched-chain amino acid modulation may be useful in cognition disorders.
“Although exploratory studies remain in their infancy, evidence suggests that BCAA modulation may be useful in cognition disorders (339–341).”
From Signalling cognition: The gut microbiota and hypothalamic-pituitary-adrenal axis (2023) · cites this paper as [341]
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Signalling cognition: The gut microbiota and hypothalamic-pituitary-adrenal axis
Rusch, J. A., Layden, B. T., & Dugas, L. R. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1130689 · Cited by 415 · see citing works
- Authors
- Siddik, M. A. B., Mullins, C. A., Kramer, A., Shah, H., Gannaban, R. B., Zabet-Moghaddam, M., Huebinger, R. M., Hegde, V. K., MohanKumar, S. M. J., MohanKumar, P. S., & Shin, A. C.
- Affiliations
- Texas Tech University (US)
- Center for Biotechnology & Genomics, Texas Tech University, Lubbock, TX 79409, USA
- The University of Texas Southwestern Medical Center (US)
- University of Georgia (US)
- Corresponding author
- Shin, Andrew C.
- ORCID
- Venue
- Cells
- Publisher
- MDPI AG
- Published
- 2022-11-07
- Volume
- 11
- Issue
- 21
- Pages
- 3523
- ISSN
- 2073-4409 (ISSN-L)
- PMC
- PMC9658564
- OpenAlex
- W4308506702
- Cited by
- 68
- References
- 104
- Citations by year
- 2026: 21 · 2025: 21 · 2024: 15 · 2023: 11
- FWCI
- 7.27
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cells (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- ThinkTech (Texas Tech University) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- NIH (AG069140-01)
- Wylie Briscoe Fund from the College of Human Sciences at TTU (AG069140-01)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolomics and Mass Spectrometry Studies
- Keywords
- branched-chain amino acids, Alzheimer's disease, type 2 diabetes, BCAA supplementation, plasma amino acids, APP/PS1 mice, 5xFAD mice, cognitive decline, phosphorylated tau, dopamine, norepinephrine, serotonin, glycemic control, neurodegeneration, dietary intervention
- MeSH terms
- Alzheimer Disease, Amino Acids, Branched-Chain, Animals, Cognition, Diabetes Mellitus, Type 2, Mice, 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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