Elevated Serum Leucine Levels Are Associated With Cognitive Impairment and Reduced Gray Matter and Cerebral Volume Across the Alzheimer's Disease Continuum

Elevated Serum Leucine Levels Are Associated With Cognitive Impairment and Reduced Gray Matter and Cerebral Volume Across the Alzheimer's Disease Continuum Publisher Pubmed

Nasiri H¹ ; Azargoonjahromi A² ; Nouri Z³ ; Azimi SM⁴ ; Zand H⁵ ; Shourideh A⁶ ; Heydari S⁷ ; Mahmoudvand B⁸ ; Barabadi S⁹ ; Samadpour N¹⁰ ; Mohamadhosseini A¹¹ ; Khodadadi A¹² ; Shakeri S¹³ ; Mayeli M¹⁴

Show Affiliations

1. Student Research Committee, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
2. Shiraz University of Medical Sciences, Shiraz, Iran
3. Department of Microbiology, University of Tehran, Tehran, Iran
4. Department of Anatomical Sciences, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
5. School of Electrical and Computer Engineering, College of Engineering, University of Tehran, Tehran, Iran
6. Faculty of Pharmacy, Eastern Mediterranean University, Famagusta, Cyprus
7. Department of Psychology, Islamic Azad University،Tehran, Iran
8. Student Research Committee, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
9. Department of Psychology, Islamic Azad University, Azadshahr, Iran
10. School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
11. School of Medicine, Babol University of Medical Science, Babol, Iran
12. School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
13. Department of Medical Genetics, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
14. School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

Source: Neuroscience Published:2025

Abstract

Leucine, a branched-chain amino acid (BCAA), exhibits paradoxical effects in Alzheimer's disease (AD), demonstrating both neuroprotective and neurotoxic roles. While prior studies have investigated leucine's systemic and metabolic impacts, its influence on brain structure remains unexplored. This study aimed to fill this critical gap by examining the relationship between serum leucine levels, brain volume metrics, and cognitive performance in individuals across the AD continuum. Serum leucine concentrations were quantified using the Nightingale Health nuclear magnetic resonance (NMR) platform. Cognitive performance was assessed using the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog 11 and 13), and structural brain volumes, including total cerebrum, cerebrum gray matter, and total brain gray matter, were derived from T1-weighted magnetic resonance imaging (MRI) via automated segmentation. Mediation analysis was employed to determine whether changes in brain volume mediate the association between serum leucine levels and cognitive performance. Elevated serum leucine levels were significantly associated with reduced total cerebrum volume, cerebrum gray matter volume, and total brain gray matter volume. Furthermore, mediation analysis revealed that these reductions in brain volume partially mediated the relationship between higher leucine levels and poorer cognitive outcomes. These findings provide evidence linking elevated leucine levels to brain atrophy and cognitive decline in AD, suggesting a potentially deleterious role of leucine in neurodegeneration. This highlights the importance of further mechanistic investigations to clarify leucine's role in AD pathology and assess its viability as a therapeutic target. © 2025 International Brain Research Organization (IBRO)

2. Alzheimer’S Disease and Infectious Agents: A Comprehensive Review of Pathogenic Mechanisms and Microrna Roles, Frontiers in Neuroscience (2024)

3. Polygenic Hazard Score Predicts Synaptic and Axonal Degeneration and Cognitive Decline in Alzheimer's Disease Continuum, Archives of Gerontology and Geriatrics (2024)

Experts (# of related papers)

Ahmad Reza Dehpour (1)

Ashraf Mohammadkhani (1)

Style	Citing Format
MLA	Nasiri H, et al.. "Elevated Serum Leucine Levels Are Associated With Cognitive Impairment and Reduced Gray Matter and Cerebral Volume Across the Alzheimer's Disease Continuum." Neuroscience, vol. 577, no. , 2025, pp. 47-53.
APA	Nasiri H, Azargoonjahromi A, Nouri Z, Azimi SM, Zand H, Shourideh A, Heydari S, Mahmoudvand B, Barabadi S, Samadpour N, Mohamadhosseini A, Khodadadi A, Shakeri S, Mayeli M (2025). Elevated Serum Leucine Levels Are Associated With Cognitive Impairment and Reduced Gray Matter and Cerebral Volume Across the Alzheimer's Disease Continuum. Neuroscience, 577(), 47-53.
Chicago	Nasiri H, Azargoonjahromi A, Nouri Z, Azimi SM, Zand H, Shourideh A, Heydari S, et al.. "Elevated Serum Leucine Levels Are Associated With Cognitive Impairment and Reduced Gray Matter and Cerebral Volume Across the Alzheimer's Disease Continuum." Neuroscience 577, no. (2025): 47-53.
Harvard	Nasiri H et al. (2025) 'Elevated Serum Leucine Levels Are Associated With Cognitive Impairment and Reduced Gray Matter and Cerebral Volume Across the Alzheimer's Disease Continuum', Neuroscience, 577(), pp. 47-53.
Vancouver	Nasiri H, Azargoonjahromi A, Nouri Z, Azimi SM, Zand H, Shourideh A, et al.. Elevated Serum Leucine Levels Are Associated With Cognitive Impairment and Reduced Gray Matter and Cerebral Volume Across the Alzheimer's Disease Continuum. Neuroscience. 2025;577():47-53.
BibTex	@article{ author = {Nasiri H and Azargoonjahromi A and Nouri Z and Azimi SM and Zand H and Shourideh A and Heydari S and Mahmoudvand B and Barabadi S and Samadpour N and Mohamadhosseini A and Khodadadi A and Shakeri S and Mayeli M}, title = {Elevated Serum Leucine Levels Are Associated With Cognitive Impairment and Reduced Gray Matter and Cerebral Volume Across the Alzheimer's Disease Continuum}, journal = {Neuroscience}, volume = {577}, number = {}, pages = {47-53}, year = {2025} }
RIS	TY - JOUR AU - Nasiri H AU - Azargoonjahromi A AU - Nouri Z AU - Azimi SM AU - Zand H AU - Shourideh A AU - Heydari S AU - Mahmoudvand B AU - Barabadi S AU - Samadpour N AU - Mohamadhosseini A AU - Khodadadi A AU - Shakeri S AU - Mayeli M TI - Elevated Serum Leucine Levels Are Associated With Cognitive Impairment and Reduced Gray Matter and Cerebral Volume Across the Alzheimer's Disease Continuum JO - Neuroscience VL - 577 IS - SP - 47 EP - 53 PY - 2025 ER -

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