Association of the fibronectin type III domain–containing protein 5 rs1746661 single nucleotide polymorphism with reduced brain glucose metabolism in elderly humans

• Published in: Brain communications Vol. 5; no. 4; p. fcad216
• Main Authors: Lima-Filho, Ricardo A S, Benedet, Andréa L, De Bastiani, Marco Antônio, Povala, Guilherme, Cozachenco, Danielle, Ferreira, Sergio T, De Felice, Fernanda G, Rosa-Neto, Pedro, Zimmer, Eduardo R, Lourenco, Mychael V
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 2023
• Subjects: Original; Alzheimer’s disease; single nucleotide polymorphism; FNDC5/irisin; PET-FDG; glucose metabolism
• ISSN: 2632-1297; 2632-1297
• DOI: 10.1093/braincomms/fcad216

Abstract Fibronectin type III domain–containing protein 5 (FNDC5) and its derived hormone, irisin, have been associated with metabolic control in humans, with described FNDC5 single nucleotide polymorphisms being linked to obesity and metabolic syndrome. Decreased brain FNDC5/irisin has been reported in subjects with dementia due to Alzheimer’s disease. Since impaired brain glucose metabolism develops in ageing and is prominent in Alzheimer’s disease, here, we examined associations of a single nucleotide polymorphism in the FNDC5 gene (rs1746661) with brain glucose metabolism and amyloid-β deposition in a cohort of 240 cognitively unimpaired and 485 cognitively impaired elderly individuals from the Alzheimer’s Disease Neuroimaging Initiative. In cognitively unimpaired elderly individuals harbouring the FNDC5 rs1746661(T) allele, we observed a regional reduction in low glucose metabolism in memory-linked brain regions and increased brain amyloid-β PET load. No differences in cognition or levels of cerebrospinal fluid amyloid-β42, phosphorylated tau and total tau were observed between FNDC5 rs1746661(T) allele carriers and non-carriers. Our results indicate that a genetic variant of FNDC5 is associated with low brain glucose metabolism in elderly individuals and suggest that FNDC5 may participate in the regulation of brain metabolism in brain regions vulnerable to Alzheimer’s disease pathophysiology. Understanding the associations between genetic variants in metabolism-linked genes and metabolic brain signatures may contribute to elucidating genetic modulators of brain metabolism in humans. Lima-Filho et al. reported that cognitively unimpaired elders carrying the FNDC5 rs1746661(T) allele develop low brain glucose metabolism and increased amyloid deposition. These findings indicate that FNDC5 may contribute to regional glucose metabolism in the human brain. Graphical Abstract Graphical Abstract