Sex differences in the progression of glucose metabolism dysfunction in Alzheimer’s disease

• Published in: Experimental & molecular medicine Vol. 55; no. 5; pp. 1023 - 1032
• Main Authors: Park, Jong-Chan, Lim, Hanbyeol, Byun, Min Soo, Yi, Dahyun, Byeon, Gihwan, Jung, Gijung, Kim, Yu Kyeong, Lee, Dong Young, Han, Sun-Ho, Mook-Jung, Inhee
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.05.2023; Springer Nature B.V; Nature Publishing Group
• Subjects: 45/91; 59/57; 59/78; 631/378/1689/1283; 631/378/1689/364; 82/1; 82/80; Alzheimer Disease - metabolism; Alzheimer's disease; Amyloid - metabolism; Amyloid beta-Peptides - metabolism; Amyloid Precursor Protein Secretases - metabolism; Aspartic Acid Endopeptidases - metabolism; Biomarkers; Biomarkers - metabolism; Biomedical and Life Sciences; Biomedicine; Brain; Brain - metabolism; Cross-Sectional Studies; Disease Progression; Female; Females; Gender differences; Genes; Genetic factors; Glucose; Glucose - metabolism; Humans; Magnetic resonance imaging; Male; Medical Biochemistry; Metabolic disorders; Metabolism; Molecular Medicine; Neurodegenerative diseases; Neurodegenerative Diseases - metabolism; Neuroimaging; Positron emission tomography; Protein Phosphatase 2 - metabolism; Senile plaques; Sex Characteristics; Sex differences; Stem Cells; Tau protein; tau Proteins - metabolism; Transcriptomes; β-Amyloid; β-Site APP-cleaving enzyme 1; β-Site APP-cleaving enzyme 2
• ISSN: 2092-6413; 1226-3613; 2092-6413
• DOI: 10.1038/s12276-023-00993-3

Alzheimer’s disease (AD) is a common neurodegenerative disease characterized by amyloid plaques and impaired brain metabolism. Because women have a higher prevalence of AD than men, sex differences are of great interest. Using cross-sectional and longitudinal data, we showed sex-dependent metabolic dysregulations in the brains of AD patients. Cohort 1 (South Korean, n  = 181) underwent Pittsburgh compound B-PET, fluorodeoxyglucose-PET, magnetic resonance imaging, and blood biomarker (plasma tau and beta-amyloid 42 and 40) measurements at baseline and two-year follow-ups. Transcriptome analysis of data from Cohorts 2 and 3 (European, n  = 78; Singaporean, n  = 18) revealed sex differences in AD-related alterations in brain metabolism. In women (but not in men), all imaging indicators displayed consistent correlation curves with AD progression. At the two-year follow-up, clear brain metabolic impairment was revealed only in women, and the plasma beta-amyloid 42/40 ratio was a possible biomarker for brain metabolism in women. Furthermore, our transcriptome analysis revealed sex differences in transcriptomes and metabolism in the brains of AD patients as well as a molecular network of 25 female-specific glucose metabolic genes (FGGs). We discovered four key-attractor FGG genes (ALDOA, ENO2, PRKACB, and PPP2R5D) that were associated with amyloid/tau-related genes (APP, MAPT, BACE1, and BACE2). Furthermore, these genes successfully distinguished amyloid positivity in women. Understanding sex differences in the pathogenesis of AD and considering these differences will improve development of effective diagnostics and therapeutic treatments for AD. Alzheimer’s disease: Metabolic and genetic factors in females Sex-dependent differences in altered metabolism and gene activity found in patients with Alzheimer’s disease might help reveal why the disease is more prevalent in females than males. Researchers in South Korea led by Inhee Mook-Jung and Sun-Ho Han at Seoul National University found clearly impaired glucose metabolism only in females during a two-year monitoring of 181 South Koreans involving brain scans and blood tests. A separate study of gene activity in 78 European and 18 Singaporean patients identified 25 female-specific genes involved in glucose metabolism. Four of these genes have a role in the events leading to abnormal accumulations of amyloid and tau proteins found in brain cells in Alzheimer’s patients. The results could enhance diagnosis of Alzheimer’s disease and help guide the choice of the most appropriate interventions for different patient groups.