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Individuals with Down syndrome (DS) are at high risk of neurodegeneration due to Alzheimer\u2019s disease (AD). This study aims to explore the relationship between mitochondrial dysfunction, brain amyloid-beta (A\u03b2) deposition, and cognitive decline in this population. Methods: We investigated mitochondrial function, brain amyloid-beta burden, and cognitive performance in a pilot study of a cohort of 10 eligible adults with DS selected from a sample of 28 individuals with DS. Phosphorus-31 magnetic resonance spectroscopy (31P-MRS) was used to assess mitochondrial function in skeletal muscle using a post-exercise paradigm, while positron emission tomography using 11C-Pittsburgh compound B (PiB-PET) measured brain A\u03b2 deposition. Cognitive performance was evaluated using the Cambridge Cognitive Examination adapted for individuals with Down syndrome (CAMCOG-DS) and executive function batteries. Results: Significant correlations were observed between slowed phosphocreatine (PCr) recovery in muscle and increased A\u03b2 deposition in key brain regions, particularly the striatum. Cognitive performance inversely correlated with mitochondrial function, with pronounced deficits in memory and executive function tasks. Notably, an individual carrying the APOE-\u03b54 allele exhibited the poorest mitochondrial function, highest A\u03b2 burden, and most severe cognitive impairment, suggesting a potential interaction between genetic risk and mitochondrial health. Conclusions: These findings highlight the role of mitochondrial dysfunction in DS-associated AD (DSAD) and its impact on cognition in adults. The results support targeting mitochondrial pathways as a potential therapeutic strategy to mitigate AD progression in DS populations. Further research with larger cohorts and longitudinal designs is needed to clarify causative mechanisms and develop effective interventions.<\/jats:p>","DOI":"10.3390\/brainsci15020130","type":"journal-article","created":{"date-parts":[[2025,1,29]],"date-time":"2025-01-29T03:26:10Z","timestamp":1738121170000},"page":"130","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Mitochondrial Dysfunction Correlates with Brain Amyloid Binding, Memory, and Executive Function in Down Syndrome: Implications for Alzheimer\u2019s Disease in Down Syndrome"],"prefix":"10.3390","volume":"15","author":[{"given":"Jessica A.","family":"Beresford-Webb","sequence":"first","affiliation":[{"name":"Cambridge Intellectual and Developmental Disabilities Research Group, Department of Psychiatry, University of Cambridge, Douglas House, Trumpington Road, Cambridge CB2 8AH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine J.","family":"McAllister","sequence":"additional","affiliation":[{"name":"Cambridge Intellectual and Developmental Disabilities Research Group, Department of Psychiatry, University of Cambridge, Douglas House, Trumpington Road, Cambridge CB2 8AH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alison","family":"Sleigh","sequence":"additional","affiliation":[{"name":"Wolfson Brain Imaging Centre, University of Cambridge and NIHR Cambridge Clinical Research Facility, Cambridge University Hospitals NHS Foundation Trust, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madeleine J.","family":"Walpert","sequence":"additional","affiliation":[{"name":"Cambridge Intellectual and Developmental Disabilities Research Group, Department of Psychiatry, University of Cambridge, Douglas House, Trumpington Road, Cambridge CB2 8AH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony J.","family":"Holland","sequence":"additional","affiliation":[{"name":"Cambridge Intellectual and Developmental Disabilities Research Group, Department of Psychiatry, University of Cambridge, Douglas House, Trumpington Road, Cambridge CB2 8AH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shahid H.","family":"Zaman","sequence":"additional","affiliation":[{"name":"Cambridge Intellectual and Developmental Disabilities Research Group, Department of Psychiatry, University of Cambridge, Douglas House, Trumpington Road, Cambridge CB2 8AH, UK"},{"name":"Cambridgeshire & Peterborough Foundation NHS Trust, Douglas House, Trumpington Road, Cambridge CB2 8AH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1038\/nature05292","article-title":"Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases","volume":"443","author":"Lin","year":"2006","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Bell, S.M., Barnes, K., De Marco, M., Shaw, P.J., Ferraiuolo, L., Blackburn, D.J., Venneri, A., and Mortiboys, H. 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