{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:20:47Z","timestamp":1792790447014,"version":"4.5.0"},"posted":{"date-parts":[[2026,10,8]]},"group-title":"Geriatric Medicine","reference-count":49,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T00:00:00Z","timestamp":1791417600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Wellcome Leap","award":["73023"],"award-info":[{"award-number":["73023"]}],"id":[{"id":"https:\/\/ror.org\/03jzgvn02","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Temasek Trust","award":["73023"],"award-info":[{"award-number":["73023"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,10,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Frailty is a prominent risk factor for dementia. Early detection of at-risk individuals may enable intervention to prevent or slow dementia pathology. Blood-based biomarker discovery could offer a path for early detection of frailty and cognitive decline.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Older adults at risk of dementia underwent comprehensive multi-disciplinary assessment at the Healthy Brain Ageing (HBA) clinic, including geriatric, neurophysiological and mood evaluations, in addition to providing a fasted blood sample. Clinical data were used to calculate a deficit accumulation frailty index (FI) score. Additional cohorts attended either one (n=118) or two (n=73) subsequent visits over an average period of 4 years. Untargeted metabolomics was performed on plasma samples, and metabolites were clustered by similarity. Linear regression was used to assess association of clusters with FI. Finally, change in plasma abundance over time was assessed.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>At assessment, participants had a mean (SD) age of 68.10 (8.07) years; 72.2% were female. Hierarchical clustering identified 10 clusters of metabolites, of which 6 were significantly associated with FI (p&lt;0.05) at baseline and contained similar classes of metabolite. Differential abundance analysis found unique temporal regulation of metabolite abundance in each cluster, but across clusters severity of frailty impacted direction of change in plasma abundance over time.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Frailty index was associated with carboxylic acids and derivatives, fatty acyls and organooxygen compounds across multiple clusters, and a large number of lipids were linked to frailty score, potentially implicating dysregulation of energy metabolism in the pathophysiology of frailty and forming a panel of predictive biomarkers of at risk patients.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.10.06.26364906","type":"posted-content","created":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T21:45:14Z","timestamp":1791495914000},"source":"Crossref","is-referenced-by-count":0,"title":["Plasma metabolomic profiling of frailty in older adults at risk of dementia"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4007-9361","authenticated-orcid":false,"given":"Isabelle","family":"Alldritt","sequence":"first","affiliation":[{"name":"Centre for Healthy Ageing, Centenary Institute, Sydney, NSW, Australia"},{"name":"Healthy Brain Ageing Program, Brain and Mind Centre and Charles Perkins Centre, School of Psychology, Faculty of Science, University of Sydney, NSW, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes C.","family":"Michaelian","sequence":"additional","affiliation":[{"name":"Healthy Brain Ageing Program, Brain and Mind Centre and Charles Perkins Centre, School of Psychology, Faculty of Science, University of Sydney, NSW, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachael","family":"Yu","sequence":"additional","affiliation":[{"name":"Healthy Brain Ageing Program, Brain and Mind Centre and Charles Perkins Centre, School of Psychology, Faculty of Science, University of Sydney, NSW, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah E.","family":"Deemer","sequence":"additional","affiliation":[{"name":"Integrative Metabolism and Disease Prevention Research Group, University of North Texas, Denton, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard J.","family":"Mills","sequence":"additional","affiliation":[{"name":"Murdoch Children\u2019s Research Institute, The Royal Children\u2019s Hospital, Melbourne, VIC, Australia"},{"name":"Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharon L.","family":"Naismith","sequence":"additional","affiliation":[{"name":"Healthy Brain Ageing Program, Brain and Mind Centre and Charles Perkins Centre, School of Psychology, Faculty of Science, University of Sydney, NSW, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Philp","sequence":"additional","affiliation":[{"name":"Centre for Healthy Ageing, Centenary Institute, Sydney, NSW, Australia"},{"name":"School of Sport, Exercise and Rehabilitation Sciences, University of Technology Sydney, Sydney, NSW, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026101303001643000_2026.10.06.26364906v1.1","unstructured":"Global Strategy and Action Plan on Ageing and Health. 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