Multi-pathway blood biomarkers to target and monitor multidimensional prevention of cognitive and functional decline (nested in the IN-TeMPO study framed within the World-Wide FINGERS network)

Gessica Sala^1*Luca Cuffaro^1,2Federico Emanuele Pozzi^1,2Simona Andreoni¹Chiara Bazzini¹Elisa Conti¹Chiara Paola Zoia¹Simone Beretta^1,2Lucio Tremolizzo^1,2Giuseppe Bellelli^3,4Chukwuma Okoye^3,4Maria Cristina Ferrara³Annamaria De Luca⁵Roberta Lenti⁵Paola Mantuano⁵Paola Pontrelli⁶Alessandra Stasi⁶Giovanni Defazio⁷Vincenzo Solfrizzi⁵Lucilla Crudele⁵Cristina Airoldi⁸Ferdinando Chiaradonna⁹Maria Pia Longhese⁹Giovanni Messina¹⁰Antonino Natalello⁹Ivan Orlandi⁹Alessandra Aloisi¹¹Simonetta Capone¹¹Assunta Ingannato^12,13Benedetta Nacmias^12,13Daniela Capello¹⁴Francesca Mangialasche^15,16,17Carlo Ferrarese^1,2

• ¹School of Medicine and Surgery and Milan Center for Neuroscience (NeuroMI), University of Milano-Bicocca, Monza, Italy
• ²Department of Neurology, Fondazione IRCCS “San Gerardo dei Tintori”, Monza, Italy
• ³School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
• ⁴Acute Geriatric Unit, Fondazione IRCCS “San Gerardo dei Tintori”, Monza, Italy
• ⁵Unit of Pharmacology, Department of Pharmacy-Drug Sciences, University of Bari "Aldo Moro", Bari, Italy
• ⁶Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari "Aldo Moro", Bari, Italy
• ⁷Department of Translational Biomedicine and Neuroscience (DiBraiN), University of Bari "Aldo Moro", Bari, Italy
• ⁸Department of Biotechnology and Biosciences and Milan Center for Neuroscience (NeuroMI), University of Milano-Bicocca, Milan, Lombardy, Italy
• ⁹Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Lombardy, Italy
• ¹⁰University of Milano-Bicocca, Milan, Lombardy, Italy
• ¹¹Institute for Microelectronics and Microsystems, National Council of Research (CNR-IMM), Lecce, Italy
• ¹²Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy
• ¹³IRCCS Fondazione Don Carlo Gnocchi, Florence, Italy
• ¹⁴Department of Translational Medicine, Centre of Excellence in Aging Sciences, University of Piemonte Orientale, Novara, Italy
• ¹⁵Division of Clinical Geriatrics, Alzheimer Research Center, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet (KI), Solna, Stockholm, Sweden
• ¹⁶Theme Inflammation and Aging, Medical Unit Aging, Karolinska University Hospital, Stockholm, Stockholm, Sweden
• ¹⁷FINGERS Brain Health Institute, Stockholm, Sweden

Background. As the population ages, the identification of preventive strategies able to delay cognitive and functional decline associated with aging represents a major challenge. To date, multidimensional approaches seem to be effective in reducing or delaying the onset of age-related diseases.Objectives. The multicentric randomized controlled trial IN-TeMPO (ItaliaN study with Tailored Multidomain interventions to Prevent functional and cognitive decline in community-dwelling Older adults, ClinicalTrials.gov ID NCT06248723), framed within the World-Wide FINGERS network, aims to verify the efficacy of guided multidomain interventions in preventing age-related cognitive and functional decline. Within this study, we will explore a comprehensive array of established and exploratory blood biomarkers of several pathologic age-related processes, including Alzheimer's disease (AD), neurodegeneration, inflammation, senescence and sarcopenia, to stratify subject risk and assess the effect of multidomain interventions on biomarkers. Design and Participants. ApoE4 status and plasma p-tau217 (AD), NfL (neurodegeneration), GFAP and IL-6 (inflammation), GDF-15 (senescence/sarcopenia) will be evaluated in all subjects (n=1662) both at the baseline and at the end of the study (12 months). Exploratory additional biomarkers will be measured at the same time points in a subgroup of 100 subjects: BDNF, ghrelin, IGF-1, irisin and redox status in plasma as markers of sarcopenia/senescence and oxidative stress, gamma-H2AX in PBMCs as marker of senescence, and amyloid beta aggregates in plasma, urine and erythrocytes as supportive markers of AD. Untargeted metabolomics analysis in plasma and untargeted volatilomics analysis in whole blood and urine will be performed to explore molecular alterations that may be associated with the pathogenesis and progression of age-related diseases in frail older adults with the aim of identifying novel potential biomarkers. Conclusions. The comprehensive clinical use of multiple laboratory biomarkers can contribute both to the early identification of trajectories of cognitive and functional decline in older adults, and to the identification of mechanisms underlying the effect of multidisciplinary interventions on age-related pathological processes.