Brain aging rejuvenation factors in adults with genetic and sporadic neurodegenerative disease

Kaitlin B Casaletto; Rowan Saloner; John Kornak; Adam M Staffaroni; Saul Villeda; Emily Paolillo; Anna M VandeBunte; Claire J Cadwallader; Argentina Lario Lago; Julia Webb; Coty Chen; Katya Rascovsky; Toji Miyagawa; Eliana Marisa Ramos; Joseph C Masdeu; Alexander Pantelyat; Maria Carmela Tartaglia; Andrea Bozoki; Peter S Pressman; Rosa Rademakers; Walter Kremers; Ryan Darby; Kyan Younes; Belen Pascual; Nupur Ghoshal; Maria Lapid; Ian R A Mackenzie; Jingyao Li; Ging-Yuek Robin Hsiung; Jacob N Hall; Maya V Yutsis; Irene Litvan; Victor W Henderson; Rajeev Sivasankaran; Katie Worringer; Kimiko Domoto-Reilly; Allison Synder; Joseph Loureiro; Joel H Kramer; Hilary Heuer; Leah K Forsberg; Howard J Rosen; Bradley Boeve; Julio C Rojas; Adam L Boxer

doi:10.1093/braincomms/fcae432

Brain aging rejuvenation factors in adults with genetic and sporadic neurodegenerative disease

Brain Commun. 2025 Jan 15;7(1):fcae432. doi: 10.1093/braincomms/fcae432. eCollection 2025.

Authors

Kaitlin B Casaletto¹, Rowan Saloner¹, John Kornak², Adam M Staffaroni¹, Saul Villeda³, Emily Paolillo¹, Anna M VandeBunte¹, Claire J Cadwallader¹, Argentina Lario Lago¹, Julia Webb¹, Coty Chen¹, Katya Rascovsky⁴, Toji Miyagawa⁵, Eliana Marisa Ramos⁶, Joseph C Masdeu⁷, Alexander Pantelyat⁸, Maria Carmela Tartaglia⁹, Andrea Bozoki¹⁰, Peter S Pressman¹¹, Rosa Rademakers¹², Walter Kremers¹³, Ryan Darby¹⁴, Kyan Younes¹⁵, Belen Pascual⁷, Nupur Ghoshal¹⁶, Maria Lapid¹⁷, Ian R A Mackenzie¹⁸, Jingyao Li¹⁹, Ging-Yuek Robin Hsiung²⁰, Jacob N Hall²¹, Maya V Yutsis²², Irene Litvan²³, Victor W Henderson²⁴, Rajeev Sivasankaran¹⁹, Katie Worringer¹⁹, Kimiko Domoto-Reilly²⁵, Allison Synder²⁶, Joseph Loureiro¹⁹, Joel H Kramer¹, Hilary Heuer²⁷, Leah K Forsberg⁵, Howard J Rosen¹, Bradley Boeve⁵, Julio C Rojas¹, Adam L Boxer¹

Affiliations

¹ Department of Neurology, Memory and Aging Center, University of California, San Francisco, CA 94158, USA.
² Department of Epidemiology and Biostatistics, University of California, San Francisco, CA 94158, USA.
³ Department of Anatomy, University of California, San Francisco, CA 94143, USA.
⁴ Department of Neurology and Penn Frontotemporal Degeneration Center, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁵ Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA.
⁶ Department of Neurology, University of California, Los Angeles, CA 90095, USA.
⁷ Department of Neurology, Houston Methodist, Houston, TX 77030, USA.
⁸ Department of Neurology, Johns Hopkins University, Baltimore, MD 21287, USA.
⁹ Tanz Centre for Research in Neurodegenerative Diseases, Division of Neurology, University of Toronto, Toronto, ON M5S 3H2, Canada.
¹⁰ Department of Neurology, University of North Carolina, Chapel Hill, NC 27599, USA.
¹¹ Department of Neurology, University of Colorado, Aurora, CO 80045, USA.
¹² Neurodegenerative Brain Diseases Group, VIB Center for Molecular Neurology, University of Antwerp-Biomedical sciences, Antwerp, 2610, Belgium.
¹³ Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN 55905, USA.
¹⁴ Department of Neurology, Vanderbilt University, Nashville, TN 37212, USA.
¹⁵ Department of Neurology, Stanford University, Palo Alto, CA 94304, USA.
¹⁶ Departments of Neurology and Psychiatry, Washington University, St. Louis, MO 63110, USA.
¹⁷ Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN 55905, USA.
¹⁸ Department of Pathology, University of British Columbia, Vancouver, BC V6T 2B5, Canada.
¹⁹ Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA.
²⁰ Department of Medicine, Division of Neurology, University of British Columbia, Vancouver, BC V6T 2B5, Canada.
²¹ The Neurology Center of Southern California, Carlsbad, CA 92011, USA.
²² Department of Neurology and Neurological Sciences, Stanford University, Palo Alto, CA 94304, USA.
²³ Department of Neurosciences, University of California, La Jolla, CA 92037, USA.
²⁴ Departments of Epidemiology and Population Health and of Neurology and Neurological Sciences, Stanford University, Palo Alto, CA 94304, USA.
²⁵ Department of Neurology, University of Washington, Seattle, WA 98195, USA.
²⁶ National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20814, USA.
²⁷ Department of Neurology, Memory and Aging Center, University of California, San Francisco, CA 94159, USA.

Abstract

The largest risk factor for dementia is age. Heterochronic blood exchange studies have uncovered age-related blood factors that demonstrate 'pro-aging' or 'pro-youthful' effects on the mouse brain. The clinical relevance and combined effects of these factors for humans is unclear. We examined five previously identified brain rejuvenation factors in cerebrospinal fluid of adults with autosomal dominant forms of frontotemporal dementia and sporadic Alzheimer's disease. Our frontotemporal dementia cohort included 100 observationally followed adults carrying autosomal dominant frontotemporal dementia mutations (M_age = 49.6; 50% female; 43% C9orf72, 24% GRN, 33% MAPT) and 62 non-carriers (M_age = 52.6; 45% female) with cerebrospinal fluid analysed on Somascan, and longitudinal (M_visits = 3 years, range 1-7 years) neuropsychological and functional assessments and plasma neurofilament light chain. Our Alzheimer's disease cohort included 35 adults with sporadic Alzheimer's disease (M_age = 69.4; 60% female) and 56 controls (M_age = 68.8, 50% female) who completed the same cerebrospinal fluid and clinical outcome measures cross-sectionally. Levels of C-C motif chemokine ligand 11, C-C motif chemokine ligand 2, beta-2-micorglobulin, bone gamma-carboxyglutamate protein (aka Osteocalcin) and colony stimulating factor 2 in cerebrospinal fluid were linearly combined into a composite score, with higher values reflecting 'pro-youthful' levels. In genetic frontotemporal dementia, higher baseline cerebrospinal fluid rejuvenation proteins predicted slower decline across cognitive, functional, and neurofilament light chain trajectories; estimates were similar across genotypes. In transdiagnostic analyses, higher cerebrospinal fluid rejuvenation proteins associated with better functional, cognitive, and neurofilament light chain outcomes in adults with sporadic Alzheimer's disease. Proteins with pre-clinical evidence for brain rejuvenation show translational clinical relevance in adults with Alzheimer's disease and related dementias and warrant further investigation.

Keywords: Alzheimer’s disease; biomarkers; cerebrospinal fluid; frontotemporal dementia; heterochronic parabiosis.