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

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 RademakersWalter 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

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Article number	fcae432
Journal	Brain Communications
Volume	7
Issue number	1
DOIs	https://doi.org/10.1093/braincomms/fcae432 https://doi.org/10.1093/braincomms/fcae432
State	Published - 2025

Keywords

Alzheimer's disease
biomarkers
cerebrospinal fluid
frontotemporal dementia
heterochronic parabiosis

ASJC Scopus subject areas

Neurology
Psychiatry and Mental health
Cellular and Molecular Neuroscience
Biological Psychiatry

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Casaletto, K. B., Saloner, R., Kornak, J., Staffaroni, A. M., Villeda, S., Paolillo, E., VandeBunte, A. M., Cadwallader, C. J., Lario Lago, A., Webb, J., Chen, C., Rascovsky, K., Miyagawa, T., Ramos, E. M., Masdeu, J. C., Pantelyat, A., Tartaglia, M. C., Bozoki, A., Pressman, P. S., ... Boxer, A. L. (2025). Brain aging rejuvenation factors in adults with genetic and sporadic neurodegenerative disease. Brain Communications, 7(1), Article fcae432. https://doi.org/10.1093/braincomms/fcae432, https://doi.org/10.1093/braincomms/fcae432

Casaletto, KB, Saloner, R, Kornak, J, Staffaroni, AM, Villeda, S, Paolillo, E, VandeBunte, AM, Cadwallader, CJ, Lario Lago, A, Webb, J, Chen, C, Rascovsky, K, Miyagawa, T, Ramos, EM, Masdeu, JC, Pantelyat, A, Tartaglia, MC, Bozoki, A, Pressman, PS, Rademakers, R, Kremers, W, Darby, R, Younes, K, Pascual, B, Ghoshal, N, Lapid, M, Mackenzie, IRA, Li, J, Hsiung, G-YR, Hall, JN, Yutsis, MV, Litvan, I, Henderson, VW, Sivasankaran, R, Worringer, K, Domoto-Reilly, K, Synder, A, Loureiro, J, Kramer, JH, Heuer, H, Forsberg, LK, Rosen, HJ, Boeve, B, Rojas, JC & Boxer, AL 2025, 'Brain aging rejuvenation factors in adults with genetic and sporadic neurodegenerative disease', Brain Communications, vol. 7, no. 1, fcae432. https://doi.org/10.1093/braincomms/fcae432, https://doi.org/10.1093/braincomms/fcae432

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title = "Brain aging rejuvenation factors in adults with genetic and sporadic neurodegenerative disease",

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 (Mage = 49.6; 50% female; 43% C9orf72, 24% GRN, 33% MAPT) and 62 non-carriers (Mage = 52.6; 45% female) with cerebrospinal fluid analysed on Somascan, and longitudinal (Mvisits = 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 (Mage = 69.4; 60% female) and 56 controls (Mage = 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.",

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

note = "Publisher Copyright: {\textcopyright} 2025 The Author(s).",

year = "2025",

doi = "10.1093/braincomms/fcae432",

language = "English (US)",

volume = "7",

journal = "Brain Communications",

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T1 - Brain aging rejuvenation factors in adults with genetic and sporadic neurodegenerative disease

AU - Casaletto, Kaitlin B

AU - Saloner, Rowan

AU - Kornak, John

AU - Staffaroni, Adam M

AU - Villeda, Saul

AU - Paolillo, Emily

AU - VandeBunte, Anna M

AU - Cadwallader, Claire J

AU - Lario Lago, Argentina

AU - Webb, Julia

AU - Chen, Coty

AU - Rascovsky, Katya

AU - Miyagawa, Toji

AU - Ramos, Eliana Marisa

AU - Masdeu, Joseph C

AU - Pantelyat, Alexander

AU - Tartaglia, Maria Carmela

AU - Bozoki, Andrea

AU - Pressman, Peter S

AU - Rademakers, Rosa

AU - Kremers, Walter

AU - Darby, Ryan

AU - Younes, Kyan

AU - Pascual, Belen

AU - Ghoshal, Nupur

AU - Lapid, Maria

AU - Mackenzie, Ian R A

AU - Li, Jingyao

AU - Hsiung, Ging-Yuek Robin

AU - Hall, Jacob N

AU - Yutsis, Maya V

AU - Litvan, Irene

AU - Henderson, Victor W

AU - Sivasankaran, Rajeev

AU - Worringer, Katie

AU - Domoto-Reilly, Kimiko

AU - Synder, Allison

AU - Loureiro, Joseph

AU - Kramer, Joel H

AU - Heuer, Hilary

AU - Forsberg, Leah K

AU - Rosen, Howard J

AU - Boeve, Bradley

AU - Rojas, Julio C

AU - Boxer, Adam L

PY - 2025

Y1 - 2025

N2 - 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 (Mage = 49.6; 50% female; 43% C9orf72, 24% GRN, 33% MAPT) and 62 non-carriers (Mage = 52.6; 45% female) with cerebrospinal fluid analysed on Somascan, and longitudinal (Mvisits = 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 (Mage = 69.4; 60% female) and 56 controls (Mage = 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.

AB - 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 (Mage = 49.6; 50% female; 43% C9orf72, 24% GRN, 33% MAPT) and 62 non-carriers (Mage = 52.6; 45% female) with cerebrospinal fluid analysed on Somascan, and longitudinal (Mvisits = 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 (Mage = 69.4; 60% female) and 56 controls (Mage = 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.

KW - Alzheimer's disease

KW - biomarkers

KW - cerebrospinal fluid

KW - frontotemporal dementia

KW - heterochronic parabiosis

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DO - 10.1093/braincomms/fcae432

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

Abstract

Keywords

ASJC Scopus subject areas

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