Brain aging rejuvenation factors in adults with genetic and sporadic neurodegenerative disease
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<sub>age</sub> = 49.6; 50% female; 43% <i>C9orf72</i>, 24% <i>GRN</i>, 33% <i>MAPT</i>) and 62 non-carriers (M<sub>age</sub> = 52.6; 45% female) with cerebrospinal fluid analysed on Somascan, and longitudinal (M<sub>visits</sub> = 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<sub>age</sub> = 69.4; 60% female) and 56 controls (M<sub>age</sub> = 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.
Authors
- Julio C. Rojas (ORCID: https://orcid.org/0000-0002-1308-646X)
- Irene Litvan (ORCID: https://orcid.org/0000-0002-3485-3445)
- Hilary W. Heuer (ORCID: https://orcid.org/0000-0002-3776-1685)
- Adam M. Staffaroni (ORCID: https://orcid.org/0000-0002-3903-9805)
- Maria Carmela Tartaglia (ORCID: https://orcid.org/0000-0002-5944-8497)
- Kyan Younes (ORCID: https://orcid.org/0000-0002-9912-1616)
- Saul Villeda (ORCID: https://orcid.org/0000-0002-2726-9582)
- Anna M. VandeBunte (ORCID: https://orcid.org/0000-0002-5167-3358)
- Joel H. Kramer (ORCID: https://orcid.org/0000-0002-2917-8297)
- Kimiko Domoto-Reilly
- Belén Pascual (ORCID: https://orcid.org/0000-0002-4467-7406)
- Joseph Loureiro (ORCID: https://orcid.org/0000-0001-7222-9160)
- Joseph C. Masdeu (ORCID: https://orcid.org/0000-0001-9955-6954)
- Maria I. Lapid (ORCID: https://orcid.org/0000-0002-1163-5584)
- Katya Rascovsky
- Maya Yutsis
- Rowan Saloner (ORCID: https://orcid.org/0000-0002-1351-6183)
- Alexander Pantelyat (ORCID: https://orcid.org/0000-0002-6427-7485)
- Kathleen A. Worringer (ORCID: https://orcid.org/0000-0001-7807-2344)
- Rosa Rademakers (ORCID: https://orcid.org/0000-0002-4049-0863)
- Toji Miyagawa (ORCID: https://orcid.org/0000-0002-9387-0253)
- Ian R. Mackenzie (ORCID: https://orcid.org/0000-0003-3875-2972)
- Walter K. Kremers (ORCID: https://orcid.org/0000-0001-5714-3473)
- Ging‐Yuek Robin Hsiung (ORCID: https://orcid.org/0000-0002-8017-0856)
- Claire J. Cadwallader (ORCID: https://orcid.org/0000-0003-3449-3803)
- Andrea Bozoki (ORCID: https://orcid.org/0000-0002-4899-9381)
- Bradley F. Boeve (ORCID: https://orcid.org/0000-0002-4153-8187)
- Howard J. Rosen (ORCID: https://orcid.org/0000-0001-9281-7402)
- Leah K. Forsberg (ORCID: https://orcid.org/0000-0003-4086-9598)
- Allison Snyder
- Victor W. Henderson (ORCID: https://orcid.org/0000-0003-1198-9240)
- Nupur Ghoshal (ORCID: https://orcid.org/0000-0002-6680-6731)
- Emily W. Paolillo (ORCID: https://orcid.org/0000-0003-4188-6998)
- Rajeev Sivasankaran (ORCID: https://orcid.org/0000-0003-3917-0181)
- Jingyao Li (ORCID: https://orcid.org/0000-0003-0246-360X)
- Jacob Hall (ORCID: https://orcid.org/0000-0002-9740-8955)
- Peter Pressman (ORCID: https://orcid.org/0000-0003-1760-1286)
- Ryan Darby
- Eliana Marisa Ramos (ORCID: https://orcid.org/0009-0003-7982-4415)
- Adam L. Boxer
- Argentina Lario Lago
- John Kornak
- Julia D Webb
- Coty Chen
Institutions
- University of North Carolina at Chapel Hill (US)
- Houston Methodist (US)
- National Institutes of Health (US)
- Mayo Clinic (US)
- University of British Columbia (CA)
- Johns Hopkins University (US)
- University of Antwerp (BE)
- University of California, Los Angeles (US)
- Palo Alto University (US)
- University of California, San Francisco (US)
- University of Toronto (CA)
- Vanderbilt University (US)
- University of Washington (US)
- Washington University in St. Louis (US)
- WinnMed (US)
- University of California San Diego (US)
- University Memory and Aging Center (US)
- National Institute of Neurological Disorders and Stroke (US)
- Occupational Cancer Research Centre (CA)
- VIB-UAntwerp Center for Molecular Neurology (BE)
- Neurology Center of Southern California (US)
- Mayo Clinic in Florida (US)
- University of Pennsylvania (US)
- University of Colorado Denver (US)
- Stanford University (US)
Publication Details
- Journal
- Brain Communications
- Published
- 2024-12-24
- DOI
- https://doi.org/10.1093/braincomms/fcae432
- Citations
- 3
- Primary Topic
- Alzheimer's disease research and treatments
- Type
- article
- Field-Weighted Citation Impact
- 0.98
Funders
- University of California, San Francisco
- National Institute on Aging
- National Institute of Neurological Disorders and Stroke
- National Center for Advancing Translational Sciences