Short- and long-term natural history of three neurodegenerative biomarkers among middle-aged and older adults

BACKGROUND: Little is known about the longitudinal trajectories of novel neurodegenerative biomarkers including neurofilament light (NfL), tau, and glial fibrillary acidic protein (GFAP). OBJECTIVES: We aimed to investigate the short- and long-term natural history of these biomarkers measured longitudinally among healthy adults. METHODS: In this cohort study from the Physicians' Health Study (PHS), VITamin D and OmegA-3 TriaL (VITAL), and COcoa Supplement and Multivitamin Outcomes Study (COSMOS), we included 1299 adults with bloods collected 2 years (VITAL and COSMOS) or 14 years (PHS) apart and without diagnosed neurodegenerative diseases before baseline or during follow-up through two years after the final blood collection. Associations between baseline characteristics and changes in NfL, tau, and GFAP were evaluated. RESULTS: Mean (SD) age at baseline was 49.8 (6.8), 67.5 (6.2), and 70.3 (5.7) in PHS, VITAL, and COSMOS, respectively. PHS enrolled only men while ∼50% of the VITAL and COSMOS populations in this study were men. Median percent changes (IQR) of NfL were 40.6% (2.4, 58.2) increase over 14 years (PHS) and 8.5% (-6.6, 28.6) over 2 years (VITAL and COSMOS); increases in tau were 101% (10.7, 285) over 14 years and 11.8% (-35.2, 106) over 2 years; and increases in GFAP were 25.1% (-1.7, 23.8) over 14 years and 5.6% (-12.8, 28.6) over 2 years. In multivariable models, age was most strongly and robustly associated with 14-year changes in NfL and GFAP (adjusted p<0.001), and increases in levels accelerated at older ages. No baseline variables were associated with changes in tau. CONCLUSION: Increases in NfL and GFAP accelerated with age, highlighting the need to improve our understanding of the clinical relevance of short- and long-term changes in these neurodegenerative biomarkers in large-scale, long-term cohorts.