Circulating Biomarkers of Neurodegeneration and All-Cause and Dementia-Specific Mortality

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Abstract
Blood-based biomarkers offer a widely available, scalable, and noninvasive method to study neurodegeneration. However, the association between blood-based biomarkers of neurodegeneration and long-term risk of mortality, as well as dementia-specific mortality in a racially diverse cohort, remains understudied. The goal of this study was to determine whether baseline biomarkers of neurodegeneration are associated with long-term risk of all-cause and dementia-specific mortality in a biracial cohort. The REasons for Geographic and Racial Differences in Stroke cohort study enrolled 30,239 Black and White participants across the continental United States from 2003 to 2007, with ongoing follow-up. Plasma neurofilament light chain (NfL), total tau, glial fibrillary acidic protein (GFAP), and ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) were measured in baseline plasma from a random sample of participants. All-cause mortality, dementia-specific mortality, cardiovascular-specific mortality, and other causes of death were adjudicated and classified using medical records, the Social Security Death Index, and the National Death Index. Cause-specific Cox regression models accounting for competing risks were used to calculate hazard ratios (HRs) of outcomes for each biomarker separately. A total of 917 participants had a mean baseline age of 67.4 years (SD 12.1), 49.4% were female, and 48.6% self-identified as Black. With a mean follow-up of 11.1 (SD 5.7) years, 51.0% (477/935) of participants died and 9.2% experienced dementia-specific mortality (86/935). No associations were observed for total tau. In fully adjusted models for other biomarkers, HRs of all-cause mortality per standard deviation increments were 1.93 (95% CI 1.48-2.52) for GFAP, 1.90 (95% CI 1.55-2.32) for NfL, and 1.23 (95% CI 1.09-1.37) for UCH-L1. Furthermore, GFAP (HR 5.66, 95% CI 2.91-11.00) and NfL (HR 2.72, 95% CI 1.57-4.71) were associated with dementia-specific mortality in fully adjusted models. GFAP (HR 2.06, 95% CI 1.22-3.49) and NfL (HR 2.16, 95% CI 1.66-2.81) were also associated with cardiovascular-specific mortality in fully adjusted models. Plasma biomarkers of neurodegeneration, particularly GFAP and NfL, were associated with increased risk of all-cause, dementia-specific, and cardiovascular-specific mortality in a biracial cohort. These associations should be considered when assessing links between these biomarkers and other outcomes, as well as when used in clinical practice.

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