Serum Nf‐L and GFAP are associated with incident dementia and dementia mortality in older adults: The Cardiovascular Health Study

Abstract

AbstractBackgroundAlthough circulating neurofilament light chain (Nf‐L) and glial fibrillary acidic protein (GFAP) have been independently associated with dementia risk, their additive association, and their associations with dementia‐specific mortality have not been investigated. Overall, prospective community‐based studies of these biomarkers, particularly those representing individuals beyond their eighth decade, are lacking.MethodWe investigated 1,712 cognitively healthy participants of the Cardiovascular Health Study (1,042 women [61%], 218 Black [13%], median [IQR] baseline age = 77 [74–80] years). Cox regression models were used to test the associations of serum Nf‐L and GFAP, measured using single molecule array technology, with 19‐year incident dementia and dementia‐specific mortality risk. These primary outcomes were complemented by repeated Modified Mini‐Mental State Exam and the Digit Symbol Substitution Test scores which were used in linear mixed models to test the associations of Nf‐L and GFAP with cognitive decline over three years.ResultMore than half of the participants were diagnosed with incident dementia (N = 975) and 183 dementia‐specific deaths occurred during follow‐up. In covariate, and mutual Nf‐L/GFAP adjusted models, each standard deviation unit higher Nf‐L or GFAP associated with a hazard ratio (HR) of 1.14 (95% confidence interval, 1.03–1.26) and 1.12 (1.04–1.21) for incident dementia, and 1.37 (1.11–1.69) and 1.55 (1.31–1.83) for dementia‐specific mortality (Table 1). These associations were graded and additive, with the strongest associations observed when Nf‐L and GFAP levels were simultaneously elevated (Figure 1). Compared to those in the lowest tertiles of both markers, we observed an additive increase in risk among individuals with both Nf‐L and GFAP levels in the highest tertile [HR, 2.06 (1.60‐2.67) for incident dementia and 9.22 (4.48–18.9) for dementia‐specific mortality, Figure 1]. Nf‐L, but not GFAP, independently associated with faster cognitive decline over three years (Table 1).ConclusionCirculating Nf‐L and GFAP may, independently and jointly, provide useful clinical insight regarding dementia risk and prognosis.