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BACKGROUND Adults with Down syndrome (DS) are at very high risk for Alzheimer's disease (AD). Neurofilament light (NF-L) has emerged as a potential blood-based biomarker of neurodegeneration due to AD. OBJECTIVE To understand the relationship between plasma NF-L with age, brain amyloid, and tau pathology, neurodegeneration as well as cognitive and functional performance. METHODS We analyzed imaging data as well as cognitive measures in relation to plasma NF-L in adults with DS, ages 30 to 60 who were enrolled in the Down Syndrome Biomarker Initiative. RESULTS We found significant correlations between NF-L plasma concentrations and amyloid pathology (r = 0.73, p = 0.007, pa = 0.041) and significant inverse correlations with regional glucose metabolism in 5 of 6 regions examined, which were Anterior cingulate (r = -0.55, p = 0.067, pa = 0.067), Posterior cingulate r = -0.90, p

The cognitive correlates of functional status are essential to dementia case-finding. Nevertheless, cognitive performance is a generally weak predictor of functional outcomes. We have employed structural equation models to explicitly distinguish functional status, and therefore "dementia-relevant" variance in cognitive task performance (i.e., δ) from the variance that is unrelated to a dementing process (i.e., g'). Together, g' + δ encompass Spearman's g. Although δ represents only a small fraction of the total variance in cognitive task performance, it is more strongly associated with dementia status than is g'. In this study, we validate δ in a well characterized Alzheimer's disease cohort, the Texas Alzheimer's Research and Care Consortium. Our approach results in "error free" continuous variables. This suggests that δ can serve as a dementia specific endophenotype. As a result, future studies may be able to associate δ with inflammatory and genetic biomarkers.