Serum neurofilament light in familial Alzheimer disease: A marker of early neurodegeneration

Abstract

Objectives: To investigate whether serum neurofilament light (NfL) concentration is increased in familial Alzheimer disease (FAD), both pre and post symptom onset, and whether it is associated with markers of disease stage and severity.

Methods: We recruited 48 individuals from families with PSEN1 or APP mutations to a cross-sectional study: 18 had symptomatic Alzheimer disease (AD) and 30 were asymptomatic but at 50% risk of carrying a mutation. Serum NfL was measured using an ultrasensitive immunoassay on the single molecule array (Simoa) platform. Cognitive testing and MRI were performed; 33 participants had serial MRI, allowing calculation of atrophy rates. Genetic testing established mutation status. A generalized least squares regression model was used to compare serum NfL among symptomatic mutation carriers, presymptomatic carriers, and noncarriers, adjusting for age and sex. Spearman coefficients assessed associations between serum NfL and (1) estimated years to/from symptom onset (EYO), (2) cognitive measures, and (3) MRI measures of atrophy.

Results: Nineteen of the asymptomatic participants were mutation carriers (mean EYO -9.6); 11 were noncarriers. Compared with noncarriers, serum NfL concentration was higher in both symptomatic (p < 0.0001) and presymptomatic mutation carriers (p = 0.007). Across all mutation carriers, serum NfL correlated with EYO (ρ = 0.81, p < 0.0001) and multiple cognitive and imaging measures, including Mini-Mental State Examination (ρ = -0.62, p = 0.0001), Clinical Dementia Rating Scale sum of boxes (ρ = 0.79, p < 0.0001), baseline brain volume (ρ = -0.62, p = 0.0002), and whole-brain atrophy rate (ρ = 0.53, p = 0.01).

Conclusions: Serum NfL concentration is increased in FAD prior to symptom onset and correlates with measures of disease stage and severity. Serum NfL may thus be a feasible biomarker of early AD-related neurodegeneration.

Figure 1. Box and whisker plots for serum neurofilament light (NfL) across the 3 groups

The measured unadjusted serum NfL concentrations are shown. Mutation carriers have been divided into those who are symptomatic and those who are presymptomatic.

Figure 2. Scatterplot of serum neurofilament light (NfL) against estimated years from symptom onset (EYO)

Mutation carriers are represented by dots and noncarriers by crosses. To ensure it is not possible to identify any of the individual asymptomatic participants (based on their EYO) and so determine their mutation status, 2 outlying participants have been removed and a jitter of up to ±2 years has been applied to all remaining participants.

Figure 3. Scatterplots of serum neurofilament light (NfL) against cognitive and imaging measures across all mutation carriers

Spearman ρ and the associated p value are shown for each scatterplot. Estimated change in IQ was calculated by subtracting the current IQ (measured by the Wechsler Abbreviated Scale of Intelligence) from the predicted premorbid IQ (measured by the National Adult Reading Test). CDR SOB = Clinical Dementia Rating Scale sum of boxes; MMSE = Mini-Mental State Examination; RMT = Recognition Memory Test.