Association of Plasma Neurofilament Light With Neurodegeneration in Patients With Alzheimer Disease

Abstract

Importance: Existing cerebrospinal fluid (CSF) or imaging (tau positron emission tomography) biomarkers for Alzheimer disease (AD) are invasive or expensive. Biomarkers based on standard blood test results would be useful in research, drug development, and clinical practice. Plasma neurofilament light (NFL) has recently been proposed as a blood-based biomarker for neurodegeneration in dementias.

Objective: To test whether plasma NFL concentrations are increased in AD and associated with cognitive decline, other AD biomarkers, and imaging evidence of neurodegeneration.

Design, setting, and participants: In this prospective case-control study, an ultrasensitive assay was used to measure plasma NFL concentration in 193 cognitively healthy controls, 197 patients with mild cognitive impairment (MCI), and 180 patients with AD dementia from the Alzheimer's Disease Neuroimaging Initiative. The study dates were September 7, 2005, to February 13, 2012. The plasma NFL analysis was performed in September 2016.

Main outcomes and measures: Associations were tested between plasma NFL and diagnosis, Aβ pathologic features, CSF biomarkers of neuronal injury, cognition, brain structure, and metabolism.

Results: Among 193 cognitively healthy controls, 197 patients with mild cognitive impairment, and 180 patients with AD with dementia, plasma NFL correlated with CSF NFL (Spearman ρ = 0.59, P < .001). Plasma NFL was increased in patients with MCI (mean, 42.8 ng/L) and patients with AD dementia (mean, 51.0 ng/L) compared with controls (mean, 34.7 ng/L) (P < .001) and had high diagnostic accuracy for patients with AD with dementia vs controls (area under the receiver operating characteristic curve, 0.87, which is comparable to established CSF biomarkers). Plasma NFL was particularly high in patients with MCI and patients with AD dementia with Aβ pathologic features. High plasma NFL correlated with poor cognition and AD-related atrophy (at baseline and longitudinally) and with brain hypometabolism (longitudinally).

Conclusions and relevance: Plasma NFL is associated with AD diagnosis and with cognitive, biochemical, and imaging hallmarks of the disease. This finding implies a potential usefulness for plasma NFL as a noninvasive biomarker in AD.

Figure 1.. Plasma Neurofilament Light (NFL) and Cerebrospinal Fluid (CSF) NFL

Fit lines are shown for individual diagnostic groups. The Spearman ρ and P values are for Spearman rank correlation in the whole cohort. Table 2 lists correlation data adjusted for covariates. AD indicates Alzheimer disease; MCI, mild cognitive impairment.

Figure 2.. Plasma Neurofilament Light (NFL) by Diagnosis and Aβ

A, Plasma NFL in controls, patients with mild cognitive impairment (MCI), and patients with Alzheimer disease (AD) dementia. B, Area under the receiver operating characteristic curve (AUROC) analyses for plasma NFL and other biomarkers to differentiate between the AD dementia group and controls. CSF indicates cerebrospinal fluid. C, Plasma NFL in controls, patients with MCI, and patients with AD dementia, stratified by occurrence of Aβ positivity (CSF Aβ42 < 192 ng/L). D, Plasma NFL in patients with stable MCI (SMCI) (no progression to dementia during ≥2 years’ follow-up) and patients with progressive MCI (PMCI) (conversion to dementia), with or without Aβ positivity. The models were adjusted for age, sex, educational level, and APOE ε4 genotype. Age retained an independent statistically significant association with higher plasma NFL (β = 0.025, P < .001 from the models shown in A). AB- indicates AB-negative; AB+, AB-positive.

Figure 3.. Associations Between Plasma Neurofilament Light and Cognitive and Neuroimaging Measures

Data from linear mixed-effects models adjusted for age, sex, educational level, APOE ε4 genotype, and diagnosis, as well as intracranial volume for the neurofilament light quartiles for hippocampal volume and ventricular volume. ADAS-COG 11 indicates Alzheimer Disease Assessment Scale–cognitive subscale; AD cortex, Alzheimer disease cortex; Digit symbol, Wechsler Adult Intelligence Scale–Revised digit symbol substitution test; FDG, 18F-fluorodeoxyglucose; Logical memory DR, delayed recall of the Wechsler Memory Scale logical memory II; MMSE, Mini-Mental State Examination; Q, quartile; TMT-B, Trail-Making test part B; and WMHs, white matter hyperintensities.