Association Between Longitudinal Plasma Neurofilament Light and Neurodegeneration in Patients With Alzheimer Disease

Abstract

Importance: Plasma neurofilament light (NfL) has been suggested as a noninvasive biomarker to monitor neurodegeneration in Alzheimer disease (AD), but studies are lacking.

Objective: To examine whether longitudinal plasma NfL levels are associated with other hallmarks of AD.

Design, setting, and participants: This North American cohort study used data from 1583 individuals in the multicenter Alzheimer's Disease Neuroimaging Initiative study from September 7, 2005, through June 16, 2016. Patients were eligible for inclusion if they had NfL measurements. Annual plasma NfL samples were collected for up to 11 years and were analyzed in 2018.

Exposures: Clinical diagnosis, Aβ and tau cerebrospinal fluid (CSF) biomarkers, imaging measures (magnetic resonance imaging and fluorodeoxyglucose-positron emission tomography), and tests on cognitive scores.

Main outcomes and measures: The primary outcome was the association between baseline exposures (diagnosis, CSF biomarkers, imaging measures, and cognition) and longitudinal plasma NfL levels, analyzed by an ultrasensitive assay. The secondary outcomes were the associations between a multimodal classification scheme with Aβ, tau, and neurodegeneration (ie, the ATN system) and plasma NfL levels and between longitudinal changes in plasma NfL levels and changes in the other measures.

Results: Of the included 1583 participants, 716 (45.2%) were women, and the mean (SD) age was 72.9 (7.1) years; 401 had no cognitive impairment, 855 had mild cognitive impairment, and 327 had AD dementia. The NfL level was increased at baseline in patients with mild cognitive impairment and AD dementia (mean levels: cognitive unimpairment, 32.1 ng/L; mild cognitive impairment, 37.9 ng/L; and AD dementia, 45.9 ng/L; P < .001) and increased in all diagnostic groups, with the greatest increase in patients with AD dementia. A longitudinal increase in NfL level correlated with baseline CSF biomarkers (low Aβ42 [P = .001], high total tau [P = .02], and high phosphorylated tau levels [P = .02]), magnetic resonance imaging measures (small hippocampal volumes [P < .001], thin regional cortices [P = .009], and large ventricular volumes [P = .002]), low fluorodeoxyglucose-positron emission tomography uptake (P = .01), and poor cognitive performance (P < .001) for a global cognitive score. With use of the ATN system, increased baseline NfL levels were seen in A-T+N+ (P < .001), A+T-N+ (P < .001), and A+T+N+ (P < .001), and increased rates of NfL levels were seen in A-T+N- (P = .009), A-T+N+ (P = .02), A+T-N+ (P = .04), and A+T+N+ (P = .002). Faster increase in NfL levels correlated with faster increase in CSF biomarkers of neuronal injury, faster rates of atrophy and hypometabolism, and faster worsening in global cognition (all P < .05 in patients with mild cognitive impairment; associations differed slightly in cognitively unimpaired controls and patients with AD dementia).

Conclusions and relevance: The findings suggest that plasma NfL can be used as a noninvasive biomarker associated with neurodegeneration in patients with AD and may be useful to monitor effects in trials of disease-modifying drugs.

Figure 1.. Plasma Neurofilament Light (NfL) Level by Diagnostic Group, Aβ-Status, and ATN Classification

Observed data in different diagnostic (DX) groups (A-C). Estimated means and 95% CI in DX groups (D), with results from a linear mixed-effects model were adjusted for age (associated with greater NfL levels, β, 1.3; P < .001) and sex (P = .21). Estimated means and 95% CI of the means for different diagnostic groups (E) were stratified by amyloid β (Aβ) status (defined by cerebrospinal fluid [CSF] Aβ42). Estimated means and 95% CIs of the means in the ATN groups (F-I) were defined using CSF Aβ42 for A, CSF phosphorylated tau (p-tau) for T, and the temporal cortical composite for N in the ATN system. Trajectories were tested in linear mixed-effects models, adjusted for age and sex. The eTables 3 and 4 in the Supplement give details on DX group and Aβ status, and eTables 6 and 7 in the Supplement give details on the ATN classification. AD indicates Alzheimer dementia; CU, cognitively unimpaired; and MCI, mild cognitive impairment.

Figure 2.. Distribution of Patient-Specific Plasma Neurofilament Light (NfL) Slopes

The ATN system is described in the Statistical Analysis subsection of the Methods section. Aβ indicates amyloid β; AD, Alzheimer disease; CU, cognitively unimpaired; and MCI, mild cognitive impairment.