Serum neurofilament dynamics predicts neurodegeneration and clinical progression in presymptomatic Alzheimer’s disease

Abstract

Neurofilament light chain (NfL) is a promising fluid biomarker of disease progression for various cerebral proteopathies. Here we leverage the unique characteristics of the Dominantly Inherited Alzheimer Network and ultrasensitive immunoas-say technology to demonstrate that NfL levels in the cerebrospinal fluid (n = 187) and serum (n = 405) are correlated with one another and are elevated at the presymptomatic stages of familial Alzheimer's disease. Longitudinal, withinperson analysis of serum NfL dynamics (n = 196) confirmed this elevation and further revealed that the rate of change of serum NfL could discriminate mutation carriers from non-mutation carriers almost a decade earlier than cross-sectional absolute NfL levels (that is, 16.2 versus 6.8 years before the estimated symptom onset). Serum NfL rate of change peaked in participants converting from the presymptomatic to the symptomatic stage and was associated with cortical thinning assessed by magnetic resonance imaging, but less so with amyloid-β deposition or glucose metabolism (assessed by positron emission tomography). Serum NfL was predictive for both the rate of cortical thinning and cognitive changes assessed by the Mini-Mental State Examination and Logical Memory test. Thus, NfL dynamics in serum predict disease progression and brain neurodegeneration at the early presymptomatic stages of familial Alzheimer's disease, which supports its potential utility as a clinically useful biomarker.Reprints and permissions information is available at www.nature.com/reprints.

Cerebrospinal fluid and plasma biomarker trajectories with increasing amyloid deposition in Alzheimer's disease

“…This could for, example, also cause the initial increase in CSF NfL that is too subtle to be clinically relevant (early change point; Figs 1A and 2), followed by a more marked change better corresponding to overt neurodegeneration (late change point; Figs 1A and 2). This hypothesis is also in agreement with the contradictory studies showing that subtle longitudinal changes in NfL can be detected 16 years before the onset of cognitive symptoms (Preische et al, 2019), while cross-sectional differences are only noticeable at the MCI and dementia stage (Mattsson et al, 2019a,b). In addition to the validity, the sensitivity of the biomarker (for detecting the underlying pathology) may also affect the results.…”

Synaptic, axonal damage and inflammatory cerebrospinal fluid biomarkers in neurodegenerative dementias

“…Any of the N biomarkers predicted the longitudinal MMSE; however, it is possible that the clinical progression of the disease could be better explained by the longitudinal change in a concrete biomarker than the basal level . In this sense, again, longitudinal data in repeated samples could provide further evidence of the relationship of biomarkers and cognitive impairment.…”

Plasma biomarkers of astrocytic and neuronal dysfunction in early‐ and late‐onset Alzheimer's disease

“…Numerous studies have begun to investigate plasma biomarkers in AD; however, most have concentrated on detecting AD proteinopathies or neuronal injury . This project aimed to contribute to the characterization of plasma biomarkers in AD, across a wider spectrum of pathways, with a particular interest in extending knowledge of early‐onset AD (EOAD).…”

“…Numerous studies have begun to investigate plasma biomarkers in AD; however, most have concentrated on detecting AD proteinopathies or neuronal injury. 13,14 This project aimed to contribute to the characterization of plasma biomarkers in AD, across a wider spectrum of pathways, with a particular interest in extending knowledge of early-onset AD (EOAD). Clinical observations suggest a more aggressive disease course in EOAD, 15 although specific molecular differences between sporadic EOAD and late-onset AD (LOAD) remain to be elucidated.…”