Cerebrospinal fluid neurofilament light chain is a marker of aging and white matter damage

• Published in: Neurobiology of disease Vol. 166; p. 105662
• Main Authors: Meeker, Karin L., Butt, Omar H., Gordon, Brian A., Fagan, Anne M., Schindler, Suzanne E., Morris, John C., Benzinger, Tammie L.S., Ances, Beau M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.05.2022; Elsevier
• Subjects: Aging; Alzheimer disease; Alzheimer Disease - pathology; Biomarkers - cerebrospinal fluid; Cerebrospinal fluid; Cerebrovascular disease; Humans; Intermediate Filaments; Neurofilament light; Neurofilament Proteins - cerebrospinal fluid; tau Proteins - cerebrospinal fluid; White matter; White Matter - diagnostic imaging; White Matter - pathology; Neurofilament light; Aging; Cerebrospinal fluid; Alzheimer disease; White matter; Cerebrovascular disease
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/j.nbd.2022.105662

Cerebrospinal fluid (CSF) neurofilament light chain (NfL) reflects neuro-axonal damage and is increasingly used to evaluate disease progression across neurological conditions including Alzheimer disease (AD). However, it is unknown how NfL relates to specific types of brain tissue. We sought to determine whether CSF NfL is more strongly associated with total gray matter, white matter, or white matter hyperintensity (WMH) volume, and to quantify the relative importance of brain tissue volume, age, and AD marker status (i.e., APOE genotype, brain amyloidosis, tauopathy, and cognitive status) in predicting CSF NfL. 419 participants (Clinical Dementia Rating [CDR] Scale > 0, N = 71) had CSF, magnetic resonance imaging (MRI), and neuropsychological data. A subset had amyloid positron emission tomography (PET) and tau PET. Pearson correlation analysis was used to determine the association between CSF NfL and age. Multiple regression was used to determine which brain volume (i.e., gray, white, or WMH volume) most strongly associated with CSF NfL. Stepwise regression and dominance analyses were used to determine the individual contributions and relative importance of brain volume, age, and AD marker status in predicting CSF NfL. CSF NfL increased with age (r = 0.59, p < 0.001). Elevated CSF NfL was associated with greater total WMH volume (p < 0.001), but not gray or white matter volume (p's > 0.05) when considered simultaneously. Age and WMH volume were consistently more important (i.e., have greater R2 values) than AD markers when predicting CSF NfL. CSF NfL is a non-specific marker of aging and white matter integrity with limited sensitivity to specific markers of AD. CSF NfL likely reflects processes associated with cerebrovascular disease. •Question: What is the relative importance of brain tissue volumes, age, and AD marker status in predicting CSF NfL?•Findings: Compared to age and white matter hyperintensity (WMH) volume, AD markers are not important predictors CSF NfL.•Meaning: CSF NfL is primarily a non-specific marker of aging and white matter integrity.