Importance

Concentrations of plasma neurofilament light (NfL) and glial fibrillary acidic protein (GFAP) should be easily interpretable in the context of a patient’s profile.

Objectives

To develop reference intervals (RI) for NfL and GFAP, accounting for common physiological modifiers of biomarkers and to compare these RIs with concentrations from participants with neurological conditions.

Design, setting, and participants

This cross-sectional study included participants with no cognitive impairment (self-reported, assessed by Mini-Mental State Examination score ≥27, or determined by a physician) to generate and validate the RIs as well as individuals, recruited from tertiary clinics, with subjective cognitive decline or mild cognitive impairment due to Alzheimer disease (AD), AD dementia, frontotemporal dementia (FTD), dementia with Lewy bodies, vascular dementia (VaD), or multiple sclerosis, for the comparison group.

Exposures

Age, biological sex (self-reported), body mass index (BMI), and kidney function (measured by estimated glomerular filtration rate [eGFR]).

Main outcomes and measures

Plasma NfL and GFAP RIs, quantified on the Simoa HD-X, defined over age and adjusted for sex, BMI, and/or eGFR.

Results

In 7989 cognitively unimpaired participants (median [range] age, 54 [30-90] years; 4877 [61.3%] female; mean [SD] BMI, 25.9 [4.2]; mean [SD] eGFR, 80.7 [14.7] mL/min/1.73 m2), older age, lower BMI, and reduced kidney function were associated with increased NfL and GFAP concentrations; female sex was associated with increased GFAP concentrations. Median NfL and GFAP concentrations were 6.58 (6.58-6.58) pg/mL and 23.4 (23.4-23.4) pg/mL higher, respectively, in participants with severe compared with no kidney damage (ie, 45 mL/min/1.73 m2 vs 90 mL/min/1.73 m2). Median NfL and GFAP concentrations were 1.72 (1.72-1.72) pg/mL and 12.6 (12.6-12.6) pg/mL lower, respectively, in participants with obesity compared with those with normal weight (ie, BMI of 30 vs 20). Median GFAP concentrations were 6.17 (6.17-6.17) pg/mL higher in female compared with male participants. NfL concentrations were most elevated in participants with FTD (165 of 179 participants [92.2%] had concentrations greater than the median) and VaD (55 of 60 participants [91.7%] had concentrations greater than the median). GFAP concentrations were most elevated in participants with AD dementia (396 of 479 participants [82.7%] had concentrations greater than the median). A user-friendly interface was developed to visualize the biomarker RIs in the context of an individual’s age, BMI, eGFR, and sex.

Conclusions and relevance

In this cross-sectional study of 7958 individuals, RIs to identify normal or abnormal biomarker concentrations in the context of a cognitively unimpaired individuals were established to aid the use of plasma NfL and GFAP measures in clinical practice for neurological diseases.