Plasma Neurofilament Light and Future Declines in Cognition and Function in Alzheimer’s Disease in the FIT-AD Trial

Abstract

Background: Utilities of blood-based biomarkers in Alzheimer’s disease (AD) clinical trials remain unknown. Objective: To evaluate the ability of plasma neurofilament light chain (NfL) to predict future declines in cognition and activities of daily living (ADL) outcomes in 26 older adults with mild-to-moderate AD dementia from the FIT-AD Trial. Methods: Plasma NfL was measured at baseline and 3 and 6 months. Cognition and ADL were assessed using the AD Assessment Scale-Cognition (ADAS-Cog) and AD Uniform Dataset Instruments and Disability Assessment for Dementia (DAD), respectively, at baseline, 3, 6, 9, and 12 months. Linear mixed effects models were used to examine the associations between baseline or change in plasma NfL and changes in outcomes. Results: Higher baseline plasma NfL was associated with greater rate of decline in ADAS-Cog from baseline to 6 months (standardized estimate of 0.00462, p = 0.02853) and in ADL from baseline to 12 months (standardized estimate of –0.00284, p = 0.03338). Greater increase in plasma NfL in short term from baseline to 3 months was associated with greater rate of decline in memory and ADL from 3 to 6 months (standardized estimate of –0.04638 [0.003], p = 0.01635; standardized estimate of –0.03818, p = 0.0435) and greater rate of decline in ADL from 3 to 12 month (standardized estimate of –0.01492, p = 0.01082). Conclusion: This study demonstrated that plasma NfL might have the potential to predict cognitive and function decline up to 12 months. However, future studies with bigger sample sizes need to confirm the findings.

Neurofilament Proteins as Biomarkers to Monitor Neurological Diseases and the Efficacy of Therapies

“…The role of NfL as a potential biomarker for AD has been extensively reviewed and recent meta-analysis regarding its association with AD can be found elsewhere (Olsson et al, 2016;Khalil et al, 2018;Bridel et al, 2019;Jin et al, 2019). Recent studies further demonstrated plasma NfL levels or together with cognitive testing as predictors of fast progression (Santangelo et al, 2021) and future declines in cognition and function in AD (Li et al, 2021). Hyperphosphorylation of tau neurofibrillary tangles is one of the hallmarks in AD.…”

Assessment of Plasma and Cerebrospinal Fluid Biomarkers in Different Stages of Alzheimer’s Disease and Frontotemporal Dementia

“…In general, individual plasma biomarkers have shown good accuracy for AD diagnosis, which could be improved by the simultaneous combination of some plasma biomarkers [ 22 , 23 , 24 , 25 ]. The neurofilament light chain (NfL) is another molecule that has been analyzed in the context of AD as a progression biomarker [ 26 ] or predictor for dementia, even more helpful in other pathologies, such as FTLD [ 27 , 28 ]. Different works pointed out the potential use of these biomarkers mentioned, which could change the clinical guides in the following years, with earlier and higher accessible diagnosis [ 29 , 30 , 31 , 32 ].…”

The associations between type 2 diabetes and plasma biomarkers of Alzheimer’s disease in the Health and Aging Brain Study: Health Disparities (HABS-HD)

“…NfL indicates subcortical large-caliber axonal degeneration [ 58 , 59 ]. Elevated plasma NfL levels have been established in AD [ 60 , 61 ], correlate to increasing symptom severity in AD [ 62 ], and predicts greater long-term cognitive decline in AD [ 63 – 65 ]. The positive association between the three T2D indicators and plasma NfL is consistent with existing evidence that used imaging biomarkers of neurodegeneration [ 30 , 35 , 36 ].…”