Plasma neurofilament light chain mediates the effect of subsyndromal symptomatic depression on cognitive decline in older adults

Abstract

Objective: Subsyndromal symptomatic depression (SSD) is associated with an increased risk of cognitive impairment in non-demented older adults. However, the mechanism underlying this relationship remains unclear. This study aimed to investigate whether plasma neurofilament light chain (NfL) mediates the relationship between SSD and cognitive decline.

Materials and methods: Data of 707 non-demented older adults from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort were analyzed. Geriatric Depression Scale (GDS) scores were collected at baseline, while plasma NfL levels and cognitive assessments were obtained at baseline, 1-year, and 2-year follow-up visits. SSD was defined as a GDS score of 1-5. Mediation analyses were performed to examine whether the rate of change in plasma NfL levels mediated the relationship between SSD and cognitive decline.

Results: Participants with SSD exhibited a greater increase in plasma NfL levels and more pronounced declines in global cognition, memory, executive function, language, and processing speed over 2 years compared to non-SSD participants. The rate of change in plasma NfL levels significantly mediated the relationship between SSD and accelerated cognitive decline, particularly in global cognition, memory, language, and processing speed.

Conclusion: Plasma NfL, which is related to neuroaxonal damage, may partially mediate the association between SSD and accelerated cognitive decline in non-demented older adults. These findings suggest that dynamic changes in plasma NfL levels may reflect early neurobiological alterations associated with SSD and could help identify individuals at increased risk of cognitive deterioration over a 2-year period.

Keywords: Alzheimer’s disease; cognition; mediation analysis; neurofilament light chain; subsyndromal symptomatic depression.

Figure 1

Associations between SSD and plasma NfL. p-values were adjusted for age, gender, years of education, diagnostic status (CN vs. MCI), and APOE ε4 status. Δ represents the rate of change in measurements. Statistical significance was set at p < 0.05. CN, cognitively normal; MCI, mild cognitive impairment; SSD, subsyndromal symptomatic depression; APOE, apolipoprotein E; NfL, neurofilament light.

Figure 2

Associations between plasma NfL levels and cognitive performance. Scatterplots show the linear regression line (solid black) and 95% confidence interval (shaded area) depicting the associations between the 2-year rate of change in plasma NfL levels (Δ Plasma NfL) and the corresponding rate of change in cognitive performance, including: (A) ADAS-Cog 11, (B) ADAS-Cog 13, (C) ADNI-MEM, (D) ADNI-EF, (E) TMT-A, (F) TMT-B, and (G) ADNI-LAN. Standardized β-values and p-values are shown in each panel. All models were adjusted for age, gender, years of education, diagnostic status (CN vs. MCI), APOE ε4 status, and baseline MMSE scores. Δ represents the rate of change in measurements. Statistical significance was defined as p < 0.05. CN, cognitively normal; MCI, mild cognitive impairment; APOE, apolipoprotein E; NfL, neurofilament light; ADAS-Cog 11/13, Alzheimer’s Disease Assessment Scale 11−/13-item version; ADNI-MEM, ADNI memory composite; ADNI-EF, ADNI executive function composite; ADNI-LAN, ADNI language composite; TMT-A/B, Trail Making Test Part A/B.

Figure 3

Mediation analysis diagram illustrating the relationship between SSD and cognitive performance. In the mediation analysis, the independent variable (X) was SSD status, the mediator (M) was the 2-year rate of change in plasma NfL levels, and the dependent variable (Y) was the rate of change in specific cognitive measures: (A) ADAS-Cog 11, (B) ADAS-Cog 13, (C) ADNI-MEM, (D) ADNI-EF, (E) TMT-A, (F) TMT-B, and (G) ADNI-LAN. Δ represents the rate of change in measurements. The indirect effect (ab), direct effect (c′), and total effect (c) are reported. All models were adjusted for age, gender, years of education, diagnostic status (CN vs. MCI), APOE ε4 status, and baseline MMSE scores. SSD, subsyndromal symptomatic depression; CN, cognitively normal; MCI, mild cognitive impairment; APOE, apolipoprotein E; NfL, neurofilament light; ADAS-Cog11/13, Alzheimer’s Disease Assessment Scale-11/13 item subscale; ADNI-MEM, ADNI Memory Composite; ADNI-EF, ADNI Executive Function Composite; ADNI-LAN, ADNI Language Composite; TMT-A/B, Trail Making Test Part A/B.