Potential role of blood pressure variability and plasma neurofilament light in the mechanism of comorbidity between Alzheimer's disease and cerebral small vessel disease

Abstract

Introduction: Long-term blood pressure variability (BPV) and plasma neurofilament light (pNfL) have been identified as potential biomarkers for Alzheimer's disease (AD) and cerebral small vessel disease (CSVD). However, the relationship between BPV, pNfL, and their association with the comorbidity of AD and CSVD remains unknown.

Methods: Participants with normal cognition and mild cognitive impairment from the Alzheimer's Disease Neuroimaging Initiative study were included in the data analysis. Linear mixed-effects regression models and causal mediation analyses were conducted to investigate the relationship among BPV, pNfL, comorbidity-related brain structural changes (hippocampal atrophy and white matter hyperintensities [WMH]), and cognitive function.

Results: BPV was associated with pNfL, volumes of hippocampus and WMH, and cognition. pNfL mediated the effects of BPV on brain structural changes and cognition.

Discussion: Our findings suggest a potential role of BPV and pNfL in the mechanism of comorbidity between AD and CSVD, underscoring the importance of BPV intervention in the general population.

Highlights: Individuals with both Alzheimer's disease (AD) and cerebral small vessel disease (CSVD) pathologies had elevated blood pressure variability (BPV) and plasma neurofilament light (pNfL). The association between different components of BPV and brain structural changes may vary. BPV was associated with pNfL levels independent of average blood pressure. pNfL mediated the effects of BPV on comorbidity-related brain structural changes and cognitive performance.

Keywords: Alzheimer's disease; biomarker; blood pressure variability; cerebral small vessel disease; neurofilament light.

FIGURE 1

The potential mechanisms by which BPV contributes to the comorbidity of AD and CSVD. Aβ, amyloid beta; AD, Alzheimer's disease; BPV, blood pressure variability; CSVD, cerebral small vessel disease.

FIGURE 2

Plasma neurofilament light levels at baseline and 2 years among different blood pressure variability groups (by tertile). Note: BPV tertiles, level 1 represented the low tertile, level 2 represented the medium tertile, and level 3 represented the high tertile. DBPV, diastolic blood pressure; MAPV, mean arterial pressure variability; PPV, pulse pressure variability; SBPV, systolic blood pressure variability.

FIGURE 3

Association of blood pressure variability with brain structural changes and cognitive performance at 2 years was mediated by plasma neurofilament light. a, the effect of blood pressure variability on the mediator variable; b, the effect of the mediator variable on the outcome variable; c', direct effect; c, total effect; DBP, diastolic blood pressure; ME, mediation effect; SBP, systolic blood pressure; WMH, white matter hyperintensities.

FIGURE 4

Association between blood pressure variability and cognition at 2 years was mediated by plasma neurofilament light and brain structural magnetic resonance imaging changes. Note: The association between systolic BPV and executive is potentially mediated by pNfL and WMH volume through three indirect effects (4A), path 1: systolic BPV → pNfL → executive (−0.017), path 2: systolic BPV → WMH volume → executive (−0.006), and path 3: systolic BPV → pNfL → WMH volume → executive (−0.003). Path 1 and path 3 demonstrated statistical significance, while path 2 did not reach a significant level (P = 0.071). Similarly, the mediating effect of pNfL and hippocampal volume on the association between diastolic BPV and memory can be attributed to three indirect effects (4B), path 1: diastolic BPV → pNfL → memory (−0.018), path 2: diastolic BPV → hippocampal volume → memory (−0.014), and path 3: diastolic BPV → pNfL → hippocampal volume → memory (−0.005). Path 1 and path 3 exhibited a significant level of association, whereas path 2 did not reach statistical significance (P = 0.061). ^* P < 0.05, ^** P < 0.01, ^*** P < 0.001. BPV, blood pressure variability; pNfL, plasma neurofilament light; WMH, white matter hyperintensities.