Cerebrovascular disease is associated with Alzheimer's plasma biomarker concentrations in adults with Down syndrome

Abstract

By age 40 years, over 90% of adults with Down syndrome have Alzheimer's disease pathology and most progress to dementia. Despite having few systemic vascular risk factors, individuals with Down syndrome have elevated cerebrovascular disease markers that track with the clinical progression of Alzheimer's disease, suggesting a role of cerebrovascular disease that is hypothesized to be mediated by inflammatory factors. This study examined the pathways through which small vessel cerebrovascular disease contributes to Alzheimer's disease-related pathophysiology and neurodegeneration in adults with Down syndrome. One hundred eighty-five participants from the Alzheimer's Biomarkers Consortium-Down Syndrome [mean (SD) age = 45.2 (9.3) years] with available MRI and plasma biomarker data were included in this study. White matter hyperintensity (WMH) volumes were derived from T2-weighted fluid-attenuated inversion recovery MRI scans, and plasma biomarker concentrations of amyloid beta 42/40, phosphorylated tau 217, astrocytosis (glial fibrillary acidic protein) and neurodegeneration (neurofilament light chain) were measured with ultrasensitive immunoassays. We examined the bivariate relationships of WMH, amyloid beta 42/40, phosphorylated tau 217 and glial fibrillary acidic protein with age-residualized neurofilament light chain across Alzheimer's disease diagnostic groups. A series of mediation and path analyses examined statistical pathways linking WMH and Alzheimer's disease pathophysiology to promote neurodegeneration in the total sample and groups stratified by clinical diagnosis. There was a direct and indirect bidirectional effect through the glial fibrillary acidic protein of WMH on phosphorylated tau 217 concentration, which was associated with neurofilament light chain concentration in the entire sample. Amongst cognitively stable participants, WMH was directly and indirectly, through glial fibrillary acidic protein, associated with phosphorylated tau 217 concentration, and in those with mild cognitive impairment, there was a direct effect of WMH on phosphorylated tau 217 and neurofilament light chain concentrations. There were no associations of WMH with biomarker concentrations among those diagnosed with dementia. The findings from this cross-sectional study suggest that among individuals with Down syndrome, cerebrovascular disease promotes neurodegeneration by increasing astrocytosis and tau pathophysiology in the presymptomatic phases of Alzheimer's disease, but future studies will need to confirm these associations with longitudinal data. This work joins an emerging literature that implicates cerebrovascular disease and its interface with neuroinflammation as a core pathological feature of Alzheimer's disease in adults with Down syndrome.

Keywords: Alzheimer’s disease; Down syndrome; biomarkers; cerebrovascular disease; magnetic resonance imaging.

Graphical abstract

Figure 1

Frequency map of white matter hyperintensities in adults with Down syndrome. A voxel-wise frequency map of WMH was created by summing voxels labelled across all 185 individual 3D and dividing by 185. Each voxel’s value represents the proportion of times it was labelled as a WMH across the 185 masks from low frequency (light blue) to high frequency (dark blue).

Figure 2

Conditional relationship between WMH and GFAP on p-tau217 concentration. Relationship between GFAP and p-tau217 concentration conditioned by WMH volume (A)and relationship between WMH and p-tau217 concentration conditioned by GFAP (B). The plots show the relationship between GFAP or WMH and p-tau217 for different ranges of WMH and GFAP, respectively. The panels are read from bottom left to top right along each row with the bottom row representing the lowest range of WMH volume or GFAP concentration and the top row representing the highest range of WMH volume or GFAP concentration, respectively. The rows demonstrating the relationship in individuals with higher distributions are indicated by rows labelled (ii) while relationships in participants with lower distributions are indicated by rows labelled (i). The columns correspond to the levels of WMH or GFAP as shown in the bar graph above the panels. For example, in Fig. 2A, the top right plot shows the relationship between GFAP and p-tau217 in individuals with the largest WMH volume (i) while the bottom left panel shows the relationship between GFAP and p-tau217 in individuals with the smallest WMH volume (ii). WMH, white matter hyperintensities; GFAP, glial fibrillary acidic protein; p-tau217, phosphorylated tau 217.

Figure 3

Path models for biomarker progression across diagnostic groups. Structural equation modelling calculates relative causal relationships among different pathophysiological contributors in the whole sample (A) and across diagnostic groups (B–D). Larger numbers (regression coefficients) signify stronger direct effects. Aβ, amyloid beta; WMH, white matter hyperintensities; p-tau217, phosphorylated tau 217; GFAP: glial fibrillary acidic protein; NfL, neurofilament light chain; MCI, mild cognitive impairment.