Cerebrovascular disease drives Alzheimer plasma biomarker concentrations in adults with Down syndrome

ImportanceBy age 40 years over 90% of adults with Down syndrome (DS) have Alzheimers disease (AD) pathology and most progress to dementia. Despite having few systemic vascular risk factors, individuals with DS have elevated cerebrovascular disease (CVD) markers that track with the clinical progression of AD, suggesting a role for CVD that is hypothesized to be mediated by inflammatory factors. ObjectiveTo examine the pathways through which small vessel CVD contributes to AD-related pathophysiology and neurodegeneration in adults with DS. DesignCross sectional analysis of neuroimaging, plasma, and clinical data. SettingParticipants were enrolled in Alzheimers Biomarker Consortium - Down Syndrome (ABC-DS), a multisite study of AD in adults with DS. ParticipantsOne hundred eighty-five participants (mean [SD] age=45.2 [9.3] years) with available MRI and plasma biomarker data were included. White matter hyperintensity (WMH) volumes were derived from T2-weighted FLAIR MRI scans and plasma biomarker concentrations of amyloid beta (A{beta}42/A{beta}40), phosphorylated tau (p-tau217), astrocytosis (glial fibrillary acidic protein, GFAP), and neurodegeneration (neurofilament light chain, NfL) were measured with ultrasensitive immunoassays. Main Outcomes and MeasuresWe examined the bivariate relationships of WMH, A{beta}42/A{beta}40, p-tau217, and GFAP with age-residualized NfL across AD diagnostic groups. A series of mediation and path analyses examined causal pathways linking WMH and AD pathophysiology to promote neurodegeneration in the total sample and groups stratified by clinical diagnosis. ResultsThere was a direct and indirect bidirectional effect through GFAP of WMH on p-tau217 concentration, which was associated with NfL concentration in the entire sample. Among cognitively stable participants, WMH was directly and indirectly, through GFAP, associated with p-tau217 concentration, and in those with MCI, there was a direct effect of WMH on p-tau217 and NfL concentrations. There were no associations of WMH with biomarker concentrations among those diagnosed with dementia. Conclusions and RelevanceThe findings suggest that among individuals with DS, CVD promotes neurodegeneration by increasing astrocytosis and tau pathophysiology in the presymptomatic phases of AD. This work joins an emerging literature that implicates CVD and its interface with neuroinflammation as a core pathological feature of AD in adults with DS. Key PointsO_ST_ABSQuestionC_ST_ABSDo white matter hyperintensities, a magnetic resonance imaging marker of small vessel cerebrovascular disease, predict plasma Alzheimers biomarker concentrations of amyloid, tau, and neuroinflammatory pathophysiology and downstream neurodegeneration in adults with Down syndrome? FindingsIncreases in white matter hyperintensity volume precede and promote inflammation- and tau-related pathophysiology, directly and indirectly, leading to downstream neurodegeneration. MeaningSmall vessel cerebrovascular disease may contribute to the pathophysiological progression of Alzheimers disease in adults with Down syndrome. These findings support the hypothesis that cerebrovascular disease is a core feature of Alzheimers disease in adults with Down syndrome.