Cerebrovascular disease drives Alzheimer plasma biomarker concentrations in adults with Down syndrome
Authors: Edwards Natalie C. , Lao Patrick J. , Alshikho Mohamad J. , Ericsson Olivia M. , Rizvi Batool , Petersen Melissa E. , O’Bryant Sid , Flores-Aguilar Lisi , Simoes Sabrina , Mapstone Mark , Tudorascu Dana L. , Janelidze Shorena , Hansson Oskar , Handen Benjamin L. , Christian Bradley T. , Lee Joseph H. , Lai Florence , Rosas H Diana , Zaman Shahid , Lott Ira T. , Yassa Michael A. , Gutierrez José , Wilcock Donna M. , Head Elizabeth , Brickman Adam M. 
Published: November 2023

Importance

By age 40 years over 90% of adults with Down syndrome (DS) have Alzheimer’s 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.

Objective

To examine the pathways through which small vessel CVD contributes to AD-related pathophysiology and neurodegeneration in adults with DS.

Design

Cross sectional analysis of neuroimaging, plasma, and clinical data.

Setting

Participants were enrolled in Alzheimer’s Biomarker Consortium – Down Syndrome (ABC-DS), a multisite study of AD in adults with DS.

Participants

One 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 (Aβ42/Aβ40), phosphorylated tau (p-tau217), astrocytosis (glial fibrillary acidic protein, GFAP), and neurodegeneration (neurofilament light chain, NfL) were measured with ultrasensitive immunoassays.

Main Outcomes and Measures

We examined the bivariate relationships of WMH, Aβ42/Aβ40, 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.

Results

There 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 Relevance

The 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 Points

Question

Do white matter hyperintensities, a magnetic resonance imaging marker of small vessel cerebrovascular disease, predict plasma Alzheimer’s biomarker concentrations of amyloid, tau, and neuroinflammatory pathophysiology and downstream neurodegeneration in adults with Down syndrome?

Findings

Increases in white matter hyperintensity volume precede and promote inflammation- and tau-related pathophysiology, directly and indirectly, leading to downstream neurodegeneration.

Meaning

Small vessel cerebrovascular disease may contribute to the pathophysiological progression of Alzheimer’s disease in adults with Down syndrome. These findings support the hypothesis that cerebrovascular disease is a core feature of Alzheimer’s disease in adults with Down syndrome.