Cerebrovascular disease is associated with Alzheimer’s 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 , Aguilar Lisi Flores , 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 ,   Alzheimer’s Biomarkers Consortium–Down Syndrome (ABC-DS) Investigators, Aizenstein Howard J , Ances Beau M , Andrews Howard F , Bell Karen , Birn Rasmus M , Brickman Adam M , Bulova Peter , Cheema Amrita , Chen Kewei , Christian Bradley T , Clare Isabel , Cohen Ann D , Constantino John N , Doran Eric W , Edwards Natalie C , Fagan Anne , Feingold Eleanor , Foroud Tatiana M , Handen Benjamin L , Harp Jordan , Hartley Sigan L , Head Elizabeth , Henson Rachel , Hom Christy , Honig Lawrence , Ikonomovic Milos D , Johnson Sterling C , Jordan Courtney , Kamboh M Ilyas , Keator David , Klunk William E , Kofler Julia K , Kreisl William Charles , Krinsky-McHale Sharon J , Lai Florence , Lao Patrick , Laymon Charles , Lee Joseph H , Lott Ira T , Lupson Victoria , Mapstone Mark , Mathis Chester A , Minhas Davneet Singh , Nadkarni Neelesh , O’Bryant Sid , Parisi Melissa , Pang Deborah , Petersen Melissa , Price Julie C , Pulsifer Margaret , Rafii Michael S , Reiman Eric , Rizvi Batool , Rosas Herminia Diana , Ryan Laurie , Schmitt Frederick , Schupf Nicole , Silverman Wayne P , Tudorascu Dana L , Tumuluru Rameshwari , Tycko Benjamin , Varadarajan Badri , White Desiree A , Yassa Michael A , Zaman Shahid , Zhang Fan , Gutierrez José , Wilcock Donna M , Head Elizabeth , Brickman Adam M 
Published: September 2024

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.