Cerebrovascular features of Alzheimer’s disease in adults with Down syndrome

Abstract

AbstractBackgroundCerebrovascular disease contributes to clinical onset and course of Alzheimer’s disease (AD) but it is unclear if it is related directly to AD pathogenesis. In late onset AD, MRI markers of small vessel cerebrovascular disease relate to AD diagnosis, genetic risk for AD, and severity of AD symptoms, but it is not possible to determine whether these associations reflect comorbidity due to risk factor exposure or whether they represent a core feature of AD. We have been studying cerebrovascular features of Alzheimer’s disease in adults with Down syndrome, who are at genetic risk for developing AD but have very low prevalence of classical vascular risk factors.MethodIn the context of the Alzheimer’s Biomarker Consortium – Down Syndrome (ABC‐DS), a US‐based multisite observational study of the clinical, biomarker, and pathological features of AD in adults with Down syndrome, our laboratory has analyzed high‐resolution, harmonized MRI scans for markers of cerebrovascular disease, including white matter hyperintensities (WMH), enlarged perivascular spaces, microbleeds, and infarcts, in adults with Down syndrome across the adult lifespan. We tested the association of these markers with age, AD‐related clinical diagnoses, proteomic profiles of vascular function and inflammation, and AD‐related biofluidic biomarker concentrations.ResultOur studies show that MRI‐derived markers of cerebrovascular disease are prevalent in adults with Down syndrome and increase in severity across AD‐associated clinical diagnoses. Age analyses suggest that there is an inflection of these markers at around age 40, when other pathological features also begin to emerge. Proteomic correlates of these cerebrovascular disease markers suggest an association with inflammatory processes in presymptomatic and neurodegenerative processes in symptomatic adults with Down syndrome. Finally, markers of cerebrovascular disease are particularly associated with plasma phosphorylated tau concentrations in adults with Down syndrome.ConclusionOur work shows that MRI‐derived markers of cerebrovascular disease are prevalent, related to AD symptoms, temporally track with AD pathology, relate to inflammation and neurodegeneration markers, and associate with markers of tau pathology. Without the confound of exposure to peripheral vascular risk factors, these observations suggest that cerebrovascular disease represents a “core feature” of AD that contributes both to symptoms and to disease pathogenesis.