Cerebrospinal fluid biomarkers for Alzheimer's disease in Down syndrome

Abstract

Down syndrome (DS), present in nearly six million people, is associated with an extremely high risk to develop Alzheimer's disease (AD). Amyloid-β and tau pathology are omnipresent from age 40 years onward, but clinical symptoms do not appear in all DS individuals. Dementia diagnostics is complex in this population, illustrating the great need for predictive biomarkers. Although blood biomarkers have not yet proven useful, cerebrospinal fluid (CSF) biomarkers (low amyloid-β42, high t-tau, and high p-tau) effectively contribute to AD diagnoses in the general population and are increasingly used in clinical practice. Surprisingly, CSF biomarkers have been barely evaluated in DS. Breaking the taboo on CSF analyses would finally allow for the elucidation of its utility in (differential) diagnoses and staging of disease severity. A sensitive and specific biomarker profile for AD in DS would be of paramount importance to daily care, adaptive caregiving, and specific therapeutic interventions.

Keywords: Alzheimer's disease; Biomarkers; Cerebrospinal fluid; Dementia; Down syndrome.

Fig. 1

Schematic illustration of AD neuropathology and related changes in CSF biomarkers in DS. DS is caused by trisomy 21. The APP gene is encoded on chromosome 21, causing an overproduction of the APP protein in DS from birth onward. The enzymes β- and γ-secretase cleave the APP protein into Aβ peptides, which aggregate into plaques. The longer Aβ1–42 fragments are most prone to aggregate. Extensive neuropathology, that is, extracellular plaques, but also intracellular neurofibrillary tangles consisting of p-tau and t-tau, increases strongly in the third and fourth decade of life in virtually all DS individuals. These neuropathologic hallmarks are reflected by altered levels of CSF biomarkers. The CSF AD profile (low levels of Aβ42, and high levels of p-tau and t-tau) demonstrates high sensitivity and specificity in the general population. Whether a similar biomarker profile is useful for AD in DS remains to be elucidated. The very limited number of small-sized CSF studies in DS suggests that CSF Aβ1–42 increases in early childhood when the aggregation of Aβ1–42 into plaques is still relatively low. Once the deposition of Aβ1–42 into plaques augments (i.e., reduced clearance from the brain), CSF Aβ1–42 gradually decreases. In contrast, CSF t-tau and p-tau both correlate positively with age in DS. Abbreviations: Aβ, amyloid-β; APP, amyloid precursor protein; CSF, cerebrospinal fluid; DS, Down syndrome; p-tau, phosphorylated tau; t-tau, total tau.