Comparison of CSF biomarkers in Down syndrome and autosomal dominant Alzheimer's disease: a cross-sectional study

FAGAN, ANNE; HENSON RACHEL; LI YAN; BOERWINKLE ANNA; XIONG, CHENGJIE; BATEMAN, RANDALL J; GOATE, ALISON; ANCES BEAU M; DORAN ERIC; CHRISTIAN BRADLEY; LAI FLORENCE; ROSAS H DIANA; SCHUPF NICOLE; KRINSKY-MCHALE SHARON; SILVERMAN WANE; LEE JOSEPH; KLUNK, WILLIAM; HANDEN BENJAMIN; ALLEGRI RICARDO; ET AL

LANCET NEUROLOGY

ELSEVIER SCIENCE INC

Lugar: Amsterdam; Año: 2021 vol. 20 p. 615 - 626

1474-4422

Background:Due to trisomy of chromosome 21 and the resultant extra copy of the amyloid precursor protein gene, virtually all adults with Down syndrome (DS) develop Alzheimer disease (AD) pathology by age 40 and are at high risk for dementia given their increased life expectancy. Comparison of cerebrospinal fluid (CSF) biomarker patterns in DS with those of autosomal dominant AD (ADAD) mutation carriers (MC) will enhance our understanding of disease mechanisms in these two genetically high risk groups.Methods:CSF samples obtained from adults with DS (n=41) and similarly-aged ADAD MC (n=192) and non-carrier (NC, n=108) siblings (aged 30–61 years) were analyzed for markers of amyloid-β (Aβ40, Aβ42), phosphorylated tau-related processes (pTau181), neuronal/axonal/synaptic injury (total tau, visinin-like protein 1 [VILIP-1], neurofilament light chain [NfL], synaptosomal-associated protein 25 [SNAP-25]), and astrogliosis/neuroinflammation (chitinase-3-like protein 1 [YKL-40]) via immunoassay. Biomarker concentrations were compared as a function of dementia status (asymptomatic/symptomatic), and linear regression was used to evaluate and compare the relationship between biomarker levels and age among groups.Findings:Adults with DS exhibited patterns of AD-related CSF biomarkers remarkably similar to ADAD MC, including reductions in the Aβ42/Aβ40 ratio and increases in markers of phosphorylated tau-related processes, neuronal/axonal/synaptic injury, and astrogliosis/neuroinflammation, with greater degrees of abnormality in individuals with dementia. Differences included overall higher levels of Aβ and YKL-40 in DS and potential elevations in CSF tau and NfL in the asymptomatic (non-demented) stage.Interpretation:CSF biomarker profiles are useful for identifying and tracking AD-related processes in DS and, as such, will likely have utility in clinical trial design in this understudied at-risk population.