CSF Biomarkers in Down Syndrome and Autosomal Dominant Alzheimer Disease

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 with those of autosomal dominant AD (ADAD) mutation carriers (MC) will enhance our understanding of disease mechanisms in these two genetically defined 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 those 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 will likely have utility for clinical care and clinical trial design in this understudied at-risk population. Funding: National Institute on Aging (U01 AG051406, U01 AG051412, UF1AG032438), Eunice Kennedy Shriver National Institute of Child Health and Human Development, German Center for Neurodegenerative Diseases, and Research and Development Grants for Dementia from Japan Agency for Medical Research and Development. Conflict of Interest: AMF has received research funding from the National Institutes of Health /National Institute on Aging, Biogen, Centene, Fujirebio, and Roche Diagnostics. She is a member of the scientific advisory boards for Roche Diagnostics, Genentech, and AbbVie and also consults for Araclon/Grifols, DiademRes, DiamiR, and Otsuka Pharmaceuticals. There are no conflicts. RJB has equity ownership interest in C2N Diagnostics and receives royalty income based on technology (stable isotope labeling kinetics and blood plasma assay) licensed by Washington University to C2N Diagnostics. He receives income from C2N Diagnostics for serving on the scientific advisory board. Washington University, with RJB as co-inventor, has submitted the US nonprovisional patent application “Cerebrospinal fluid (CSF) tau rate of phosphorylation measurement to define stages of Alzheimer’s disease and monitor brain kinases/phosphatases activity.” He has received honoraria from Janssen and Pfizer as a speaker, and from Merck and Pfizer as an advisory board member. He has been an invited speaker, advisory board member, and consultant for F. Hoffman La Roche, Ltd., an invited speaker and consultant for AC Immune and Janssen, and a consultant for Amgen and Eisai. There are no conflicts. AMG has consulted for Eisai, Biogen, Pfizer, AbbVie, Cognition Therapeutics, and GSK. She also served on the Scientific Advisory Board of Denali Therapeutics (2015–2018). There are no conflicts. Ethical Approval: Informed consent was obtained directly from all participants whenever possible; otherwise, assent was obtained, and informed consent obtained from the participant’s legally authorized representative. Institutional Review Board approval was obtained at all sites.