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

Background: Due to trisomy of chromosome 21 and the resultant extra copy of the amyloid precursor protein gene, nearly all adults with Down syndrome develop Alzheimer's disease pathology by the age of 40 years and are at high risk for dementia given their increased life expectancy compared with adults with Down syndrome in the past. We aimed to compare CSF biomarker patterns in Down syndrome with those of carriers of autosomal dominant Alzheimer's disease mutations to enhance our understanding of disease mechanisms in these two genetic groups at high risk for Alzheimer's disease.
Methods: We did a cross-sectional study using data from adults enrolled in the Alzheimer's Biomarker Consortium-Down Syndrome (ABC-DS) study, a multisite longitudinal study of Alzheimer's disease in Down syndrome, as well as a cohort of carriers of autosomal dominant Alzheimer's disease mutations and non-carrier sibling controls enrolled in the Dominantly Inherited Alzheimer Network (DIAN) study. For ABC-DS, participants with baseline CSF, available clinical diagnosis, and apolipoprotein E genotype as of Jan 31, 2019, were included in the analysis. DIAN participants with baseline CSF, available clinical diagnosis, and apolipoprotein E genotype as of June 30, 2018, were evaluated as comparator groups. CSF samples obtained from adults with Down syndrome, similarly aged carriers of autosomal dominant Alzheimer's disease mutations, and non-carrier siblings (aged 30-61 years) were analysed for markers of amyloid β (Aβ _1-40 , Aβ _1-42 ); tau phosphorylated at threonine 181-related processes; neuronal, axonal, or synaptic injury (total tau, visinin-like protein 1, neurofilament light chain [NfL], synaptosomal-associated protein 25); and astrogliosis and neuroinflammation (chitinase-3-like protein 1 [YKL-40]) via immunoassay. Biomarker concentrations were compared as a function of dementia status (asymptomatic or symptomatic), and linear regression was used to evaluate and compare the relationship between biomarker concentrations and age among groups.
Findings: We assessed CSF samples from 341 individuals (178 [52%] women, 163 [48%] men, aged 30-61 years). Participants were adults with Down syndrome (n=41), similarly aged carriers of autosomal dominant Alzheimer's disease mutations (n=192), and non-carrier siblings (n=108). Individuals with Down syndrome had patterns of Alzheimer's disease-related CSF biomarkers remarkably similar to carriers of autosomal dominant Alzheimer's disease mutations, including reductions (all p<0·0080) in Aβ _1-42 to Aβ _1-40 ratio and increases in markers of phosphorylated tau-related processes; neuronal, axonal, and synaptic injury (p<0·080); and astrogliosis and neuroinflammation, with greater degrees of abnormality in individuals with dementia. Differences included overall higher concentrations of Aβ and YKL-40 (both p<0·0008) in Down syndrome and potential elevations in CSF tau (p<0·010) and NfL (p<0·0001) in the asymptomatic stage (ie, no dementia symptoms).
Funding: National Institute on Aging, Eunice Kennedy Shriver National Institute of Child Health and Human Development, German Center for Neurodegenerative Diseases, and Japan Agency for Medical Research and Development.
Competing Interests: Declaration of interests 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, outside the submitted work. RJB has equity ownership interest in C2N Diagnostics and receives royalty income based on technology (stable isotope labelling 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 non-provisional 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, an invited speaker and consultant for AC Immune and Janssen, and a consultant for Amgen and Eisai, outside the submitted work. 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), outside the submitted work. BJH has received research funding from Roche Pharmaceuticals and Autism Speaks, outside the submitted work. JPC has served on a medical advisory board for Otsuka Pharmaceuticals, outside the submitted work. GSD is supported by National Institutes of Health/National Institute on Aging (K23AG064029). He serves as a topic editor on dementia for DynaMed Plus (EBSCO Industries), a consultant for Parabon NanoLabs, is the clinical director for the Anti-NMDA Receptor Encephalitis Foundation (uncompensated), has provided record review and expert medical testimony on legal cases pertaining to management of Wernicke encephalopathy, and holds stocks (>$10 000) in ANI Pharmaceuticals (a generic pharmaceutical company), outside the submitted work. NRGR takes part in multicentre trials supported by AbbVie, Eli Lilly, and Biogen, outside the submitted work. JL reports speaker fees from Bayer Vital and Roche, consulting fees from Axon Neuroscience and Ionis Pharmaceuticals, author fees from Thieme medical publishers and W Kohlhammer GmbH medical publishers, non-financial support from Abbvie, and compensation for duty as part-time CMO from MODAG, outside the submitted work. CJM has been a member of advisory scientific board for Biogen, IONIS, Wave, and Roche and consulted for Eisai, outside the submitted work. RNM has received funding from the US Alzheimer's Foundation to undertake an intervention trial for the prevention of Alzheimer's disease. He is a member of the scientific advisory board for Eisai, outside the submitted work. SS reports consulting to Eisai, Novartis, Genentech, F Hoffmann-La Roche, Gemvax, Avid Radiopharmaceuticals, and Eli Lilly and Company, outside the submitted work. All other authors declare no competing interests.
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