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. 2019 May;15(5):655-665.
doi: 10.1016/j.jalz.2018.12.019. Epub 2019 Mar 4.

Emerging cerebrospinal fluid biomarkers in autosomal dominant Alzheimer's disease

Suzanne E Schindler  1 , Yan Li  2 , Kaitlin W Todd  2 , Elizabeth M Herries  3 , Rachel L Henson  4 , Julia D Gray  4 , Guoqiao Wang  2 , Danielle L Graham  5 , Leslie M Shaw  6 , John Q Trojanowski  7 , Jason J Hassenstab  1 , Tammie L S Benzinger  8 , Carlos Cruchaga  9 , Mathias Jucker  10 , Johannes Levin  11 , Jasmeer P Chhatwal  12 , James M Noble  13 , John M Ringman  14 , Neill R Graff-Radford  15 , David M Holtzman  4 , Jack H Ladenson  3 , John C Morris  1 , Randall J Bateman  4 , Chengjie Xiong  16 , Anne M Fagan  17 ; Dominantly Inherited Alzheimer Network
Affiliations

Emerging cerebrospinal fluid biomarkers in autosomal dominant Alzheimer's disease

Suzanne E Schindler et al. Alzheimers Dement. 2019 May.

Abstract

Introduction: Four less well-studied but promising "emerging" cerebrospinal fluid (CSF) biomarkers are elevated in late-onset Alzheimer disease (AD): neurogranin, synaptosomal-associated protein-25 (SNAP-25), visinin-like protein 1 (VILIP-1), and chitinase-3-like protein 1 (YKL-40).

Methods: CSF neurogranin, SNAP-25, VILIP-1, and YKL-40 were measured in families carrying autosomal-dominant AD mutations.

Results: The four emerging CSF biomarkers were significantly elevated in the mutation carriers (n = 235) versus noncarriers (n = 145). CSF SNAP-25, VILIP-1, and YKL-40 were altered very early in the AD time course, approximately 15-19 years before estimated symptom onset. All CSF biomarkers predicted important AD-related outcomes including performance on a cognitive composite, brain amyloid burden as measured by amyloid positron emission tomography, and the estimated years from symptom onset.

Discussion: Early abnormalities in CSF tTau, pTau, SNAP-25, VILIP-1, and YKL-40 suggest that synaptic damage, neuronal injury, and neuroinflammation begin shortly after the commencement of brain amyloid accumulation.

Keywords: Alzheimer's disease; Autosomal-dominant Alzheimer's disease; Biomarkers; Cerebrospinal fluid; Dementia; Neuroinflammation.

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Conflict of interest statement

Potential Conflicts of Interest

S.E.S. has a family member with stock in Eli Lilly, which is developing drugs for Alzheimer disease. D.L.G. is a full time employee at Biogen, which funded this study and is developing drugs for Alzheimer disease. L.M.S. receives research support from Eli Lilly, Hoffman LaRoche, MJFox Foundation for Parkinson’s Research for Biofind study and has served as consultant and/or advisory boards for Roche Diagnostics and Eli Lilly. He provides quality control oversight for Roche Elecsys immunoassays in the ADNI study. J.J.H. is on the advisory board and consults for both Biogen and Lundbeck A/S. T.L.S.B. consults for Eli Lilly and receives research funding from Avid Radiopharmaceuticals. J.L. reports personal fees from Aesku, Bayer Vital, the Willi Gross Foundation, Axon Neuroscience, and Ionis Pharmaceuticals. He has received non-financial support from AbbVie that is outside the submitted work. D.M.H. co-founded and is on the scientific advisory board of C2N Diagnostics. D.M.H. consults for Genentech, AbbVie, Eli Lilly, Proclara, and Denali. Washington University receives research grants to the lab of D.M.H. from C2N Diagnostics, Eli Lilly, AbbVie, and Denali. J.H.L. reports being named on patents related to the use of VILIP-1. These are being managed by Washington University in accordance with University policy. J.H.L. is a co-inventor on patent 11/630582 (2005) (Markers for brain damage) and patent 60957132 (2008) (Alzheimer’s diagnosis). J.C.M. has or is currently participating in clinical trials of anti-dementia drugs sponsored by Janssen Immunotherapy, Eli Lilly and Company, and Pfizer. He has served as a consultant for or has received speaking honoraria from Eisai, Esteve, Janssen Alzheimer Immunotherapy Program/Elan, GlaxoSmithKline, Novartis, and Pfizer. He receives research support from Eli Lilly/Avid Radiopharmaceuticals. R.J.B. co-founded and is on the scientific advisory board of C2N Diagnostics. He consults for Roche, Genentech, AbbVie, Pfizer, Boehringer-Ingelheim, and Merck. A.M.F. has received research funding from Biogen, Fujirebio and Roche Diagnostics. She is a member of the scientific advisory boards for Roche, Genentech and AbbVie and also consults for Araclon/Griffols and DiamiR. Y.L., K.W.T., E.M.H., R.L.H., J.D.G., G.W., J.Q.T., C.C., M.J., J.P.C., J.M.N., J.M.R., N.R.G-R., and C.X. have nothing to report.

Figures

Fig. 1.
Fig. 1.. CSF, imaging, clinical and cognitive measures as a function of EYO in the ADAD mutation carriers and non-carriers.
The unadjusted levels of each measure are shown as a function of EYO. Values for the mutation carriers are shown in red and values for the noncarriers are shown in blue. Each point represents one measurement. Thin lines between points connect measurements within the same individual. Thick lines are the LOESS curves for all values (red for the mutation carriers and blue for the non-carriers) and are depicted to aid with visualization of trends in the data. For Aβ42, tTau, pTau, Ng, SNAP-25, and VILIP-1, units are in pg/ml. For YKL-40, units are in ng/ml. For amyloid PET, units are in mean cortical SUVR. For hippocampus, units are in mm3. For entorhinal cortex and precuneus, units are in mm. The cognitive composite is a Z-score, with a mean of 0 and units in standard deviations from the mean. CDR, CDR-SB and MMSE are the raw test score. To prevent inadvertent disclosure of mutation status to research participants, the plot does not include the EYO scale, points from EYO outliers were omitted, and points after >3 data collections are not shown.
Fig. 2.
Fig. 2.. Comparison of baseline CSF, imaging, clinical and cognitive measures as a function of EYO.
The difference between values in the ADAD mutation carriers and non-carriers for each unadjusted standardized measure at baseline is shown as a function of EYO. The y-axis represents the degree of abnormality consistent with AD pathology so that trajectories are more comparable. Lines are LOESS curves for the values. To prevent inadvertent disclosure of mutation status to research participants, plots do not include the EYO scale.
See this image and copyright information in PMC

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