Longitudinal Cerebrospinal Fluid Biomarker Changes in Preclinical Alzheimer Disease During Middle Age
Courtney L. Sutphen,Mateusz S. Jasielec,Aarti R. Shah,Elizabeth M. Macy,Chengjie Xiong,Andrei G. Vlassenko,Tammie L.S. Benzinger,Erik Stoops,Hugo Vanderstichele,Britta Brix,Heather Darby,Manu Vandijck,Jack H. Ladenson,John C. Morris,David M. Holtzman,Anne M. Fagan +15 more
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TLDR
Longitudinal CSF biomarker patterns consistent with AD are first detectable during early middle age and are associated with later amyloid positivity and cognitive decline, useful for targeting middle-aged, asymptomatic individuals for therapeutic trials designed to prevent cognitive decline.Abstract:
Importance Individuals in the presymptomatic stage of Alzheimer disease (AD) are increasingly being targeted for AD secondary prevention trials. How early during the normal life span underlying AD pathologies begin to develop, their patterns of change over time, and their relationship with future cognitive decline remain to be determined. Objective To characterize the within-person trajectories of cerebrospinal fluid (CSF) biomarkers of AD over time and their association with changes in brain amyloid deposition and cognitive decline in cognitively normal middle-aged individuals. Design, Setting, and Participants As part of a cohort study, cognitively normal (Clinical Dementia Rating [CDR] of 0) middle-aged research volunteers (n = 169) enrolled in the Adult Children Study at Washington University, St Louis, Missouri, had undergone serial CSF collection and longitudinal clinical assessment (mean, 6 years; range, 0.91-11.3 years) at 3-year intervals at the time of analysis, between January 2003 and November 2013. A subset (n = 74) had also undergone longitudinal amyloid positron emission tomographic imaging with Pittsburgh compound B (PiB) in the same period. Serial CSF samples were analyzed for β-amyloid 40 (Aβ40), Aβ42, total tau, tau phosphorylated at threonine 181 (P-tau 181 ), visinin-like protein 1 (VILIP-1), and chitinase-3-like protein 1 (YKL-40). Within-person measures were plotted according to age and AD risk defined by APOE genotype (e4 carriers vs noncarriers). Linear mixed models were used to compare estimated biomarker slopes among middle-age bins at baseline (early, 45-54 years; mid, 55-64 years; late, 65-74 years) and between risk groups. Within-person changes in CSF biomarkers were also compared with changes in cortical PiB binding and progression to a CDR higher than 0 at follow-up. Main Outcomes and Measures Changes in Aβ40, Aβ42, total tau, P-tau 181 , VILIP-1, and YKL-40 and, in a subset of participants, changes in cortical PiB binding. Results While there were no consistent longitudinal patterns in Aβ40 ( P = .001-.97), longitudinal reductions in Aβ42 were observed in some individuals as early as early middle age ( P ≤ .05) and low Aβ42 levels were associated with the development of cortical PiB-positive amyloid plaques (area under receiver operating characteristic curve = 0.9352; 95% CI, 0.8895-0.9808), especially in mid middle age ( P 181 , and VILIP-1) dramatically increased in some individuals in mid and late middle age ( P ≤ .02), whereas the neuroinflammation marker YKL-40 increased consistently throughout middle age ( P ≤ .003). These patterns were more apparent in at-risk e4 carriers (Aβ42 in an allele dose-dependent manner) and appeared to be associated with future cognitive deficits as determined by CDR. Conclusions and Relevance Longitudinal CSF biomarker patterns consistent with AD are first detectable during early middle age and are associated with later amyloid positivity and cognitive decline. Such measures may be useful for targeting middle-aged, asymptomatic individuals for therapeutic trials designed to prevent cognitive decline.read more
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Piotr Lewczuk,Peter Riederer,Sid E. O'Bryant,Marcel M. Verbeek,Bruno Dubois,Pieter Jelle Visser,Kurt A. Jellinger,Sebastiaan Engelborghs,Alfredo Ramirez,Lucilla Parnetti,Clifford R. Jack,Charlotte E. Teunissen,Harald Hampel,Alberto Lleó,Frank Jessen,Lidia Glodzik,Mony J. de Leon,Anne M. Fagan,José Luis Molinuevo,Willemijn J. Jansen,Bengt Winblad,Leslie M. Shaw,Ulf Andreasson,Markus Otto,Brit Mollenhauer,Jens Wiltfang,Martin R Turner,Inga Zerr,Ron Handels,Alexander G. Thompson,Gunilla Johansson,Natalia Ermann,John Q. Trojanowski,Ilker Karaca,Holger Wagner,Patrick Oeckl,Linda J C van Waalwijk van Doorn,Maria Bjerke,Dimitrios Kapogiannis,H. Bea Kuiperij,Lucia Farotti,Yi Li,Brian A. Gordon,Stéphane Epelbaum,Stephanie J.B. Vos,Catharina J.M. Klijn,William E. Van Nostrand,Carolina Minguillon,Matthias Schmitz,Carla Gallo,Andrea Lopez Mato,Florence Thibaut,Simone Lista,Daniel Alcolea,Henrik Zetterberg,Kaj Blennow,Johannes Kornhuber +56 more
TL;DR: In the 12 years since the publication of the first Consensus Paper of the WFSBP on biomarkers of neurodegenerative dementias, enormous advancement has taken place in the field, and the Task Force takes the opportunity to extend and update the original paper.
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