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In a 200\u2010person \u201ctraining\u201d set, Least Absolute Shrinkage and Selection Operator regression estimated model weights for the 23 proteins, and for the AD biomarkers themselves, as predictors of ADAS\u2010Cog<jats:sub>11<\/jats:sub> scores. In the remaining 106 participants (\u201cvalidation\u201d set), fully adjusted regression models then tested the Least Absolute Shrinkage and Selection Operator\u2013derived models and a related protein marker summary score as predictors of ADAS\u2010Cog<jats:sub>11<\/jats:sub>, ADNI diagnostic category, and longitudinal cognitive trajectory.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>AD biomarkers alone explained 26% of the variance in validation set cognitive scores. Surprisingly, the 23 AD\u2010related proteins explained 31% of this variance. The biomarkers and protein markers appeared independent in this respect, jointly explaining 42% of test score variance. The composite protein marker score also predicted ADNI diagnosis and subsequent cognitive trajectory. Cognitive outcome prediction redounded principally to ten markers related to lipid or vascular functions or to microglial activation or chemotaxis. In each analysis, apoE protein and four markers in the latter immune\u2010activation group portended better outcomes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>CSF markers of vascular, lipid\u2010metabolic and immune\u2010related functions may explain much of the disjunction between AD biomarker abnormality and symptom severity. In particular, our results suggest the hypothesis that innate immune activation improves cognitive outcomes in persons with AD pathology. This hypothesis should be tested by further study of cognitive outcomes related to CSF markers of innate immune activation.<\/jats:p><\/jats:sec>","DOI":"10.1016\/j.jalz.2019.05.007","type":"journal-article","created":{"date-parts":[[2019,8,9]],"date-time":"2019-08-09T07:54:39Z","timestamp":1565337279000},"page":"1160-1171","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Hypothesis: cerebrospinal fluid protein markers suggest a pathway toward symptomatic resilience to AD pathology"],"prefix":"10.1002","volume":"15","author":[{"given":"Pierre\u2010Fran\u00e7ois","family":"Meyer","sequence":"first","affiliation":[{"name":"Faculty of Medicine McGill University Montr\u00e9al QC Canada"},{"name":"Center for Studies on the Prevention of Alzheimer's Disease (StoP\u2010AD) Douglas Mental Health University Institute Montr\u00e9al QC 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