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O1‐05‐02: The amyloid‐beta‐dependent phosphorylation of CRMP‐2 dissociates kinesin in Alzheimer's disease
Author(s) -
Mokhtar Sara H.,
Petratos Steven,
Aui Peimun,
Magee Kylie,
Bakhuraysah Maha,
Alrehaili Amani,
Steer David,
Azari Michael,
McLean Catriona,
Kenny Rachel
Publication year - 2015
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2015.07.052
Subject(s) - kinesin , phosphorylation , microbiology and biotechnology , neuroscience , biology , immunostaining , axoplasmic transport , chemistry , microtubule , immunohistochemistry , immunology
identification of biomarkers predicting the risk of developing AD in asymptomatic subjects could provide key insights into the biology and permit risk stratification and targeted preventive intervention in the early stages of AD, prior to onset of clinical symptoms. We used a metabolomics based approach to identify plasma biomarkers potentially associated with risk of developing dementia. Methods: 2067 dementia-free participants from the Framingham Offspring study (mean age1⁄455.969.7 years; 52.4% women) had comprehensive blood metabolite assessment on sera stored at their 5 examination (1991-1995) using liquid chromatography – mass spectrometry (LC-MS) and have also been prospectively assessed for incident dementia (mean follow-up 1⁄4 15.665.2 years). We used multivariate Cox models to relate log-transformed levels of 217metabolites to dementia occurrence, adjusting for age, sex, APOEε4, education and plasma homocysteine. A metabolite set enrichment analysis (MSEA) was also performed using Metaboanalyst 3.0 including all metabolites with a p-value 0.1. Results:A total of 93 participants developed incident dementia. After correction for multiple testing, only plasma anthranilic acid levels were significantly associated with risk of incident dementia (HR1⁄41.40; 95% CI1⁄4[1.15-1.70] per standard deviation increase in level; p1⁄48.08310). Three additional biologically plausible metabolites reached nominal significance: glutamic acid (HR1⁄41.38; 95% CI1⁄4[1.11-1.72]; p1⁄43.80310), taurine (HR1⁄40.74; 95% CI1⁄4[0.60-0.92]; p1⁄46.91310) and hypoxanthine (HR1⁄40.74; 95% CI1⁄4[0.60-0.92]; p1⁄46.93310). Using a set a 28 metabolites with a p-value 0.1, we observed a nominally significant enrichment for metabolites related to stroke (p1⁄42.77310). Conclusions: We have identified four candidate plasma biomarkers for dementia, each of which has been previously associated with dementia risk in small cerebrospinal fluid and nuclear magnetic resonance metabolomics studies. The MSEA adds to the evidence for an important vascular contribution to dementia and AD. We are now attempting to replicate these results through collaborations and study of various endophenotypes.