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[P1–155]: SHOTGUN LIPIDOMICS AND RNA‐SEQ REVEAL EXTENSIVE CHANGES IN CARDIOLIPIN AND PHOSPHOLIPID PATHWAYS IN BRAINS OF APOEε3/3, APOEε3/4 AND APOEε4/4 ALZHEIMER'S DISEASE PATIENTS
Author(s) -
Nam Kyong Nyon,
Fitz Nicholas F.,
Wolfe Cody M.,
Schug Jonathan,
Lefterov Iliya,
Koldamova Radosveta
Publication year - 2017
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.2017.06.222
Subject(s) - lipidomics , apolipoprotein e , biology , cardiolipin , lipid metabolism , transcriptome , endocrinology , medicine , phospholipid , lipidome , microbiology and biotechnology , genetics , biochemistry , gene , gene expression , disease , membrane
Methods: Our subjects are from Religious Orders Study and the Rush Memory and Aging Project (ROS-MAP), two communitybased longitudinal cohort studies of aging and dementia that were designed for combined analyses. We assessed whether APOE ε4 allele count was associated with more advanced TDP-43 stages (stage 0 1⁄4 no inclusions; stage 1 1⁄4 inclusions in amygdala only; stage 2 1⁄4 stage 1 + entorhinal cortex or hippocampus CA1; stage 31⁄4 stage 2 + neocortex), using an ordinal logistic regression model adjusting for age, sex, and study cohort. Stratified analysis was done in subjects with and without pathologic diagnosis of AD. We used logistic regression models to examine the extent to which the effect of APOEε4 on AD dementia was attributable to AD (bamyloid, paired helical filament (PHF) tau) and TDP-43 pathologies. Results: In 1,084 deceased subjects from ROS-MAP, APOE ε4 was strongly associated with more advanced TDP-43 stage (odds ratio (OR) 1.9, 95% confidence interval (CI) 1.5–2.4, p1⁄44.4310). In stratified analyses, the association of APOE ε4 with TDP-43 stage was observed only in the subgroup with pathologic diagnosis of AD (OR1⁄41.7, 95% CI 1.3–2.3, p1⁄45.8310 (n1⁄4677); OR1⁄41.3, p1⁄40.32 for people without the diagnosis (n1⁄4387)). Of note, APOE ε4 count was marginally associated with higher likelihood of AD dementia, even after controlling for beta-amyloid load and PHF-tau tangle density (OR1⁄41.4, 95% CI 1.0–1.9, p1⁄40.049 (n1⁄4917)). However, this association was no longer significant when TDP-43 stage was included in the model (p1⁄40.13 (n1⁄4917)), suggesting that previously reported effect of APOEε4 in AD dementia is partially mediated by the increased burden of TDP-43 pathology. Conclusions:APOE ε4 is a risk factor of more advanced stages of TDP-43 proteinopathy, especially in the presence of AD pathology, and higher TDP-43 proteinopathy burden contributes to worse clinical outcome associated with APOE ε4.