van Duijn, Cornelia M.;
Ahmad, Shahzad;
Sáez, María Eugenia;
Bennett, Keiryn;
Socorro, Alfredo Cabrera;
Bakker, Margot H.M.;
Ramirez, Alfredo;
Ruiz, Agustín;
Hankemeier, Thomas
Cross‐omics studies of the role of apolipoprotein E in Alzheimer’s disease and dementia: Searching common pathways in patients, populations and cellular models
: Alzheimer's disease apolipoprotein pathology for treatment elucidation and development: The adapted project results
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Medientyp:
E-Artikel
Titel:
Cross‐omics studies of the role of apolipoprotein E in Alzheimer’s disease and dementia: Searching common pathways in patients, populations and cellular models
:
Alzheimer's disease apolipoprotein pathology for treatment elucidation and development: The adapted project results
Beteiligte:
van Duijn, Cornelia M.;
Ahmad, Shahzad;
Sáez, María Eugenia;
Bennett, Keiryn;
Socorro, Alfredo Cabrera;
Bakker, Margot H.M.;
Ramirez, Alfredo;
Ruiz, Agustín;
Hankemeier, Thomas
Beschreibung:
<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Genetic and transcriptomic studies in patients and cellular models are converging on a key role for lipids and the immune system. ADAPTED aimed to develop a comprehensive atlas of changes in metabolic and protein pathways in the blood and brain and determine whether these are driven by the apolipoprotein E gene (APOE). We conducted cross‐omics studies in human populations and integrated the findings with that of isogenic APOE ε2/ε2, APOE ε3/ε3, and APOE ε4/ε4 cell lines.</jats:p></jats:sec><jats:sec><jats:title>Method</jats:title><jats:p>Human studies were embedded in the Rotterdam Study and prospective studies of patients with mild cognitive impairment (MCI) in memory clinics of Fundació ACE and the Central Institute of Mental Health (Mannheim). State‐of‐the‐art RNA‐sequencing, proteomics and metabolomics were used to characterize changes in blood and cerebrospinal fluid (CSF). Metabolomics included comprehensive analysis of cholesterol subfractions, signalling lipids including lysophosphatic acids (LPA), amino acids and proteins using NMR and LC‐MS/MS. Proteomics studies are based on high‐multiplex immunoassays and LC‐MS/MS.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>In blood, we identified a broad spectrum of metabolites associated with risk of AD, including HDL‐subfractions, DHA, amino acids and glycoproteins. We found systemic changes in the levels of metabolites in circulation are driven by APOE in concert with other genes implicated in AD. In blood, we found a weak correlation between LPA levels and risk of AD. However, LPA levels in CSF strongly associated with amyloid, phosphorylated and total tau, with APOE driving the profiles. LPA 16:0 and 16:1 CSF levels were associated with MCI to AD conversion. Our proteomic studies show a large number of proteins associated with amyloid, phosphorylated and total tau levels in CSF of MCI patients. However, in blood we also discovered two proteins associated with future risk of dementia: CDH6 and Hagh. Integrating the findings with RNA sequence data in iPSC based cellular models showed that CDH6 is differentially expressed across APOE genotypes in isogenic neurons but not in macrophages.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>We show a wide range of metabolic and proteomic changes that may be relevant for the development and course of AD. The findings show the potential of cross omics‐research connecting findings in human populations and cellular models.</jats:p></jats:sec>