Abstract
Late-onset Alzheimer's disease (LOAD) risk is strongly influenced by genetic factors such as the presence of the apolipoprotein E ε4 allele (referred to here as APOE4), as well as non-genetic determinants including ageing. To pursue mechanisms by which these affect human brain physiology and modify LOAD risk, we initially analysed whole-transcriptome cerebral cortex gene expression data in unaffected APOE4 carriers and LOAD patients. APOE4 carrier status was associated with a consistent transcriptomic shift that broadly resembled the LOAD profile. Differential co-expression correlation network analysis of the APOE4 and LOAD transcriptomic changes identified a set of candidate core regulatory mediators. Several of these--including APBA2, FYN, RNF219 and SV2A--encode known or novel modulators of LOAD associated amyloid beta A4 precursor protein (APP) endocytosis and metabolism. Furthermore, a genetic variant within RNF219 was found to affect amyloid deposition in human brain and LOAD age-of-onset. These data implicate an APOE4 associated molecular pathway that promotes LOAD.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
-
Retracted Publication
MeSH terms
-
Age of Onset
-
Aged
-
Alleles
-
Alzheimer Disease / epidemiology
-
Alzheimer Disease / genetics*
-
Amyloid beta-Protein Precursor / metabolism
-
Apolipoprotein E4 / genetics*
-
Brain / drug effects
-
Brain / metabolism
-
Cells, Cultured
-
Cerebral Cortex / metabolism
-
Endocytosis
-
Epistasis, Genetic
-
Female
-
Fibroblasts
-
Gene Expression Profiling
-
Genome, Human / genetics*
-
Genome-Wide Association Study
-
Genomics*
-
Heterozygote
-
Humans
-
Levetiracetam
-
Membrane Glycoproteins / antagonists & inhibitors
-
Membrane Glycoproteins / genetics
-
Membrane Glycoproteins / metabolism
-
Nerve Tissue Proteins / antagonists & inhibitors
-
Nerve Tissue Proteins / genetics
-
Nerve Tissue Proteins / metabolism
-
Neurons / drug effects
-
Neurons / metabolism
-
Phenotype
-
Piracetam / analogs & derivatives
-
Piracetam / pharmacology
-
Polymorphism, Genetic / genetics
-
Proteolysis / drug effects
-
Transcriptome / genetics
Substances
-
Amyloid beta-Protein Precursor
-
Apolipoprotein E4
-
Membrane Glycoproteins
-
Nerve Tissue Proteins
-
SV2A protein, human
-
Levetiracetam
-
Piracetam