Project description:Epigenome Analysis of Post-Mortem Human Temporal Pole Brain Tissue For more information, please refer to DOI: 10.3233/JAD-141989 Temporal Pole regions from 24 age-matched causcasian males: 8 samples which died of normal causes, 8 samples with Alzheimer's disease (stage 3/4) and 8 samples with dementia with lewy bodies
Project description:Alzheimer’s disease (AD) is a chronic neurodegenerative disorder that is characterized by progressive neuropathology and cognitive decline. We performed a cross-tissue analysis of methylomic variation in AD using samples from three independent human post-mortem brain cohorts. We identified a differentially methylated region in the ankyrin 1 (ANK1) gene that was associated with neuropathology in the entorhinal cortex, a primary site of AD manifestation. This region was confirmed as being substantially hypermethylated in two other cortical regions (superior temporal gyrus and prefrontal cortex), but not in the cerebellum, a region largely protected from neurodegeneration in AD, or whole blood obtained pre-mortem from the same individuals. Neuropathology-associated ANK1 hypermethylation was subsequently confirmed in cortical samples from three independent brain cohorts. This study represents, to the best of our knowledge, the first epigenome-wide association study of AD employing a sequential replication design across multiple tissues and highlights the power of this approach for identifying methylomic variation associated with complex disease. For the first (discovery) stage of our analysis, we used multiple tissues from donors (N = 122) archived in the MRC London Brainbank for Neurodegenerative Disease. From each donor, we isolated genomic DNA from four brain regions (EC, superior temporal gyrus (STG), prefrontal cortex (PFC) and CER) and, where available, from whole blood obtained pre-mortem. Our analyses focused on identifying differentially methylated positions (DMPs) associated with Braak staging, a standardized measure of neurofibrillary tangle burden determined at autopsy.
Project description:INTRODUCTION: Neuropsychiatric symptoms are common in people with Alzheimer’s disease (AD) across all severity stages. Their heterogeneous presentation and variable temporal association with cognitive decline suggest shared and distinct biological mechanisms. We hypothesized that specific patterns of gene expression associate with distinct NIMH Research Domain Criteria (RDoC) domains in AD. METHODS: Post-mortem bulk RNAseq on the insula and anterior cingulate cortex from 60 brain donors representing the spectrum of canonical AD neuropathology combined with natural language processing approaches based on the RDoC Clinical Domains. RESULTS: Distinct sets of >100 genes (pFDR<0.05) were specifically associated with at least one clinical domain (Cognitive, Social, Negative, Positive, Arousal). In addition, dysregulation of immune response pathways was shared across domains and brain regions. DISCUSSION: Our findings provide evidence for distinct transcriptional profiles associated with RDoC domains suggesting that each dimension is characterized by specific sets of genes providing insight into the underlying mechanisms.