A Meta-Analysis of Alzheimer’s Disease Brain Transcriptomic Data

Abstract

BackgroundMicroarray technologies have identified imbalances in the expression of specific genes and biological pathways in Alzheimer's disease (AD) brains. However, there is a lack of reproducibility across individual AD studies, and many related neurogenerative and mental health disorders exhibit similar perturbations. We are yet to identify robust transcriptomic changes specific to AD brains. This study meta-analysed publicly available brain-related disorders along with healthy cognitive individuals to decipher common and AD-specific brain transcriptomic changes. Methods and ResultsTwenty-two AD, eight Schizophrenia, five Bipolar Disorder, four Huntington's disease, two Major Depressive Disorder and one Parkinson's disease dataset totalling 2667 samples and mapping to four different brain regions (Temporal lobe, Frontal lobe, Parietal lobe and Cerebellum) were analysed. Differential expression analysis was performed independently in each dataset, followed by metaanalysis using a combining p-value method known as Adaptively Weighted with One-sided Correction. This identified 323, 435, 1023 and 828 differentially expressed genes specific to the AD temporal lobe, frontal lobe, parietal lobe and cerebellum brain regions respectively. Seven of these genes were consistently perturbed across all AD brain regions and are considered disease-specific, while twenty-two genes are perturbed specifically in AD brain regions affected by both plaques and tangles, suggesting involvement in AD neuropathology. Biological pathways involved in the "metabolism of proteins" and viral components were significantly enriched across AD brains. ConclusionWe identify specific transcriptomic changes in AD brains which could make a significant contribution towards the understanding of AD disease mechanisms and provides new therapeutic targets.providing an opportunity to identify imbalances in the expression of specific genes and biological pathways. However, microarray reproducibility has always been questionable, with replication of differentially expressed genes (DEG's) very poor [6]. For example, two independent microarray transcriptomic studies performed differential expression analysis in the hippocampus of AD brains. The first study by Miller et al. identified 600 DEG's [7], and a similar study by Hokama et al. identified 1071 DEG's [8]. An overlap of 105 DEG's exist between the two studies; however, after accounting for multiple testing, no gene was replicated between the two studies. The Miller study consisted of 7 AD and 10 control subjects expression profiled on the Affymetrix platform while the Hakoma study consisted of 31 AD and 32 control subjects expression profiled on the Illumina platform. Replication between the Illumina and Affymetrix platform has been shown to be generally very high [9];therefore, the lack of replication between the two studies is probably down to a range of other factors including low statistical power, sampling bias and disease heterogeneity.Unlike DEG's, replication of the molecular changes at a pathwa...

Partial inhibition of mitochondrial complex I ameliorates Alzheimer’s disease pathology and cognition in APP/PS1 female mice

“…The comparison between vehicle-treated NTG and APP/PS1 mice identified 3320 differentially expressed genes (DEGs) ( . Processes affected by the disease in APP/PS1 mice overlap with pathways well-established in AD patients including ATP metabolism, ion transport, nervous system development, synaptic transmission, and inflammation [51][52][53][54][55][56] ( Supplementary Fig. 13b).…”

Partial inhibition of mitochondrial complex I attenuates neurodegeneration and restores energy homeostasis and synaptic function in a symptomatic Alzheimer’s mouse model

“…10b. Processes affected by the disease in APP/PS1 mice overlap with pathways well-established in AD patients including ATP metabolism, ion transport, nervous system development, synaptic transmission, and inflammation [49][50][51][52][53][54] (Extended Data Fig. 10b).…”

Working Towards a Blood-Derived Gene Expression Biomarker Specific for Alzheimer’s Disease

“…A recent study identified common viral species in normal and ageing brains, with an increased human herpesvirus 6A and human herpesvirus 7 in AD brains [48]. In addition, a recent transcriptomic meta-analysis study identified genes involved with “ interspecies interactions ” were specifically enriched in AD brains when taking into account expression changes in related neurological disorders [49]. The current observation extends the previous suggestions of viral involvement in AD brains to blood, as the expression of blood-derived genes involved in the “ Herpes simplex infection” can be used to distinguish AD from other neurological diseases and control subjects in this study.…”