Abstract
BackgroundAlzheimer’s disease (AD) is the most common type of dementia, and patients with advanced AD frequently lose the ability to identify family members. The fusiform gyrus (FUS) of the brain is critical in facial recognition. However, AD etiology in the FUS of AD patients is poorly understood. New analytical strategies are needed to reveal the genetic and epigenetic basis of AD in FUS.ResultsA complex of new analytical paradigms that integrates an array of transcriptomes and methylomes of normal controls, AD patients, and “AD-in-dish” models were used to identify genetic and epigenetic signatures of AD in FUS. Here we identified changes in gene expression that are specific to the FUS in brains of AD patients. These changes are closely linked to key genes in the AD network. Profiling of the methylome (5mC/5hmC/5fC/5caC) at base resolution identified 5 signature genes (COL2A1, CAPN3, COL14A1, STAT5A, SPOCK3) that exhibit perturbed expression, specifically in the FUS and display altered DNA methylome profiles that are common across AD-associated brain regions. Moreover, we demonstrate proof-of-principle that AD-associated methylome changes in these genes effectively predict the disease prognosis with enhanced sensitivity compared to presently used clinical criteria.ConclusionsThis study identified a set of previously unexplored FUS-specific AD genes and their epigenetic characteristics, which may provide new insights into the molecular pathology of AD, attributing the genetic and epigenetic basis of FUS to AD development.
Highlights
Alzheimer’s disease (AD) is the most common type of dementia, and patients with advanced AD frequently lose the ability to identify family members
Changes in AD-specific gene networks are linked to specific brain regions By comparing transcriptomes of AD patients with normal controls (n = 108) in 4 different brain regions, we identified 2861 differentially expressed (DE) genes in the fusiform gyrus (FUS), 716 in the hippocampus (HPC), 375 in the prefrontal cortex (PFC), and 2166 in the temporal lobe (TPL) (Fig. 1a, Table S1)
We should note that comparing the DE analysis between brain regions only in controls, we found 4315 overlapping DE genes were differentially expressed in FUS, while there were 865, 1993, and 1512 overlapping DE genes in HPC, TPL, and PFC, respectively (Figure S1a-d)
Summary
Alzheimer’s disease (AD) is the most common type of dementia, and patients with advanced AD frequently lose the ability to identify family members. The fusiform gyrus (FUS) is a structure that lies on the basal surface of the temporal and occipital lobes in Brodmann’s area 37. It contains the critical fusiform face area (FFA) responsible for facial recognition [9]. Compared with well-studied and documented brain areas such as the hippocampus (HPC) [11], prefrontal cortex (PFC) [12], and temporal lobe (TPL) [13], the gene expression characteristics and molecular mechanisms of action involved in AD pathology in the FUS [14] remain unexplored. The identification of AD-related expression and epigenetic signatures in different brain regions can provide support of inherent molecular mechanisms for the heterogeneous symptoms and improve the individualized early detection, prevention, and treatment of AD patients [15]
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