Biological and Disease Hallmarks of Alzheimer’s Disease Defined by Alzheimer’s Disease Genes

Abstract

AbstractAn increasing number of genes associated with Alzheimer’s disease (AD) have been reported. However, despite previous studies, there is a lack of overview of the genetic relationship between AD and age-related comorbidities, such as hypertension, myocardial infarction, and diabetes, among others. Previously, we used Reactome analysis in conjunction with the genes that are associated with AD (AD genes) to identify both the biological pathways and the neurological diseases involved. Here we provide systematic updates on the genetic and disease hallmarks defined by AD genes. There are a total of 11 pathways (defined as genetic biological hallmarks) including 6 existing hallmarks and 5 newly updated hallmarks, the latter of which are developmental biology (axon and adipose development), gene expression (RNA transcription), metabolism of proteins (Amyloid formation, regulation of IGF-1/Insulin, and small ubiquitin-like modifiers/SUMOs), metabolism of RNA (mitochondrial tRNA and rRNA processing), and signal transduction (ErbB, NOTCH and p75 NTR death signaling). The AD genes further identified 20 diverse diseases that we define as disease hallmarks including: (1) existing hallmarks, including neurological diseases (Alzheimer’s disease, Amyotrophic Lateral Sclerosis, Parkinson’s Disease, and Schizophrenia); (2) as well as newly identified hallmarks, including Type 2 Diabetes, Cardiovascular diseases (Myocardial Infarction, Heart Disease, Hypertension, Cardiovascular system disease, Vascular Disease), Quantitative trait loci (lipoprotein and body mass index), Cancer (Breast cancer, Colorectal cancer, Prostate cancer, and Lung cancer); (3) and other health conditions; note that cancers reportedly have an inverse relation with AD. We previously suggested that a single gene is associated with multiple neurological diseases, and we are further extending the finding that AD genes are associated with common age-related comorbidities and others. This study indicates that heterogeneity of Alzheimer’s disease predicts complex clinical presentations in people living with AD. Taken together, the genes define AD as a part of age-related comorbidities with shared biological mechanisms and may raise awareness of a healthy lifestyle as potential prevention and treatment of the comorbidities.