Biological and disease hallmarks of Alzheimer's disease defined by Alzheimer's disease genes

Abstract

An increasing number of genes associated with Alzheimer's disease (AD genes) have been reported. However, there is a lack of an 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 AD genes to identify both the biological pathways and the neurological diseases. Here we provide systematic updates on the genetic and disease hallmarks defined by AD genes. The analysis identified 50 pathways (defined as biological hallmarks). Of them, we have successfully compiled them into a total of 11 biological hallmarks, including 6 existing hallmarks and 5 newly updated hallmarks. The AD genes further identified 20 diverse diseases (defined as disease hallmarks), summarized into three major categories: (1) existing hallmarks, including neurological diseases; (2) newly identified hallmarks, including common age-related diseases such as diabetes, hypertension, other cardiovascular diseases, and cancers; (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 the 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.

Keywords: Alzheimer’s disease; cancer; comorbidity; diabetes; genetics; hypertension; metabolism.

FIGURE 1

Interaction network pathways of new biological hallmarks. (A) Network display of all AD genes. (B) Developmental Biology (axon and adipose development); (C) gene expression (RNA polymerase II transcription); (D) metabolism of proteins (Amyloid formation, regulation of IGF-1/Insulin, and small ubiquitin-like modifiers/SUMOs); (E) metabolism of RNA (mitochondrial tRNA and rRNA processing); (F) signal Transduction (ErbB, NOTCH, and p75 NTR death signaling). The interaction network was created by STRING-DB. Node colors are for visual only. Edge colors are as follows: blue: from the curated database; pink: experimentally determined; black: co-expression; green: text mining.

FIGURE 2

(A) Updated biological hallmarks. We extended the list indicated by Table 1, using the threshold (p-value < 1.00E-05) and summarized the 11 general biological hallmarks (circle) and more specific hallmarks (square). (B) Updated disease hallmarks. The diseases listed in Table 2 are organized and grouped into 6 general disease criteria. They are further classified into: (1) neurological diseases (Alzheimer’s Disease, Familial, 1, Amyotrophic Lateral Sclerosis 1, Parkinson’s Disease, Late-Onset, Schizophrenia, Peripheral Nervous System Disease, Nervous System Disease, others); (2) common age-related diseases (Diabetes, Cardiovascular Disease, Cancer and Osteoporosis); and (3) other diseases (Quantitative Trait Loci and Cystic fibrosis). Note that cancers are reported to show an inverse relationship with AD genes (indicated by asterisks).