Abstract
BackgroundAlzheimer’s disease (AD) reserve theory is based on specific individual characteristics that are associated with a higher resilience against neurodegeneration and its symptoms. A given degree of AD pathology may contribute to varying cognitive decline levels in different individuals. Although this phenomenon is attributed to reserve, the biological mechanisms that underpin it remain elusive, which restricts translational medicine research and treatment strategy development.MethodsNetwork-based approaches were integrated to identify AD reserve related genes. Then, AD brain transcriptomics data were clustered into co-expression modules, and a Bayesian network was developed using these modules plus AD reserve related phenotypes. The directed acyclic graph suggested that the module was strongly associated with AD reserve. The hub gene of the module of interest was filtered using the topological method. Validation was performed in the multi-AD brain transcriptomic dataset.ResultsWe revealed that the RALYL (RALY RNA Binding Protein-like) is the hub gene of the module which was highly associated with AD reserve related phenotypes. Pseudo-time projections of RALYL revealed the changes in relative expression drivers in the AD and control subjects over pseudo-time had distinct transcriptional states. Notably, the expression of RALYL decreased with the gradual progression of AD, and this corresponded to MMSE decline. Subjects with AD reserve exhibited significantly higher RALYL expression than those without AD reserve.ConclusionThe present study suggests that RALYL may be associated with AD reserve, and it provides novel insights into the mechanisms of AD reserve and highlights the potential role of RALYL in this process.
Highlights
Alzheimer’s disease (AD) reserve theory is based on specific individual characteristics that are associated with a higher resilience against neurodegeneration and its symptoms
Subjects were initially categorized into four groups [18]: 9 controls (MMSE > 25), 7 incipient AD (MMSE 20–25), 8 moderate AD (MMSE 14–19), and 7 severe AD (MMSE < 14)
Based on the concept of AD reserve [2, 27], subjects in GSE1297 were initially categorized into two groups, termed “reserve” (MMSE > 26, Braak ≥ 3), and “loss reserve” (MMSE < 26)
Summary
Alzheimer’s disease (AD) reserve theory is based on specific individual characteristics that are associated with a higher resilience against neurodegeneration and its symptoms. A given degree of AD pathology may contribute to varying cognitive decline levels in different individuals. This phenomenon is attributed to reserve, the biological mechanisms that underpin it remain elusive, which restricts translational medicine research and treatment strategy development. Alzheimer’s disease (AD) reserve refers to the differences in cognitive processes as a function of AD risk factors (genes, personality, lifestyle, and external environment) that explain differential susceptibility to functional impairment during pathology or other neurological insults [1,2,3]. The number of risk factors or pathology needed before the cognitive function is greatly affected by a higher reserve, leading to a later change point of cognitive decline. Since all human physiologic systems exhibit a reserve, a hypothetical therapeutic strategy could be used to offset most common AD brain pathologies that alter cognition
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