Massive changes in gene expression and their cause(s) can be a unifying principle in the pathobiology of Alzheimer's...

Understanding of the biology of Alzheimer's disease (AD) has long been fragmented, with various investigators concentrating on amyloid beta (Aβ) or tau, inflammation, cell death pathways, misfolded proteins, glia, and more. Yet data from multiple authors has repeatedly shown altered expression of myriad genes related to these seemingly disparate phenomena. In 2022, Morgan et al. organized the massive data on changes in AD in a meticulous survey of the literature and related these changes to Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Their data showed that 91% of the known KEGG pathways are involved in AD and that many of these pathways are represented by the known cellular/molecular phenomena of AD. Such data then raise the fundamental question: What mechanism(s) may be responsible for such widespread changes in gene expression? We review evidence for a unifying model based on sequestrations in stress granules and alteration of nucleocytoplasmic transport in AD. HIGHLIGHTS: In Alzheimer's disease (AD), critical changes take place in neurons before the appearance of plaques or tangles. Addressing these early changes provides a path to early detection and effective intervention in AD.