Most Pathways Can Be Related to the Pathogenesis of Alzheimer's Disease

Sarah L Morgan; Pourya Naderi; Katjuša Koler; Yered Pita-Juarez; Dmitry Prokopenko; Ioannis S Vlachos; Rudolph E Tanzi; Lars Bertram; Winston A Hide

doi:10.3389/fnagi.2022.846902

Most Pathways Can Be Related to the Pathogenesis of Alzheimer's Disease

Front Aging Neurosci. 2022 Jun 24:14:846902. doi: 10.3389/fnagi.2022.846902. eCollection 2022.

Authors

Sarah L Morgan^{1

2

3}, Pourya Naderi^{1

2}, Katjuša Koler⁴, Yered Pita-Juarez^{1

2

5}, Dmitry Prokopenko^{2

6}, Ioannis S Vlachos^{1

2

5}, Rudolph E Tanzi^{2

6}, Lars Bertram^{7

8}, Winston A Hide^{1

2}

Affiliations

¹ Harvard Medical School Initiative for RNA Medicine, Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, United States.
² Harvard Medical School, Boston, MA, United States.
³ Blizard Institute, Department of Neuroscience, Surgery and Trauma, Queen Mary University of London, London, United Kingdom.
⁴ Department of Computer Science, The University of Sheffield, Sheffield, United Kingdom.
⁵ Broad Institute of MIT and Harvard, Cambridge, MA, United States.
⁶ Genetics and Aging Research Unit, The Henry and Allison McCance Center for Brain Health, Department of Neurology, Massachusetts General Hospital, Boston, MA, United States.
⁷ Lübeck Interdisciplinary Platform for Genome Analytics, Institutes of Neurogenetics and Cardiogenetics, University of Lübeck, Lübeck, Germany.
⁸ Center for Lifespan Changes in Brain and Cognition, Department of Psychology, University of Oslo, Oslo, Norway.

Abstract

Alzheimer's disease (AD) is a complex neurodegenerative disorder. The relative contribution of the numerous underlying functional mechanisms is poorly understood. To comprehensively understand the context and distribution of pathways that contribute to AD, we performed text-mining to generate an exhaustive, systematic assessment of the breadth and diversity of biological pathways within a corpus of 206,324 dementia publication abstracts. A total of 91% (325/335) of Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways have publications containing an association via at least 5 studies, while 63% of pathway terms have at least 50 studies providing a clear association with AD. Despite major technological advances, the same set of top-ranked pathways have been consistently related to AD for 30 years, including AD, immune system, metabolic pathways, cholinergic synapse, long-term depression, proteasome, diabetes, cancer, and chemokine signaling. AD pathways studied appear biased: animal model and human subject studies prioritize different AD pathways. Surprisingly, human genetic discoveries and drug targeting are not enriched in the most frequently studied pathways. Our findings suggest that not only is this disorder incredibly complex, but that its functional reach is also nearly global. As a consequence of our study, research results can now be assessed in the context of the wider AD literature, supporting the design of drug therapies that target a broader range of mechanisms. The results of this study can be explored at www.adpathways.org.

Keywords: Alzheimer’s disease; dementia; disease mechanism; pathway; text-mining.