Somatic Mutations and Alzheimer’s Disease

Article type: Review Article

Authors: Downey, Jocelyn^{a; *} | Lam, Jacqueline C.K.^{a; b; 1; *} | Li, Victor O.K.^{a; 1; *} | Gozes, Illana^{c; 1; *}

Affiliations: [a] Department of Electrical and Electronic Engineering, The University of Hong Kong, Hong Kong, China | [b] Department of Computer Science and Technology, University of Cambridge, UK | [c] The Elton Laboratory for Molecular Neuroendocrinology, Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Adams Super Center for Brain Studies and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel

Correspondence: [*] Correspondence to: Jocelyn Downey, Jacqueline C.K. Lam, and Victor O.K. Li, Department of Electrical and Electronic Engineering, The University of Hong Kong, Hong Kong, China. Tel.: +447876706435 (JD), +85239174843 (JCKL), +85239178425 (VOKL); E-mails: jocelyn.downey@cantab.net, jcklam@eee.hku.hk and vli@eee.hku.hk and Illana Gozes, The Elton Laboratory for Molecular Neuroendocrinology, Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Adams Super Center for Brain Studies and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel. Tel.: +97236407240; E-mail: igozes@tauex.tau.ac.il.

Note: [1] These senior authors contributed equally to this work.

Abstract: Alzheimer’s disease (AD) represents a global health challenge, with an estimated 55 million people suffering from the non-curable disease across the world. While amyloid-β plaques and tau neurofibrillary tangles in the brain define AD proteinopathy, it has become evident that diverse coding and non-coding regions of the genome may significantly contribute to AD neurodegeneration. The diversity of factors associated with AD pathogenesis, coupled with age-associated damage, suggests that a series of triggering events may be required to initiate AD. Since somatic mutations accumulate with aging, and aging is a major risk factor for AD, there is a great potential for somatic mutational events to drive disease. Indeed, recent data from the Gozes team/laboratories as well as other leading laboratories correlated the accumulation of somatic brain mutations with the progression of tauopathy. In this review, we lay the current perspectives on the principal genetic factors associated with AD and the potential causes, highlighting the contribution of somatic mutations to the pathogenesis of late onset Alzheimer’s disease. The roles that artificial intelligence and big data can play in accelerating the progress of causal somatic mutation markers/biomarkers identification, and the associated drug discovery/repurposing, have been highlighted for future AD and other neurodegenerations, with the aim to bring hope for the vulnerable aging population.

Keywords: Alzheimer’s disease, amyloid-β peptide, artificial intelligence, big data, late onset Alzheimer’s disease, somatic mutations, tau

DOI: 10.3233/JAD-220643

Journal: Journal of Alzheimer's Disease, vol. 90, no. 2, pp. 475-493, 2022