{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:33:59Z","timestamp":1760060039881,"version":"build-2065373602"},"reference-count":51,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,7,29]],"date-time":"2025-07-29T00:00:00Z","timestamp":1753747200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brain Sciences"],"abstract":"<jats:p>Background: The mechanisms by which sporadic young-onset neurodegenerative processes develop are uncertain. Methods: We have previously proposed that stochastic processes involving sequence changes at a DNA, RNA, or protein level in critical genes and proteins might be important to this process. Further investigation points to the contribution of probabilistic states in other factors involved in neurodegenerative conditions, such as\u2014in the case of young onset Alzheimer\u2019s disease\u2014head injury, apolipoprotein \u03b54 alleles and other elements that, by the interaction of conditional probabilities in these variables, influence the evolution of neurodegenerative conditions. Results: This proposal might help to explain why some autosomal dominant neurodegenerative conditions, such as trinucleotide repeat disorder (Huntington\u2019s disease), might have variable ages of onset given the same disease-causing CAG repeat mutation length. Conclusions: The detection of somatic mutations in single brain cells provides some experimental support for these emerging concepts.<\/jats:p>","DOI":"10.3390\/brainsci15080814","type":"journal-article","created":{"date-parts":[[2025,7,29]],"date-time":"2025-07-29T10:25:34Z","timestamp":1753784734000},"page":"814","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Probability and Neurodegeneration: Alzheimer\u2019s Disease and Huntington\u2019s Disease"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4996-2361","authenticated-orcid":false,"given":"Peter K.","family":"Panegyres","sequence":"first","affiliation":[{"name":"Neurodegenerative Disorders Research Pty Ltd., Perth, WA 6005, Australia; Tel.: +61-8-6317-9472"},{"name":"School of Medicine, The University of Western Australia, Perth, WA 6009, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"663","DOI":"10.3233\/ADR-210309","article-title":"The clinical spectrum of young onset dementia points to its stochastic origins","volume":"5","author":"Panegyres","year":"2021","journal-title":"J. Alzheimers Dis. Rep."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Panegyres, P.K. (2022). Stochasticity, entropy and neurodegeneration. Brain Sci., 12.","DOI":"10.3390\/brainsci12020226"},{"key":"ref_3","first-page":"473","article-title":"Stochastic considerations into the origins of sporadic adult onset neurodegenerative disorders","volume":"9","author":"Panegyres","year":"2019","journal-title":"J. Alzheimers Dis. Park."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1080","DOI":"10.1001\/jamaneurol.2021.2161","article-title":"Global Prevalence of Young-Onset Dementia: A Systematic Review and Meta-analysis","volume":"78","author":"Hendriks","year":"2021","journal-title":"JAMA Neurol."},{"key":"ref_5","unstructured":"National Institute of Aging (2025, January 13). The NIA Monthly Update, Available online: https:\/\/www.linkedin.com\/pulse\/nia-monthly-update-july-2024-national-institute-on-aging-5qxrf?trk=organization_guest_main-feed-card_feed-article-content."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1016\/S0140-6736(24)01296-0","article-title":"Dementia prevention, intervention, and care: 2024 report of the Lancet Sanding Commission","volume":"404","author":"Livingston","year":"2024","journal-title":"Lancet"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Sato, N. (2021). Is organization of living systems explained by probability?. Philosophies, 6.","DOI":"10.3390\/philosophies6010003"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1006\/jtbi.1999.0977","article-title":"Biological probability: Cognitive processes of generating probabilities of events in biological systems","volume":"200","author":"Nakajima","year":"1999","journal-title":"J. Theor. Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.pbiomolbio.2013.03.007","article-title":"Probability in biology: Overview of a comprehensive theory of probability in living systems","volume":"113","author":"Nakajima","year":"2013","journal-title":"Prog. Biophys. Mol. Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1006\/jtbi.1997.0554","article-title":"Ecological mechanisms of evolution by natural selection: Causal processes generating density-and-frequency dependent fitness","volume":"190","author":"Nakajima","year":"1998","journal-title":"J. Theor. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1006\/jtbi.2001.2354","article-title":"Probabilities of encounters between objects in biological systems: Meta-observer view","volume":"211","author":"Nakajima","year":"2001","journal-title":"J. Theor. Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1006\/jtbi.2003.3168","article-title":"Probabilities of encounters between objects in biological systems 2: Cognizer view","volume":"221","author":"Nakajima","year":"2003","journal-title":"J. Theor. Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1006\/jtbi.1997.0476","article-title":"Molecular complementarity I: The complementarity theory of the origin and evolution of life","volume":"188","author":"Dillon","year":"1997","journal-title":"J. Theor. Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/B978-0-444-53860-4.00002-7","article-title":"Genetic correlates of the evolving primate brain","volume":"195","author":"Vallender","year":"2012","journal-title":"Prog. Brain. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"R1109","DOI":"10.1016\/j.cub.2016.09.030","article-title":"The Molecular Basis of Human Brain Evolution","volume":"26","author":"Enard","year":"2016","journal-title":"Curr. Biol."},{"key":"ref_16","first-page":"75","article-title":"Internal Probability Theory and the Evolution of Life","volume":"16","author":"Nakajima","year":"2008","journal-title":"Ann. Jpn. Assoc. Philos. Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1038\/scientificamerican1085-164","article-title":"The molecular basis of evolution","volume":"253","author":"Wilson","year":"1985","journal-title":"Sci. Am."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"109989","DOI":"10.1016\/j.isci.2024.109989","article-title":"Signal execution modes emerge in biochemical reaction networks calibrated to experimental data","volume":"27","author":"Ortega","year":"2024","journal-title":"iScience"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"15190","DOI":"10.1073\/pnas.1017972108","article-title":"Bayesian design of synthetic biological systems","volume":"108","author":"Barnes","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Szallasi, Z., Stelling, J., and Periwal, V. (2006). Bayesian inference of biological systems: The logic of biology. System Modelling in Cellular Biology: From Concepts to Nuts and Bolts, MIT Press.","DOI":"10.7551\/mitpress\/9780262195485.001.0001"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e012174","DOI":"10.1136\/bmjopen-2016-012174","article-title":"Comparisons of neurodegeneration over time between healthy ageing and Alzheimer\u2019s disease cohorts via Bayesian inference","volume":"7","author":"Cespedes","year":"2017","journal-title":"BMJ Open"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"103144","DOI":"10.1016\/j.nicl.2022.103144","article-title":"Alzheimer\u2019s Disease Neuroimaging Initiative (ADNI) and the Dominantly Inherited Alzheimer\u2019s Network (DIAN). Detection of emerging neurodegeneration using Bayesian linear mixed-effect modeling","volume":"36","author":"Cobigo","year":"2022","journal-title":"Neuroimage Clin."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Khrennikov, A. (2023). Open Systems, Quantum Probability, and Logic for Quantum-like Modeling in Biology, Cognition, and Decision-Making. Entropy, 25.","DOI":"10.3390\/e25060886"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"386","DOI":"10.2976\/1.3244985","article-title":"Quantum physics meets biology","volume":"3","author":"Arndt","year":"2009","journal-title":"HFSP J."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1360","DOI":"10.1126\/science.adj2244","article-title":"Neurosurgery elucidates somatic mutations","volume":"382","author":"Maury","year":"2023","journal-title":"Science"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1038\/d41586-020-00341-9","article-title":"Revolutionary cryo-EM is taking over structural biology","volume":"578","author":"Callaway","year":"2020","journal-title":"Nature"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e2312905120","DOI":"10.1073\/pnas.2312905120","article-title":"Structure determination by cryoEM at 100 keV","volume":"120","author":"McMullan","year":"2023","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1016\/j.cell.2012.09.035","article-title":"Single-neuron sequencing analysis of L1 retrotransposition and somatic mutation in the human brain","volume":"151","author":"Evrony","year":"2012","journal-title":"Cell"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.neuron.2014.12.028","article-title":"Cell lineage analysis in human brain using endogenous retroelements","volume":"85","author":"Evrony","year":"2015","journal-title":"Neuron"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1126\/science.aab1785","article-title":"Somatic mutation in single human neurons tracks developmental and transcriptional history","volume":"350","author":"Lodato","year":"2015","journal-title":"Science"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1126\/science.aao4426","article-title":"Aging and neurodegeneration are associated with increased mutations in single human neurons","volume":"359","author":"Lodato","year":"2018","journal-title":"Science"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1237758","DOI":"10.1126\/science.1237758","article-title":"Somatic mutation, genomic variation, and neurological disease","volume":"341","author":"Poduri","year":"2013","journal-title":"Science"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"4257","DOI":"10.1038\/s41467-018-06331-w","article-title":"High prevalence of focal and multi-focal somatic genetic variants in the human brain","volume":"9","author":"Keogh","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1126\/science.abm6222","article-title":"Analysis of somatic mutations in 131 human brains reveals aging-associated hypermutability","volume":"377","author":"Bae","year":"2022","journal-title":"Science"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1750","DOI":"10.1038\/s12276-024-01284-1","article-title":"Low-level brain somatic mutations in exonic regions are collectively implicated in autism with germline mutations in autism risk genes","volume":"56","author":"Kim","year":"2024","journal-title":"Exp. Mol. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1126\/science.aak9761","article-title":"One brain, many genomes","volume":"354","author":"Evrony","year":"2016","journal-title":"Science"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1280","DOI":"10.1016\/j.celrep.2014.07.043","article-title":"Single-cell, genome-wide sequencing identifies clonal somatic copy-number variation in the human brain","volume":"8","author":"Cai","year":"2014","journal-title":"Cell Rep."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1016\/j.cell.2024.11.038","article-title":"Long somatic DNA-repeat expansion drives neurodegeneration in Huntington\u2019s disease","volume":"188","author":"Handsaker","year":"2025","journal-title":"Cell"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1038\/s41591-024-03424-6","article-title":"Somatic CAG repeat expansion in blood associates with biomarkers of neurodegeneration in Huntington\u2019s disease decades before clinical motor diagnosis","volume":"31","author":"Scahill","year":"2025","journal-title":"Nat. Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1111\/nan.12465","article-title":"Review: Somatic mutations in neurodegeneration","volume":"44","author":"Piette","year":"2018","journal-title":"Neuropathol. Appl. Neurobiol."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Proukakis, C. (2020). Somatic mutations in neurodegeneration: An update. Neurobiol. Dis., 144.","DOI":"10.1016\/j.nbd.2020.105021"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1725","DOI":"10.1073\/pnas.0909343106","article-title":"Evolution in health and medicine Sackler colloquium: Somatic evolutionary genomics: Mutations during development cause highly variable genetic mosaicism with risk of cancer and neurodegeneration","volume":"107","author":"Frank","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1186\/s40478-019-0873-5","article-title":"Investigation of somatic CNVs in brains of synucleinopathy cases using targeted SNCA analysis and single cell sequencing","volume":"7","author":"Kalyva","year":"2019","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1812","DOI":"10.1038\/s41436-020-0900-8","article-title":"Reduced penetrance of pathogenic ACMG variants in a deeply phenotyped cohort study and evaluation of ClinVar classification over time","volume":"22","author":"Arp","year":"2020","journal-title":"Genet. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1632","DOI":"10.1016\/j.jalz.2018.06.3056","article-title":"Somatic variants in autosomal dominant genes are a rare cause of sporadic Alzheimer\u2019s disease","volume":"14","author":"Nicolas","year":"2018","journal-title":"Alzheimers Dement."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"904","DOI":"10.1038\/s41436-018-0274-3","article-title":"Frequency and signature of somatic variants in 1461 human brain exomes","volume":"21","author":"Wei","year":"2019","journal-title":"Genet Med."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Lobon, I., Sol\u00eds-Moruno, M., Juan, D., Muhaisen, A., Abascal, F., Esteller-Cucala, P., Garc\u00eda-P\u00e9rez, R., Mart\u00ed, M.J., Tolosa, E., and \u00c1vila, J. (2022). Somatic Mutations detected in Parkinson disease could affect genes with a role in synaptic and neuronal processes. Front. Aging, 3.","DOI":"10.3389\/fragi.2022.851039"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1007\/s00401-018-1850-y","article-title":"Somatic mutations in neurons during aging and neurodegeneration","volume":"135","author":"Verheijen","year":"2018","journal-title":"Acta Neuropathol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1186\/s40478-022-01452-2","article-title":"Somatic copy number variant load in neurons of healthy controls and Alzheimer\u2019s disease patients","volume":"10","author":"Turan","year":"2022","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1111\/nyas.14786","article-title":"Brain somatic mutations as RNA therapeutic targets in neurological disorders","volume":"1514","author":"Lee","year":"2022","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"915","DOI":"10.3233\/JAD-221065","article-title":"A 19-year-old adolescent with probable Alzheimer\u2019s disease","volume":"91","author":"Jia","year":"2023","journal-title":"J. Alzheimer\u2019s Dis."}],"container-title":["Brain Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3425\/15\/8\/814\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:17:55Z","timestamp":1760033875000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3425\/15\/8\/814"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,29]]},"references-count":51,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2025,8]]}},"alternative-id":["brainsci15080814"],"URL":"https:\/\/doi.org\/10.3390\/brainsci15080814","relation":{},"ISSN":["2076-3425"],"issn-type":[{"type":"electronic","value":"2076-3425"}],"subject":[],"published":{"date-parts":[[2025,7,29]]}}}