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Somatic CAG expansion occurs throughout life and understanding the impact of somatic expansion on neurodegeneration is key to developing therapeutic targets. In 57 HD gene expanded (HDGE) individuals, ~23 years before their predicted clinical motor diagnosis, no significant decline in clinical, cognitive or neuropsychiatric function was observed over 4.5 years compared with 46 controls (false discovery rate (FDR)\u2009&gt;\u20090.3). However, cerebrospinal fluid (CSF) markers showed very early signs of neurodegeneration in HDGE with elevated neurofilament light (NfL) protein, an indicator of neuroaxonal damage (FDR\u2009=\u20093.2\u2009\u00d7\u200910\n                    <jats:sup>\u221212<\/jats:sup>\n                    ), and reduced proenkephalin (PENK), a surrogate marker for the state of striatal medium spiny neurons (FDR\u2009=\u20092.6\u2009\u00d7\u200910\n                    <jats:sup>\u22123<\/jats:sup>\n                    ), accompanied by brain atrophy, predominantly in the caudate (FDR\u2009=\u20095.5\u2009\u00d7\u200910\n                    <jats:sup>\u221210<\/jats:sup>\n                    ) and putamen (FDR\u2009=\u20091.2\u2009\u00d7\u200910\n                    <jats:sup>\u22129<\/jats:sup>\n                    ). Longitudinal increase in somatic CAG repeat expansion ratio (SER) in blood was a significant predictor of subsequent caudate (FDR\u2009=\u20090.072) and putamen (FDR\u2009=\u20090.148) atrophy. Atypical loss of interruption\n                    <jats:italic>HTT<\/jats:italic>\n                    repeat structures, known to predict earlier age at clinical motor diagnosis, was associated with substantially faster caudate and putamen atrophy. We provide evidence in living humans that the influence of CAG length on HD neuropathology is mediated by somatic CAG repeat expansion. These critical mechanistic insights into the earliest neurodegenerative changes will inform the design of preventative clinical trials aimed at modulating somatic expansion. ClinicalTrials.gov registration:\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/clinicaltrials.gov\/study\/NCT06391619\" ext-link-type=\"uri\">NCT06391619<\/jats:ext-link>\n                    .\n                  <\/jats:p>","DOI":"10.1038\/s41591-024-03424-6","type":"journal-article","created":{"date-parts":[[2025,1,17]],"date-time":"2025-01-17T05:04:05Z","timestamp":1737090245000},"page":"807-818","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":88,"title":["Somatic CAG repeat expansion in blood associates with biomarkers of neurodegeneration in Huntington\u2019s disease decades before clinical motor diagnosis"],"prefix":"10.1038","volume":"31","author":[{"given":"Rachael I.","family":"Scahill","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0679-0117","authenticated-orcid":false,"given":"Mena","family":"Farag","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J.","family":"Murphy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicola Z.","family":"Hobbs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michela","family":"Leocadi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5061-2820","authenticated-orcid":false,"given":"Christelle","family":"Langley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harry","family":"Knights","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7663-4080","authenticated-orcid":false,"given":"Marc","family":"Ciosi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kate","family":"Fayer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitsuko","family":"Nakajima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivia","family":"Thackeray","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6193-6193","authenticated-orcid":false,"given":"Johan","family":"Gobom","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"R\u00f6nnholm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-2298-220X","authenticated-orcid":false,"given":"Sophia","family":"Weiner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yara R.","family":"Hassan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-9576-5753","authenticated-orcid":false,"given":"Nehaa K. 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The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. J.B.R. has undertaken paid consultancy for Asceneuron, Astronautx, Astex, ClinicalInk, CumulusNeuro, Curasen, Invivro, Prevail and SVHealth; received research funding unrelated to the current work from AstraZeneca, Lily, GSK and Janssen; and is Chief Scientific Advisor to Alzheimer\u2019s Research UK. D.G.M. has been a scientific consultant and\/or received honoraria\/grants from AMO Pharma, Dyne, F. Hoffman-La Roche, Function Rx, LoQus23, MOMA Therapeutics, Novartis, Ono Pharmaceuticals, Pfizer Pharmaceuticals, Rgenta Therapeutics, Sanofi and Sarepta Therapeutics. J.G. is supported by Alzheimerfonden (AF-980746) and Stiftelsen f\u00f6r Gamla tj\u00e4narinnor (2022-01324). J.B.R. has appeared as an expert witness to the Medicines and Healthcare products Regulatory Agency, unrelated to the current work. D.G.M. is on the Scientific Advisory Board of the Myotonic Dystrophy Foundation and EuroDyMA (European Dystrophia Myotonica Association), is a scientific advisor to the Myotonic Dystrophy Support Group and is a vice president for research of Muscular Dystrophy UK. G.R. is a nonexecutive director of UCL Business. D.R.L. is an unpaid academic member of the Critical Path Institute HD-RSC Consortium Coordinating Committee. B.J.S. is a co-inventor of the Cambridge Neuropsychological Test Automated Battery. I.B.M. is an associate editor for Frontiers in Neurology. The other authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}