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When expanded beyond 39 repeats, this region leads to Huntington\u2019s disease (HD). However, several studies have suggested that increasing the number of CAG repeats below the pathological threshold may confer functional advantages by enhancing <jats:italic>HTT<\/jats:italic> activity. In the present study, we aim to investigate the association between CAG repeat length below the pathological threshold and neurodegeneration biomarkers in prodromal Alzheimer\u2019s disease (AD).<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>Ninety-five patients (36 with SCD and 59 with MCI) underwent blood collection for NfL measurement and <jats:italic>HTT<\/jats:italic> genetic analysis. Cerebrospinal fluid was collected for the measurement of A\u03b2\u2084\u2082, A\u03b2\u2084\u2080, total tau, and phosphorylated tau, and\/or amyloid PET imaging was performed. Thirty-nine patients who were positive for both A\u03b2 and phosphorylated tau biomarkers were classified as \u201cA+\/T+\u201d, while 56 patients who were either negative for both markers or positive for only one were classified as \u201cisolated A\u03b2\/non-AD.\u201d<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>In the A+\/T+\u2009group, quadratic models described the association between CAG repeat length with NfL concentrations and 18F-FDG uptake. In particular, a concave curve was observed in the medial and middle frontal gyri, while a convex curve was found in the parahippocampal and fusiform gyri.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Interpretation<\/jats:title>\n            <jats:p>Among individuals with SCD and MCI who show evidence of AD pathology, CAG repeat length in the <jats:italic>HTT<\/jats:italic> gene below the HD pathological threshold is associated with biomarkers of neurodegeneration in a region-specific and U-shaped manner. These findings suggest a modulatory role of <jats:italic>HTT<\/jats:italic> in prodromal AD.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1007\/s00415-025-13312-9","type":"journal-article","created":{"date-parts":[[2025,8,22]],"date-time":"2025-08-22T10:15:50Z","timestamp":1755857750000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["The HTT gene influences plasma neurofilament light chain and brain metabolism in prodromal Alzheimer\u2019s disease"],"prefix":"10.1007","volume":"272","author":[{"given":"Salvatore","family":"Mazzeo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Crucitti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Lassi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Assunta","family":"Ingannato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Berti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matilde","family":"Nerattini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Giacomucci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Bagnoli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Moschini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmen","family":"Morinelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonia","family":"Padiglioni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Galdo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Filippo","family":"Emiliani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Salsone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimo","family":"Filippi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandro","family":"Sorbi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto","family":"Mazzoni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6176-3584","authenticated-orcid":false,"given":"Valentina","family":"Bessi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benedetta","family":"Nacmias","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,8,22]]},"reference":[{"key":"13312_CR1","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1111\/ene.13413","volume":"25","author":"P McColgan","year":"2018","unstructured":"McColgan P, Tabrizi SJ (2018) Huntington\u2019s disease: a clinical review. 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