Interplay Between Sex and Cytosine‐Adenine‐Guanine‐Age Product Score in Huntington's Disease: Clinical and Neuroimaging Perspectives

Background Huntington's disease (HD) is a progressive neurodegenerative disorder caused by a cytosine‐adenine‐guanine (CAG) repeat expansion in the huntingtin gene. The disease exhibits sex‐related differences in symptomatology and disease progression, but the effect on brain structural biomarkers and the interaction between sex and CAG‐age product score (CAPS), a widely used index combining the effect of CAG expansion and age, remains underexplored. Objective The aim of this study was to investigate the interplay between sex and CAPS on clinical measures and neuroimaging biomarkers in HD. Methods We retrospectively analyzed data from Enroll‐HD, TRACK‐HD/ON, PREDICT‐HD, and IMAGE‐HD studies, including a combined dataset of 19,738 participants with CAG ≥ 40. Linear mixed models were employed to evaluate the influence of sex and the sex‐CAPS interaction on clinical evaluations, including Unified HD Rating Scale (UHDRS) UHDRS and Problem Behaviors Assessment, and neuroimaging biomarkers (striatal volumes and cortical thickness), while controlling for covariates. Results Female participants exhibited less pronounced striatal atrophy and cortical thinning with increasing CAPS (caudate: = −3.449/−2.931, P = 0.05; putamen: = −4.770/−3.902, P < 0.01). Regarding clinical measures, females experience greater motor decline with increasing CAPS (total motor score: = 3.008/3.230, P < 0.0001), greater cognitive decline (symbol digit modalities test: = −34.52/−38.57, P < 0.0001), and greater functional decline (total functional capacity: = −6.413/−6.783, p < 0.05; Independence Scale: = −32.26/−34.85, P < 0.001). Conclusions The sex‐CAPS interaction significantly impacts both clinical and neuroimaging biomarkers of HD, underscoring the importance of incorporating sex‐specific considerations into the clinical staging and management of HD.