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Jannis Achenbach, Benjamin Stodt, Carsten Saft

• \(\bf Background:\) The Total Functional Capacity (TFC) score is commonly used in Huntington’s disease (HD) research. The classification separates each disease stage (1–5), e.g., as an inclusion criterion or endpoint in clinical trials accepted by the Food and Drug Administration (FDA). In addition to the quantification of age- and CAG-repeat-dependent effects as well as interacting effects of both on the TFC, we aimed to investigate factors influencing the TFC, such as neuropsychiatric, educational, and cognitive disease burden using data from the largest HD observational study to date. In addition, we analyzed data from pre-manifest stages to investigate the influence of the above-mentioned factors on the TFC in that stage. \(\bf Methods:\) A moderated regression analysis was conducted to analyze the interaction effects of age and CAG-repeat length on the TFC in HD patients. A simple slope analysis was calculated to illustrate the effects. Depending on TFC results, motor-manifest patients were grouped into five stages. Data from pre-manifest participants were analyzed with regard to years to onset and CAP scores. \(\bf Results:\) We identified \(\it N\) = 10,314 participants as manifest HD. A significant part of variance on the TFC was explained by age (\(\it {R}^{2}\) = 0.029, \(\it F\) (1;10,281) = 308.02, \(\it p\) < 0.001), CAG-repeat length (∆\(\it {R}^{2}\) = 0.132, \(\Delta\)\(\it F\) (1;10,280) = 1611.22, \(\it p\) < 0.001), and their interaction (\(\Delta\)\(\it {R}^{2}\) = 0.049, \(\Delta\)\(\it F\) (1;10,279) = 634.12, \(\it p\) < 0.001). The model explained altogether 20.9% of the TFC score’s variance (\(\it F\) = 907.60, \(\it p\) < 0.001). Variance of psychiatric and cognitive symptoms significantly differed between stages. Exploratory analysis of median data in pre-manifest participants revealed the highest scores for neuropsychiatric changes between 5 to <20 years from the disease onset. \(\bf Conclusions:\) TFC is mainly explained by the neurobiological factors, CAG-repeat length, and age, with subjects having more CAG-repeats showing a faster decline in function. Our study confirms TFC as a robust measure of progression in manifest HD.