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Cognitive reserve and physical exercise has been found to have positive function and brain effects in a number of neurodegenerative disorders. No study to date has examined whether these factors can beneficially modulate functional brain activity during the premanifest stages of Huntington’s disease (pre-HD).We examined the relationship between cognitive reserve, level of physical exercise and functional brain activity in pre-HD, compared with healthy controls, using functional MRI (fMRI) while individuals performed a visuospatial working memory task.Pre-HD (n=15; M=37.33; SD=10.82) and age- and gender-matched healthy controls (n=15; M=35.60; SD=10.69), completed the Cognitive Reserve Index Questionnaire (CRIq) and the International Physical Activity Questionnaire Long (IPAQ-L). Participants also performed an 18 min fMRI visuospatial working memory task with low (2 items), intermediate-1 (3 items), intermediate-2 (4 items), and high (5 items) memory loads.Pearson’s correlation revealed that greater cognitive reserve (CRIq) was associated with decreased functional brain activity in the left posterior medial frontal cortex in pre-HD at intermediate-1 memory load (r=−0.52, p=0.045) and intermediate-2 memory load (r=−0.56, p=0.030), compared with healthy controls. Higher level of physical exercise (IPAQ-L) was also related to reduced functional brain activity in pre-HD, including in left (r=−0.52, p=0.050) and right (r=−0.65, p=0.009) anterior insula, left (r=−0.69, p=0.004) and right (r=−0.72, p=0.002) inferior frontal gyrus, left intraparietal sulcus (r=−0.64, p=0.01) and left dorsolateral prefrontal cortex (r=−0.57, p=0.03) at low memory load; and, right intraparietal sulcus (r=−0.61, p=0.015) at intermediate-1 memory load, compared with healthy controls.These findings demonstrate that cognitive reserve and level of physical exercise can modulate functional brain reorganisation in pre-HD.