Abstract
INTRODUCTION: With accumulating evidence that motor manifestations in Alzheimer's disease (AD) may emerge from AD pathology independent of other copathologies, we investigated the neural basis of motor dysfunction under the amyloid/tau/neurodegeneration (ATN) framework. METHODS: This study included 125 patients with AD, excluding individuals with severe leukoaraiosis or comorbid Lewy body features beyond Parkinsonism. Associations of ATN burden with motor dysfunction were tested using multivariate regression models, followed by mediation analyses exploring the cognitive contribution to these associations. RESULTS: Tau burden in the prefrontal, sensorimotor, and parietal regions was associated with motor dysfunction independent of amyloid or neurodegeneration. The effect of parietal tau on motor function was fully mediated by visuospatial dysfunction, whereas prefrontal/sensorimotor tau exerted direct effects without cognitive mediation. DISCUSSION: Increased tau burden in the sensorimotor and frontoparietal association cortices may elicit motor dysfunction in AD through either cognition-dependent or cognition-independent mechanisms, with effects depending on the affected regions. HIGHLIGHTS: Tau burden was intimately associated with motor symptoms independent of Aβ or atrophy. Tau in sensorimotor and frontoparietal association cortices may elicit motor symptoms. Prefrontal/sensorimotor tau exerted cognition-independent effects on motor symptoms. Parietal tau indirectly influenced motor symptoms through visuospatial dysfunction. Parietal tau-related motor dysfunction may be partly explained by apraxic features.