The dual effect of cholesterol on cognitive functions in REM sleep behavior disorder: A pilot study

Isolated REM sleep behavior disorder (iRBD) is widely recognized as a prodromal stage of α-synucleinopathies. However, the factors influencing its clinical progression to a neurological syndrome remain poorly understood. Cholesterol metabolism has increasingly been implicated in the pathophysiology of neurodegenerative diseases, including Parkinson's disease and Dementia with Lewy Bodies. Yet, its role in iRBD has not been previously explored. This pilot study is the first to investigate the relationship between cholesterol levels and cognitive performance in individuals with iRBD. We assessed total cholesterol levels across 77 individuals with video polysomnography-confirmed iRBD, consecutively recruited at the Sleep Disorders Center of IRCSS San Raffaele Hospital in Milan, Italy. All subjects underwent an extensive neuropsychological assessment. Cholesterol levels were positively associated with language and visuospatial long-term memory performance among cognitively unimpaired individuals. Conversely, a trend toward a negative association between cholesterol levels and verbal long-term memory was observed in cognitively impaired participants. These opposite associations suggest that cholesterol may have a differential impact on cognitive function depending on cognitive status in iRBD, highlighting its complex role in early neurodegenerative processes. Further longitudinal studies are needed to confirm these associations and evaluate cholesterol's potential as a modifiable factor in the trajectory of prodromal α-synucleinopathies.