Background: Published literature on cognitive functioning in adults with sickle cell disease (SCD) is sparse when compared to children. A few reports describe deficits in processing speed and executive functioning. Some studies suggest that these deficits are more severe in patients with silent cerebral infarcts (SCI). Even in the absence of radiological evidence of ischemic injury, some cognitive deficits have been depicted in adults . We hypothesize that in SCD adults, the cognitive profile varies with the presence of ischemic injury (SCI or overt stroke). The aims of this study were 1) to describe the neuropsychological profiles of SCD adults, and 2) to characterize clusters of patients with similar cognitive profiles.Methods: We conducted a retrospective analysis of all consecutive SCD adults who underwent comprehensive neuropsychological assessment during routine care at the UMGGR clinic at Henri Mondor Hospital, Créteil (France), between January 2017 and April 2021. The Montreal Cognitive Assessment (MoCA) and Hospital Anxiety and Depression Scale (HADS) were used for cognitive disorder, anxiety and depression screening, respectively. The cognitive battery combined standardized neuropsychological tests with established clinical utility and validity. Educational attainment was scored based on the number of years of schooling for the highest completed diploma. Principal component analysis was performed. ANOVA was used to compare patients' characteristics between clusters.Results: 80 patients, median age 36.5 [range 19-63] years were included. 40 (50.0%) were male. Genotype distribution was 62 patients (77.5%) with SS/Sbeta 0, 12 (15.0%) with SC and 6 (7.5%) with Sbeta +. On Principal Component Analysis, a 5-factor model presented the best fit (Bartlett's sphericity test (χ²(171)=1174; p<0.001)), explaining 71.8% of the variance in neuropsychological scores. The first factor encompassed tests specifically assessing visual attention/visual organization (right hemisphere). The second included tests for mental/cognitive control (frontal lobe), the third tests of selective inhibition/attention (fronto-parietal), the fourth tests for language/memory (left temporal lobe) and the last referred to shifting skill (sub-cortical loop). On hierarchical classification, 3 different clusters emerged: 32 patients in cluster 1, 32 in cluster 2 and 16 in cluster 3. Cluster 1 had a lower mean educational level (F(2,77) = 15,65; p<0,001). Cluster 1 showed the lowest mean MoCA score (20.0/30.0), relative to cluster 2 and 3 (24.6 and 26.4; p<0.001 and p<0.001, respectively). Cluster 1 patients presented deficits on all five factors. Cluster 2 patients compared to cluster 3 were altered in 4 factors (factors 1-4), but to a lesser extent than cluster 1. Processing speed was slower and some frontal-executive deficits were present in cluster 2 compared to cluster 3. There was no statistical difference between clusters in terms of ethnic origins. There was a trend for the presence of more cerebral vasculopathy in cluster 1 (chi2; p=0.06). Regarding stroke, 70% occurred during childhood in cluster 1, whereas 70% during adulthood in cluster 2, and 100% during adulthood in cluster 3.Conclusions: Overall, these results suggest at least three different cognitive profiles in adults with SCD: 1) few or no cognitive deficits (cluster 3), 2) some cognitive impairment with a sub-cortical cognitive profile (cluster 2) and 3) more global cognitive impairment with cortical/sub-cortical profile and specific deficits of memory, language and constructional praxis, depending on the location of prior overt neurological events (cluster 1). To reduce the long-term cognitive morbidity of SCD, patients can be identified by their distinct cognitive profiles and neurorehabilitation tailored to their unique profile should be applied. The large proportion of childhood stroke in patients with global cognitive impairment in contrast with majority of those with milder to no cognitive impairment having had their stroke in adulthood emphasize the crucial importance of preventing early childhood stroke and implementing early neurorehabilitation. DisclosuresForté: Canadian Hematology Society: Research Funding; Pfizer: Research Funding; Novartis: Honoraria. Kuo: Pfizer: Consultancy, Research Funding; Bluebird Bio: Consultancy; Novartis: Consultancy, Honoraria; Apellis: Consultancy; Alexion: Consultancy, Honoraria; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Bioverativ: Membership on an entity's Board of Directors or advisory committees. Bartolucci: Jazz Pharma: Other: Lecture fees; AGIOS: Consultancy; Emmaus: Consultancy; GBT: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy; Hemanext: Consultancy; INNOVHEM: Other: Co-founder; Bluebird: Consultancy, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Lecture fees, Steering committee, Research Funding; Fabre Foundation: Research Funding; Addmedica: Consultancy, Other: Lecture fees, Research Funding.