BACKGROUND:
Repeat expansions in C9orf72 represent the most common genetic cause of frontotemporal dementia (FTD). Emerging evidence from genetic FTD cohort studies suggest subtle psychiatric and cognitive features may emerge in the presymptomatic stage, accompanied by structural and functional brain changes. Such findings raise the possibility of early, potentially neurodevelopmental alterations in C9orf72-associated FTD. However, few studies have systematically examined cognitive phenotypes in young adult presymptomatic carriers.
METHODS:
Cross-sectional data were available from 541 presymptomatic participants in the Genetic Frontotemporal dementia Initiative (GENFI) cohort who underwent comprehensive neuropsychology and clinical assessment. Presymptomatic C9orf72 expansion carriers (with a CDR® plus NACC FTLD-NM global score <0.5, N=284) were compared to mutation-negative controls (N=257). Linear regression models with bootstrapping, adjusting for education and sex, examined group differences on cognitive tasks across age deciles (“20s”, “30s”, “40s”, or “50s+”).
RESULTS:
Cognitive differences between C9orf72 carriers and non-carriers were evident in the 30s, in tasks assessing processing speed (Trail Making Test A: b=4.76, p=.001), and executive function (Trail Making Test B: b=11.35, p=.00; Stroop Ink Naming: b=6.45, p=.001; Digit Symbol: b=4.71, p=.009). By the 40s, additional group differences emerged in social cognition (Ekman Faces: b=1.14, p=.020) and episodic memory (FCSRT Delayed Free: b=1.21, p=.013), extending to broader semantic and executive domains by the 50s (Verbal Fluency Animals b=2.15 p=.015; Boston Naming Test b=1.17 p=.002; Camel and Cactus b=0.76 p=.008).
CONCLUSION:
Presymptomatic C9orf72 expansion carriers exhibit measurable cognitive differences compared to familial non-carriers as early as the third decade of life, greatly preceding expected age of symptom onset. These findings suggest that disease-related processes manifest earlier than anticipated and may represent a neurodevelopmental phenotype. Ongoing work will incorporate neuroimaging and longitudinal follow-up to delineate trajectories of cognitive and structural change.