BACKGROUND:
Understanding early cognitive changes in familial frontotemporal dementia (fFTD) remains a major challenge, particularly distinguishing the timing of onset and progression profiles of genetic subtypes. While neuropsychological testing is used in both research and clinical settings, conventional testing batteries may lack the sensitivity to detect gene-specific patterns of decline. The GENFI-Cog addresses this by integrating multiple cognitive domains into one weighted metric. Here, we aimed to characterise gene-specific cognitive trajectories in asymptomatic and symptomatic C9orf72, GRN, and MAPT mutation carriers by comparing GENFI-Cog composite scores across disease stages.
METHODS:
We analysed neuropsychological data from 1,245 GENFI participants (mean age 46.6 years; 44% male; education 14.8 years), including 372 C9orf72, 262 GRN, and 134 MAPT, and 610 non-carriers. Mutation carriers were stratified by disease stage using CDR+NACC FTLD-NM, asymptomatic (0), prodromal (0.5), or symptomatic (≥1). Raw test scores were converted into W-scores adjusted for age, sex, education, and language. These scores were then combined based on previously derived gene-specific composite scores (GENFI-Cog), using linear regression coefficients to weight individual test contributions. Cross-sectional differences in weighted composite scores between genetic groups were assessed across disease stages using bootstrapped linear regression models.
RESULTS:
Across all genetic groups, cognitive composite scores significantly declined as disease severity increased. All mutation carriers, with a CDR score of 0.5 or above, performed worse than non-carriers (<i>p</i><0.005). Notably, asymptomatic <i>C9orf72</i> carriers (CDR 0), also performed significantly worse than non-carriers (p<0.001).
CONCLUSION:
GENFI-Cog composite scores sensitively capture gene-specific patterns of cognitive decline. The results also suggest early sensitivity to cognitive impairment, particularly in <i>C9orf72 </i>expansion carriers, supporting the use of weighted composite measures to detect subtle, preclinical cognitive changes in fFTD. However, further longitudinal analysis of the GENFI-Cog will allow for an improved understanding of disease progression and more accurate fFTD prognostic models.