Cognitive-behavioral phenotypes in FMR1 premutation carriers: a cross-population comparison with mild cognitive...

Carriers of the FMR1 premutation are at risk for cognitive decline, though premutation-specific markers of age-related risk are largely unknown. One approach to determining relevant risk markers is to assess cross-population comparisons with individuals with known clinical trajectories.

The present study evaluated a cross-sectional sample of male and female FMR1 premutation carriers and controls in comparison to a longitudinal sample of individuals with known progression to mild cognitive impairment (MCI) within an enriched cohort of individuals at risk for Alzheimer's Disease and Related Dementias (ADRD) to assess potential similarities across cognitive-behavioral and genetic features. Both participant samples completed measures of working memory (digit span), language (verbal fluency, narrative elicitation), and depression. Exploratory analyses evaluated the role of FMR1 CGG repeat length and APOE on cognitive-linguistic phenotypes.

Findings suggest that premutation carriers and controls largely differed from MCI groups across measures; however, a subgroup of premutation carriers (according to T-MoCA performance) evidenced a distinct profile characterized by differences in depression and language. No effects of CGG repeat length or APOE were observed in the premutation sample.

This study generates preliminary evidence for a possible risk profile of FMR1 premutation carriers, with important implications for longitudinal studies evaluating the progression of cognitive decline.