The apolipoprotein gene: a modulating role on brain volume and cognitive function in carriers of the fragile X premutation

Fragile X-associated tremor/ataxia syndrome (FXTAS), caused by the FMR1 premutation allele, is associated with brain degeneration, yet the mechanisms behind this neurodegeneration still need to be elucidated. Apoε polymorphism has been widely implicated in brain aging in cognitively healthy individuals and brain deterioration in Alzheimer's disease. This study aimed to examine the interaction of Apoε genotypes, FXTAS clinical symptoms, FMR1 molecular measures, and age, towards brain pathophysiology and cognitive functions. This longitudinal study includes MRI data collected from 205 male premutation carriers with and without FXTAS clinical symptoms and compared to 86 healthy male controls aged 40–85 years. The investigation includes FXTAS-related brain volumes, IQ, self-control behaviors, FMR1 molecular measures, and Apoε genotypes. In carriers with FXTAS, the presence of the Apoε2 allele showed a possible association with more favorable neuroimaging markers, such as reduced white matter hyperintensities, and lower incidence of the middle cerebellar peduncle sign, patterns that were not observed in carriers without FXTAS. Specifically, the presence of Apoε2 allele exhibited a potential protective effect on brain degeneration, and cognitive functions among FXTAS patients; on the contrary, the Apoε4 allele was associated with a worsening of brain volume and brain degeneration in carriers with no FXTAS symptoms. The identification of Apoε genotypes in FMR1 premutation carriers before any clinical symptoms of FXTAS are observed may improve symptomatic management leading to better outcomes for these individuals. • Apoε2 allele shows protective effects in PM carriers with FXTAS, including reduced white matter hyperintensities, smaller ventricles, and slower cerebellar atrophy. • Apoε4 allele is linked to worsening brain pathology and cognition even in premutation carriers without FXTAS symptoms. • Protective cognitive effects of Apoε2 , and detrimental effects of Apoε4 , are observed in FMR1 PM carriers. • Findings suggest Apoε status modulates the course of neurodegeneration in FXTAS. • Early Apoε genotyping in FMR1 premutation carriers may enable better risk stratification and clinical management.