Cognitive dysfunction in women with the FMR1 premutation during midlife: The LASSI-L reveals curvilinear CGG-dependent risk buffered by college education

Background The FMR1 premutation (FXPM) is a common genetic variant (∼1:151 females) linked to increased risk for neurodegenerative disease. Midlife cognitive phenotypes remain poorly defined. Objective To characterize episodic memory performance in midlife FXPM women and examine potential risk moderation via genetic (i.e., FMR1 CGG repeat expansion size) and environmental (i.e., college degree attainment) influences. Methods Eighty-eight FXPM women and 84 matched controls, aged 30–55, completed the Loewenstein-Acevedo Scales for Semantic Interference and Learning (LASSI-L), a measure of specific episodic memory processes sensitive to subtle Alzheimer's disease (AD)-related cognitive and neuropathological changes. Results FXPM women demonstrated deficits in proactive semantic interference (PSI), recovery from PSI, and intrusion errors relative to controls. College education buffered these effects: college-educated FXPM women performed comparably to controls, while those without a college degree showed deficits. Gene-environment interactions showed patterns consistent with differential susceptibility: LASSI-L performance in women with mid-range CGG repeats (∼80–100) was strongly influenced by educational attainment, whereas education effects were absent in women with lower/higher CGG lengths. Conclusions Midlife FXPM women showed episodic memory deficits, paralleling LASSI-L deficits seen in prodromal AD. College education offered protective benefits, particularly for women with mid-range CGG expansions. Findings highlight a critical midlife window for cognitive monitoring, identify education as a potential protective factor, and inform personalized risk assessment based on CGG length to promote earlier detection and targeted prevention for FXPM women. Findings suggest potential overlapping mechanisms with AD that merit further study.