Associations of cognitive reserve with IGF-1 and global cognition differ by early-life conditions and APOE genotype.

Insulin-like growth factor-1 (IGF-1) plays a crucial role in brain health and cognitive function, with levels varying across APOE genotypes, a major risk factor for Alzheimer's disease. Here, cross-lagged path modeling was used to examine longitudinal associations between IGF-1 levels, cognitive performance, and sociodemographic factors across APOE genotypes in 1247 older adults from the Rancho Bernardo Study of Healthy Aging. Distinct association patterns emerged across genotypes. Both IGF-1 and Mini-Mental State Examination (MMSE) were associated with age and sex in ε2 and ε3 carriers. IGF-1 was differently related to early-life conditions, occupation, and education across genotypes, while MMSE was related to early-life conditions, occupation, and physical activity. Evidence of partial reciprocity was observed between IGF-1 and global cognition only among ε4 carriers, although associations were modest. These findings suggest genotype-specific patterns linking metabolic aging, cognitive performance, and life trajectories, and provide support for associations between early-life experiences and cognitive reserve proxies.