APOE ε4-related structural vulnerability in mild cognitive impairment: a subsystem-based analysis of the default mode network.
Research Square May 11, 2026 Xiaoming Yang, Jian Lyu, Jubo Wang et al.
In people with mild cognitive impairment (MCI), carrying the APOE ε4 gene variant—the strongest genetic risk factor for cognitive decline—is linked to shrinkage in specific parts of the brain's default mode network (DMN), particularly the dorsomedial prefrontal cortex (DMPFC) subsystem. Among 116 MCI patients and 60 cognitively normal older adults, APOE ε4 carriers with MCI showed selective atrophy in the gyrus rectus and superior temporal pole (TPOsup) compared to non-carriers. The TPOsup atrophy explained about 30% of the negative effect of APOE ε4 on global cognition, measured by the Mini-Mental State Examination, and was strongly tied to impaired orientation. The TPOsup may be a key brain region linking APOE ε4 to cognitive decline in MCI and could serve as an imaging marker for risk stratification.