Imminent cognitive decline in normal elderly individuals is associated with hippocampal hyperconnectivity in the variant neural correlates of episodic memory

The secondary prevention trials of Alzheimer’s disease (AD) require an enrichment strategy to recruit individuals with imminent cognitive decline at the preclinical stage. Previously, we demonstrated a variant neural correlates of episodic memory (EM) function in apolipoprotein E (APOE) ε4 carriers. Herein, we investigated whether this variation was associated with longitudinal EM performance. This 3-year longitudinal study included 88 normal elderly subjects with EM assessment and resting-state functional MRI data at baseline; 48 subjects (27 ε3 homozygotes and 21 ε4 carriers) underwent follow-up EM assessment. In the identified EM neural correlates, multivariable regression models examined the association between hippocampal functional connectivity (HFC) and longitudinal EM change. Independent validation was performed using the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset. At baseline, the EM neural correlates were characterized in the Papez circuit regions in the ε3 homozygotes, but in the sensorimotor cortex and cuneus in the ε4 carriers. Longitudinally, the ε4 carriers exhibited a negative association of the baseline HFC strength in the EM neural correlates with annual rate of EM change ( R 2 = 0.25, p = 0.05). This association also showed a trend in the ADNI dataset ( R 2 = 0.42, p = 0.06). These results indicate that hippocampal hyperconnectivity in the variant EM neural correlates is associated with imminent EM decline in ε4 carriers, which may serve as a promising enrichment strategy for secondary prevention trials of AD.