Public Health.

Area of Science:

• Neuroscience
• Genetics
• Gerontology

Background:

• Mild Cognitive Impairment (MCI) is linked to the apolipoprotein E4 allele (APOE4), a risk factor for cognitive decline.
• The SYNERGIC trial showed physical exercise (PE) improves cognition in MCI, with cognitive training adding benefits.
• The influence of APOE4 status on intervention response in MCI is not well understood.

Purpose of the Study:

• To investigate the impact of APOE4 genetic status on cognitive outcomes in individuals with MCI undergoing multidomain interventions.
• To compare the efficacy of different intervention combinations (PE, cognitive training, vitamin D) based on APOE4 status.

Main Methods:

• Analysis of 67 participants from the SYNERGIC trial with APOE4 genotyping.
• Participants received 6-month interventions: PE + Cognitive Training + Vitamin D; PE + Cognitive Training; PE + Vitamin D; or PE alone.
• Global cognition (ADAS-Cog-13) changes were compared between APOE4-positive and APOE4-negative groups using ANOVA.

Main Results:

• APOE4-positive participants demonstrated attenuated global cognitive improvements compared to APOE4-negative individuals (p=0.052).
• The PE + Vitamin D arm showed a significant worsening of global cognition over time (p=0.03).
• Sensitivity analysis excluding vitamin D confirmed reduced cognitive benefits for APOE4-positive individuals (p=0.05).

Conclusions:

• APOE4-positive status is associated with reduced responsiveness to multidomain interventions aimed at improving global cognition in MCI.
• Underlying genetic neurodegeneration associated with APOE4 may contribute to this diminished response.
• Intervention strategies may need tailoring based on APOE4 genetic profile for optimal cognitive outcomes in MCI.