A 3-year randomized clinical trial investigated the impact of omega-3 polyunsaturated fatty acid treatment on white matter lesion (WML) progression and neuronal integrity breakdown in older adults at risk for dementia. While no significant reduction in WML progression or neuronal integrity breakdown was observed in the overall population, potential benefits were seen for carriers of the apolipoprotein E ε4 allele. It was noted that omega-3 treatment was safe and well-tolerated. Although it failed to reach significant reduction in WML progression and neuronal integrity breakdown among all participants at risk for dementia, significant reduction was observed among APOE*E4 carriers, suggesting potential amplification of the effects of omega-3 for these individuals.