We investigated if lifelong engagement in activities promoting cognitive reserve (eg. early life education, midlife substantive work complexity, late life leisure activities and social networks) modified the risk of dementia attributable to Apolipoprotein ε4 allele (APOE‐ε4), a well‐known genetic risk factor for dementia. Using 9-year follow-up data on 2,556 SNAC-K participants, we found that relative to APOE‐ε4 carriers with low cognitive reserve, ε4 carriers with high reserve experienced dementia risk reduction equivalent to ε4 noncarriers with high reserve. These results indicate that lifelong engagement in reserve‐enhancing activities attenuates the risk of dementia attributable to APOE‐ε4. Importantly, these findings suggest that promoting cognitive reserve might be especially effective in subpopulations with high genetic risk of dementia (Dekhtyar et al., Annals of Neurology 2019).