Abstract
OBJECTIVE: We investigated whether cognitive reserve modifies the risk of dementia attributable to apolipoprotein ε4 (APOE-ε4), a well-known genetic risk factor for dementia. METHODS: We followed 2,556 cognitively intact participants aged ≥60 years from the ongoing prospective community-based Swedish National Study on Aging and Care in Kungsholmen (SNAC-K). Dementia was ascertained through clinical and neuropsychological assessments and diagnosed according to Diagnostic and Statistical Manual of Mental Disorders, 4th edition criteria. Structural equation modeling was used to generate a cognitive reserve indicator from 4 previously validated contributors: early life education, midlife substantive work complexity, late life leisure activities, and late life social networks. Cox proportional hazard models estimated dementia risk in relation to cognitive reserve indicator. The interaction between the cognitive reserve indicator and APOE-ε4 was assessed on multiplicative and additive scales. RESULTS: After an average of 6.3 years (range = 2.1-10.7) of follow-up, 232 dementia cases were ascertained. Relative to individuals in the lowest tertile of cognitive reserve indicator, those with moderate and high reserve were at a reduced risk of dementia. There was no multiplicative interaction between APOE-ε4 status and cognitive reserve indicator (p = 0.113). Additive interaction was statistically significant. Relative to APOE-ε4 carriers with low cognitive reserve, ε4 carriers with high reserve had a reduced risk of dementia (hazard ratio [HR] = 0.28, 95% confidence interval [CI] = 0.13-0.59). The magnitude of risk reduction was similar in ε4 noncarriers with a high cognitive reserve indicator (HR = 0.24, 95% CI = 0.15-0.40). INTERPRETATION: Lifelong engagement in reserve-enhancing activities attenuates the risk of dementia attributable to APOE-ε4. Promoting cognitive reserve might be especially effective in subpopulations with high genetic risk of dementia. ANN NEUROL 2019.