Independent, but not synergistic, associations of APOEε4 and systemic inflammation on cognitive decline: findings from the Women’s Health Initiative

Introduction: Understanding the risk factors that associate with early cognitive decline in Alzheimer’s disease (AD) is important to identify high-risk individuals and initiate early intervention. Existing studies show that APOEε4, systemic inflammation, and diabetes may play roles in cognitive decline, but the extent to which these factors interact with each other remains unclear. Our objective was to examine the main effects and higher-order interactions between APOEε4, high sensitivity-C-reactive protein (hs-CRP) as a measure of systemic inflammation, and diabetes on domain-specific measures of cognitive function in two ancillary studies of post-menopausal women from the Women’s Health Initiative (WHI). Method: We identified 2979 cognitively unimpaired women from the WHI Epidemiology of Cognitive Health Outcomes and the WHI Memory Study of Younger Women with cognitive follow-up of up to 13 years. Linear mixed-effects models examined the main and interactive effects of APOEε4, hs-CRP, and diabetes on longitudinal changes in the personal communication for Cognitive Status-modified Test (TICS-m), East Boston Memory Test (immediate and delayed; EBMT), Oral Trail Making Test (OTMT), Verbal Fluency Test (VF-A), Digit Span Test Backwards (DST-backward), and the California Verbal Learning Test (CVLT). All models were adjusted for baseline age, education, body mass index, the WHI randomization arm, and the cohort. Results: APOEε4 carriers had steeper cognitive decline in TICS-m, EBMT (immediate and delayed), VF-A, and CVLT scores relative to non-carriers. Higher levels of hs-CRP were associated with steeper cognitive decline in the DST-backwards scores. There was no association of diabetes or any evidence of interactive effects on cognitive decline in our study. Conclusions: In this large longitudinal study of post-menopausal women, our findings support the hypothesis that genetic risk and systemic inflammation independently influence cognitive decline, but there was no evidence of synergistic effects in postmenopausal women. Further research is needed to elucidate the mechanistic pathways underlying these associations with cognitive decline.