Association of Apolipoprotein E in Lipoprotein Subspecies With Risk of Dementia

Question What is the association of apolipoprotein E (apoE) protein levels in different lipoproteins with cognitive function and risk of dementia? Findings In this case-cohort study including 1351 community-dwelling participants 74 years and older, the presence of apoE in high-density lipoproteins that lack apoC3 was associated with better cognitive function and decreased risk of dementia. In contrast, the presence of apoE in high-density lipoproteins that contain apoC3 was unrelated to cognitive function and risk of dementia. Meaning The findings of this study extend the beneficial associations of the novel apoE-positive, apoC3-negative lipoprotein from cardiovascular disease to dementia. To evaluate associations of apolipoprotein E protein levels in different lipoproteins with cognitive function and risk of dementia, this case-cohort study embedded in the Ginkgo Evaluation of Memory Study analyzed data from 1351 community-dwelling participants 74 years and older, and found the presence of apoE in high-density lipoproteins that lack apolipoprotein C3 was associated with better cognitive function and decreased risk of dementia. Importance The epsilon 4 allele of the apolipoprotein E (APOE) gene and lower apolipoprotein E (apoE) protein levels in plasma are risk factors for Alzheimer disease, but the underlying biological mechanisms are not fully understood. Half of plasma apoE circulates on high-density lipoproteins (HDLs). Higher apoE levels in plasma HDL were previously found to be associated with lower coronary heart disease risk, but the coexistence of another apolipoprotein, apoC3, modified this lower risk. Objective To investigate associations between the presence of apoE in different lipoproteins with cognitive function, particularly the risk of dementia. Design, Setting, and Participants This prospective case-cohort study embedded in the Ginkgo Evaluation of Memory Study (2000-2008) analyzed data from 1351 community-dwelling participants 74 years and older. Of this group, 995 participants were free of dementia at baseline (recruited from September 2000 to June 2002) and 521 participants were diagnosed with incident dementia during follow-up until 2008. Data analysis was performed from January 2018 to December 2019. Exposures Enzyme-linked immunosorbent assay-measured concentration of apoE in whole plasma, HDL-depleted plasma (non-HDL), HDL, and HDL subspecies that contain or lack apoC3 or apoJ. Main Outcomes and Measures Adjusted hazard ratios for risk of dementia and Alzheimer disease during follow-up and adjusted differences (beta coefficients) in Alzheimer Disease Assessment-Cognitive Subscale (ADAS-cog) and Modified Mini-Mental State Examination scores at baseline. Results Among 1351 participants, the median (interquartile range) age was 78 (76-81) years; 639 (47.3%) were women. The median (interquartile range) follow-up time was 5.9 (3.7-6.5) years. Higher whole plasma apoE levels and higher apoE levels in HDL were associated with better cognitive function assessed by ADAS-cog (whole plasma, beta coefficient, -0.15; 95% CI, -0.24 to -0.06; HDL, beta coefficient, -0.20; 95% CI, -0.30 to -0.10) but were unassociated with dementia or Alzheimer disease risk. When separated by apoC3, a higher apoE level in HDL that lacks apoC3 was associated with better cognitive function (ADAS-cog per SD: beta coefficient, 0.17; 95% CI, -0.27 to -0.07; Modified Mini-Mental State Examination score per SD: beta coefficient, 0.25; 95% CI, 0.07 to 0.42) and lower risk of dementia (hazard ratio per SD, 0.86; 95% CI, 0.76 to 0.99). In contrast, apoE levels in HDL that contains apoC3 were unassociated with any of these outcomes. Conclusions and Relevance In a prospective cohort of older adults with rigorous follow-up of dementia, the apoE level in HDL that lacked apoC3 was associated with better cognitive function and lower dementia risk. This finding suggests that the cardioprotective associations of this novel lipoprotein extend to dementia.