Research Article: Differential associations of plasma lipids with incident dementia and dementia subtypes in the 3C Study: A longitudinal, population-based prospective cohort study

Date Published: March 28, 2017

Publisher: Public Library of Science

Author(s): Sabrina Schilling, Christophe Tzourio, Aïcha Soumaré, Sara Kaffashian, Jean-François Dartigues, Marie-Laure Ancelin, Cécilia Samieri, Carole Dufouil, Stéphanie Debette, Bruce L Miller

Abstract: BackgroundVascular risk factors have been proposed as important targets for the prevention of dementia. As lipid fractions represent easily modifiable targets, we examined the longitudinal relationship of baseline lipid fractions with 13-y incident dementia and its subtypes (Alzheimer disease [AD] and mixed or vascular dementia) in older community-dwelling persons.Methods and findingsNon-institutionalized persons aged 65+ y (n = 9,294) were recruited for the Three-City Study (3C Study), a population-based cohort study from the electoral rolls of the cities of Dijon, Bordeaux, and Montpellier, France, between March 1999 and March 2001. Follow-up examinations were performed every 2 y after the baseline assessment. The final study sample comprised 7,470 participants from the 3C Study (mean age ± standard deviation [SD] 73.8 ± 5.3 y, 61.0% women) who were prospectively followed up for up to 13 y. Fasting lipid fractions (triglycerides [TGs], high-density lipoprotein cholesterol [HDL-C], low-density lipoprotein cholesterol [LDL-C], total cholesterol [TC]) were studied as continuous variables, and results are reported per SD increase of each lipid fraction. Incident dementia and its subtypes were studied as censored variables using Cox models with age as time scale. Analyses were adjusted for sex, study center, and educational level, as well as vascular risk factors and apolipoprotein E (APOE) ε4 genotype. We corrected for multiple testing, yielding a significance threshold of 0.0169. p-Values above the significance threshold but less than 0.05 were considered nominally significant.During a mean (± SD) follow-up period of 7.9 ± 3.6 y, 779 participants developed incident dementia (n = 532 AD and n = 154 mixed or vascular dementia). Higher LDL-C and TC concentrations at baseline were associated with an increased risk of AD (hazard ratio [HR] per SD increase = 1.13 [95% CI 1.04–1.22], p = 0.0045, and HR = 1.12 [1.03–1.22], p = 0.0072, respectively). These associations were largely unchanged after adjustment for vascular risk factors and were attenuated after adjustment for APOEε4 (HR per SD increase = 1.12 [1.03–1.23], p = 0.0110, and HR = 1.12 [1.02–1.23], p = 0.0171, respectively). Higher TG concentrations at baseline were associated with an increased risk of all dementia (HR per SD increase = 1.11 [1.03–1.19], p = 0.0044) and mixed or vascular dementia (HR = 1.21 [1.04–1.41], p = 0.0163). However, these associations disappeared after adjusting for vascular risk factors (HR = 1.07 [0.98–1.17], p = 0.1374, and HR = 1.17 [0.96–1.42], p = 0.1206, respectively). Main limitations of the study include interval censoring of incident dementia cases, potential selective survival bias, and the fact that variation in lipid concentrations during follow-up could not be accounted for in the analyses.ConclusionsIn a large population-based sample of older community-dwelling persons with up to 13 y of follow-up, we observed that higher LDL-C and TC concentrations were associated with an increased risk of AD. This result was independent of vascular risk factors and was attenuated after adjustment for APOEε4 carrier status. TG and HDL-C concentrations were not associated with risk of incident dementia or its subtypes after accounting for vascular risk factors.

Partial Text: Dementia refers to a group of neurological disorders characterized by memory loss, cognitive impairment, and disability in activities of daily living. As the primary risk factor for dementia is old age, the prevalence of dementia is increasing dramatically with aging populations worldwide. As no effective preventive treatment is currently available, the societal burden of dementia is huge and threatening to increase further [1]. The most common form is Alzheimer disease (AD), a neurodegenerative disease representing 50%–70% of dementia cases. Cerebrovascular disease is also a major contributor to dementia risk, often in conjunction with neurodegenerative lesions [2]. Vascular risk factors have been proposed as important targets for the prevention of dementia, with around a third of AD cases being attributable to potentially modifiable risk factors, especially vascular risk factors [3,4], although trials have been inconclusive so far. As lipid fractions represent easily modifiable potential targets for prevention, exploring their relation with dementia risk is of major interest. So far, published studies have shown inconsistent results, including associations of adverse lipid profiles with an increased dementia risk [5–10], absence of an association [11–17], or even inverse associations [18–20]. Important differences between studies—regarding the timing of the measurement of lipid fraction in relation to the diagnosis of dementia, the age at which plasma lipid concentrations were measured, and the duration of follow-up—might at least partly explain these discrepancies. Significant associations of high cholesterol concentrations with dementia [6], AD [7–10], or dementia death [21,22] are described mostly in studies where lipid concentrations were measured in midlife and/or participants were followed for a long period until advanced late life, hence with a long exposure to high cholesterol concentrations. In contrast, studies with lipid measurements in later life or short follow-up periods not reaching the ages at which dementia prevalence is highest either do not observe any association [4,13–15] or sometimes observe inverse relations with dementia risk [18,19]. Moreover, most studies have focused either on total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) or on triglycerides (TGs) and high-density lipoprotein cholesterol (HDL-C); few studies have studied all fractions simultaneously in the same dataset. Interestingly, we and others have recently shown that lipid fractions, notably higher TG concentrations, are significantly associated with white matter hyperintensity (WMH) volume on brain MRI [23–25], a powerful predictor of dementia risk [26]. In the present work, we aimed to evaluate the relationship of lipid fractions (TGs, HDL-C, LDL-C, and TC) with incident dementia in a large cohort of community-dwelling older individuals over a follow-up period of 13 y.

Our sample comprised 7,470 individuals, the characteristics of whom are described in Table 1. Compared to individuals who could not be included in the present study, individuals included were younger; were less likely to have hypercholesterolemia, hypertension, diabetes, and a history of cardiovascular disease; and were less likely to be APOEε4 carriers, but were more likely to take lipid-lowering medication. Included individuals also had lower TG and higher HDL-C concentrations, lower systolic and diastolic blood pressures, a higher educational level, and a higher MMSE score at baseline. As expected, lipid fractions were correlated with one another, the strongest correlations being observed between LDL-C and TC, and between TG and HDL-C (S1 Table).

In a cohort comprising 7,470 community-dwelling older persons, of whom 779 developed dementia over 13 y, associations of higher LDL-C, TC, and TGs with incident dementia were observed. When looking at dementia subtypes, we observed distinct patterns for the different lipid fractions: higher baseline LDL-C and TC concentrations were associated with AD, while higher baseline TG concentrations were associated with vascular or mixed dementia. For LDL-C and TC, associations were unchanged after accounting for vascular risk factors, but were attenuated after adjusting for APOEε4 carrier status. For TGs, the results were no longer significant after adjusting for vascular risk factors. HDL-C concentrations were not associated with risk of incident dementia or its subtypes.



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