Elsevier

Neurobiology of Aging

Volume 33, Issue 1, January 2012, Pages 196.e1-196.e12
Neurobiology of Aging

Abstract of online article
The role of lipoproteins and inflammation in cognitive decline: Do they interact?

https://doi.org/10.1016/j.neurobiolaging.2010.05.024Get rights and content

Abstract

The aim of this study was to examine the associations between high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol, triglycerides, and cognition and focus on the modifying effect of inflammation. Data were collected in the population-based Longitudinal Aging Study Amsterdam and analyzed with mixed linear models. The sample comprised 1003 persons ≥ 65 years with cognitive data on at least 2 occasions over 6 years of follow-up. Cognition was measured with the Mini-Mental State Examination (general cognition), Auditory Verbal Learning Test (memory), and Coding Task (information processing speed). We found an independent association between high HDL cholesterol and better memory performance. In addition, low LDL cholesterol was predictive of worse general cognitive performance and faster decline on information processing speed. Furthermore, a significant modifying effect of inflammation (C-reactive protein, α-antichymotrypsin) was found. A negative additive effect of low LDL cholesterol and high inflammation was found on general cognition and memory performance. Also, high triglycerides were associated with lower memory performance in those with high inflammation. Thus, a combination of these factors may be used as markers of prolonged lower cognitive functioning.

Introduction

Both lipoproteins, lipids, and inflammation have been linked to dementia and cognitive decline, although their role is complex and mechanisms are still far from clear. In the current study, we focus on the additive effect of these biomarkers on cognitive decline in a population-based sample of older persons.

High levels of low-density lipoprotein (LDL) cholesterol, and low levels of high-density lipoprotein (HDL) cholesterol, both major transport lipoproteins of cholesterol, as well as high lipid levels of triglycerides have been shown to be independently associated with cardiovascular disease (CVD) (Boden, 2000, Morrison and Hokanson, 2009), which in turn is associated with an increased risk of dementia and cognitive impairment (Van Vliet et al., 2009). Inconsistent and even contrasting results have been found in studies focusing on the direct association between lipoproteins and dementia. While some studies have shown an association between high LDL cholesterol and increased dementia risk or worse cognitive functioning (Helzner et al., 2009, Lesser et al., 2009, Moroney et al., 1999, Yaffe et al., 2002), other studies found the opposite effect (Henderson et al., 2003, Packard et al., 2007), or failed to detect an independent association (Reitz et al., 2004, Romas et al., 1999, Yoshitake et al., 1995). High HDL cholesterol has been shown to be associated with better cognitive functioning (Atzmon et al., 2002; Merched et al., 2000, Van Exel et al., 2002) and has been suggested as a protective factor for dementia in most cross-sectional studies (Bonarek et al., 2000, Van Exel et al., 2002, Wolf et al., 2004), while longitudinal studies have not found a significant association with dementia, mild cognitive impairment (MCI), cognitive decline or functioning (Henderson et al., 2003, Reitz et al., 2004, Reitz et al., 2005, Reitz et al., 2008, Tan et al., 2003). In contrast, autopsy studies have shown that higher late-life levels of HDL cholesterol were associated with higher levels of Alzheimer's disease (AD) pathology (Launer et al., 2001) and increasing pathological certainty of AD (Lesser et al., 2009). Some studies focusing on triglycerides have shown that higher triglyceride levels were associated with cognitive decline (De Frias et al., 2007) and poorer cognitive performance (Perlmuter et al., 1988; Sims et al., 2008), while several other studies showed no association with dementia or cognitive decline (Hall et al., 2006, Romas et al., 1999, Yaffe et al., 2002). Furthermore, the metabolic syndrome (MetS), which is defined as a cluster of low HDL cholesterol, high triglycerides, abdominal obesity, impaired fasting glucose, and/or hypertension (Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults, 2001), has been linked to increased risk of dementia, cognitive decline, and poorer cognitive functioning (Dik et al., 2007, Kalmijn et al., 2000; Solfrizzi et al., 2010; Yaffe et al., 2004). Kalmijn et al. (2000) showed that a higher level of triglycerides during midlife was significantly associated with a higher risk of dementia 25 years later. A recent study focusing on MetS, found that higher triglycerides and also lower HDL cholesterol were associated with a higher risk of cognitive impairment in Apolipoprotein E (ApoE) e4 carriers (Lee et al., 2010). Possibly, differences in sample characteristics (e.g., age, baseline cognition, outcome measure (AD, vascular dementia (VaD), cognition), level of lipoproteins, presence of CVD), and adjustment for possible mediating or modifying factors could explain the inconsistent results regarding the role of lipoproteins and triglycerides. Moreover, we hypothesize that inflammation plays a modifying role with respect to the association between lipoproteins and cognition.

Inflammatory processes have been shown to be strongly associated with CVD (Stampfer, 2006) and may play a role in the development of dementia and cognitive decline (Peila and Launer, 2006). Furthermore, inflammatory markers including C-reactive protein (CRP), Interleukin-6 (IL-6), and α-antichymotrypsin (ACT), have been linked to increased dementia risk (Engelhart et al., 2004) and cognitive decline (Dik et al., 2005, Weaver et al., 2002). However, associations have not been found consistently between studies.

Some previous studies have focused on the association between lipids, lipoproteins, and inflammation in older persons. Both lower levels of HDL cholesterol (Arai et al., 2001, Lehtimäki et al., 2005, Zuliani et al., 2007), LDL cholesterol, and total cholesterol (Lehtimäki et al., 2005) as well as acquired hypocholesterolemia (Arai et al., 2001, Ettinger et al., 1995) have been shown to be associated with higher IL-6 (Arai et al., 2001, Ettinger et al., 1995, Lehtimäki et al., 2005, Zuliani et al., 2007) and higher CRP levels (Arai et al., 2001, Ettinger et al., 1995). Furthermore, it has been hypothesized that higher HDL cholesterol may diminish dementia risk by its anti-inflammatory effects (Cockerill et al., 2001). In addition, a synergistic effect of MetS and high inflammation has been shown with respect to increased risk of VaD (Solfrizzi et al., 2010), nonamnestic MCI (Roberts et al., 2010), cognitive decline (Yaffe et al., 2004), and worse cognitive function (Dik et al., 2007). To our knowledge, no study to date has focused on the modifying or mediating effect of inflammation on each of the associations between lipoproteins and triglycerides, and cognitive decline or dementia. In the current study, we focus on the interaction between HDL and LDL cholesterol, triglycerides, and the inflammatory markers CRP, IL-6, and ACT with respect to the trajectory of cognitive functioning in a population-based sample of older persons.

Section snippets

Study sample

For the present study, data were used from the ongoing population-based Longitudinal Aging Study Amsterdam (LASA). Procedures on sampling and data collection have been described in detail elsewhere (Deeg et al., 2002). In short, a random sample of men and women aged 55–85 stratified for age and sex according to the expected 5-year mortality, was drawn from the population registries of 11 municipalities in 3 areas of the Netherlands. Data collection started in 1992/1993, main and medical

Results

In Table 1 the baseline characteristics of the study sample with data on cognitive functioning on at least 2 occasions are shown.

Discussion

In the present longitudinal study we have studied the associations between HDL and LDL cholesterol, triglycerides, and cognitive functioning over 6 years of follow-up and focused on the modifying effect of inflammation on these associations in persons aged 65 years and older. We showed a significant independent nonlinear association between lower LDL cholesterol and a lower level of general cognitive performance and information processing speed, and a faster rate of decline on information

Disclosure statement

None of the authors report any actual or potential conflicts of interest. The authors state that the institution has no contracts relating to this research through which it or any other organization may stand to gain financially now or in the future. The authors state that there are no agreements of authors or their institutions that could be seen as involving a financial interest in this work.

Informed consent was obtained from all respondents, and the study was approved by the Ethical Review

Acknowledgements

The Longitudinal Aging Study Amsterdam is funded largely by the Dutch Ministry of Health, Welfare and Sports, and the Vrije Universiteit.

References (69)

  • G. Zuliani et al.

    High interleukin-6 plasma levels are associated with low HDL-C levels in community-dwelling older adults: the InChianti study

    Atherosclerosis

    (2007)
  • Y. Arai et al.

    Lipoprotein metabolism in Japanese centenarians: effects of apolipoprotein E polymorphism and nutritional status

    J. Am. Geriatr. Soc

    (2001)
  • G. Atzmon et al.

    Plasma HDL levels highly correlate with cognitive function in exceptional longevity

    J. Gerontol. A Biol. Sci. Med. Sci

    (2002)
  • A.T.F. Beekman et al.

    Criterion validity of the Center for Epidemiologic Studies Depression scale (CES-D): results from a community-based sample of older subjects in the Netherlands

    Psychol. Med

    (1997)
  • S. Bhakdi et al.

    Complement and atherogenesis: binding of CRP to degraded, nonoxidized LDL enhances complement activation

    Arterioscler. Thromb. Vasc. Biol

    (1999)
  • W.E. Boden

    High density lipoprotein cholesterol as an independent risk factor in cardiovascular disease: assessing the data from Framingham to the veterans affairs high density lipoprotein intervention trial

    Am. J. Cardiol

    (2000)
  • M. Bonarek et al.

    Relationships between cholesterol, apolipoprotein E polymorphism and dementia: a cross-sectional analysis from the PAQUID study

    Neuroepidemiology

    (2000)
  • S. Brescianini et al.

    Low total cholesterol and increased risk for dying: are low levels clinical warning signs in elderly?Results from the Italian Longitudinal study on Aging

    J. Am. Geriatr. Soc

    (2003)
  • P. Bruins et al.

    Activation of the complement system during and after cardiopulmonary bypass surgery: postsurgery activation involves C-reactive protein and is associated with postoperative arrhythmia

    Circulation

    (1997)
  • G.W. Cockerill et al.

    Elevation of plasma high density lipoprotein concentration reduces interleukin-1-induced expression of E-selectin in an in vivo model of acute inflammation

    Circulation

    (2001)
  • C.A. De Frias et al.

    Cholesterol and triglycerides moderate the effect of apolipoprotein E on memory functioning in older adults

    J. Gerontol. B Psychol. Sci. Soc. Sci

    (2007)
  • M.G. Dik et al.

    Serum inflammatory proteins and cognitive decline in older persons

    Neurology

    (2005)
  • M.G. Dik et al.

    Contribution of metabolic syndrome components to cognition in older individuals

    Diabetes Care

    (2007)
  • M.J. Engelhart et al.

    Inflammatory proteins in plasma and the risk of dementia: the Rotterdam study

    Arch. Neurol

    (2004)
  • W.H. Ettinger et al.

    Evidence for inflammation as a cause of hypocholesterolemia in older people

    J. Am. Geriatr. Soc

    (1995)
  • Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III)

    JAMA

    (2001)
  • W.T. Friedewald et al.

    Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge

    Clin. Chem

    (1972)
  • K. Hall et al.

    Cholesterol, APOE genotype, and Alzheimer disease: an epidemiologic study of Nigerian Yoruba

    Neurology

    (2006)
  • E.P. Helzner et al.

    Contribution of vascular risk factors to the progression in Alzheimer Disease

    Arch. Neurol

    (2009)
  • V.W. Henderson et al.

    Serum lipids and memory in a population based cohort of middle age women

    J. Neurol. Neurosurg. Psychiatry

    (2003)
  • J. Jolles et al.

    Cognitive impairment in elderly peoplePredisposing factors and implications for experimental drug studies

    Drugs Aging

    (1995)
  • K.R. Jun et al.

    Effects of total cholesterol and triglyceride on the percentage difference between the low-density lipoprotein cholesterol concentration measured directly and calculated using the Friedewald formula

    Clin. Chem. Lab. Med

    (2008)
  • S. Kalmijn et al.

    Metabolic cardiovascular syndrome and risk of dementia in Japanese-American elderly men: the Honolulu-Asia Aging Study

    Arterioscler. Thromb. Vasc. Biol

    (2000)
  • L.J. Launer et al.

    Cholesterol and neuropathologic markers of AD: a population-based autopsy study

    Neurology

    (2001)
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