Plasma apolipoproteins and physical and cognitive health in very old individuals

Abstract

Apolipoproteins play a crucial role in lipid metabolism with implications in cardiovascular disease, obesity, diabetes, Alzheimer's disease, and longevity. We quantified 7 apolipoproteins in plasma in 1067 individuals aged 56–105 using immunoassays and explored relationships with APOE polymorphism ε2/3/4, vascular health, frailty, and cognition. ApoA1, ApoA2, ApoB, ApoC3, ApoE, ApoH, and ApoJ decreased from mid-life, although ApoE and ApoJ had U-shaped trends. Centenarians had the highest ApoE levels and the lowest frequency of APOE ε4 allele relative to younger groups. Apolipoprotein levels trended lower in APOE ε4 homozygotes and heterozygotes compared with noncarriers, with ApoE and ApoJ being significantly lower. Levels of all apolipoproteins except ApoH were higher in females. Sex- and age-related differences were apparent in the association of apolipoproteins with cognitive performance, as only women had significant negative associations of ApoB, ApoE, ApoH, and ApoJ in mid-life, whereas associations at older age were nonsignificant or positive. Our findings suggest levels of some apolipoproteins, especially ApoE, are associated with lifespan and cognitive function in exceptionally long-lived individuals.

Introduction

The population of the world is aging, with individuals over the age of 90 being the fastest growing proportion of the population. By 2050, the number of centenarians is expected to reach 2.2 million individuals worldwide (Yang et al., 2013). Exceptionally long-lived individuals may be regarded as models of longevity and successful aging, and their study presents a unique opportunity to discover factors that are protective from age-related disease and cognitive decline. This is particularly important as assumptions based on findings from “younger” old cohorts around 70–85 years do not necessarily apply to exceptionally long-lived individuals (Sachdev et al., 2013).

A protein family that has recently been suggested to be of particular relevance to the aging process and longevity are the apolipoproteins. The majority of apolipoproteins are constituents of lipoprotein particles, such as chylomicrons, very low–density lipoproteins, low-density lipoproteins (LDL), and high-density lipoproteins (HDL), which transport lipids between tissues for fuel and cholesterol metabolism (Fig. 1). The apolipoproteins serve as carrier, receptor-binding, and regulatory proteins in these particles. They are therefore crucial components in lipid metabolism with implications for cardiovascular disease, obesity, diabetes mellitus and other diseases (for a review see [Dominiczak and Caslake, 2011]). Apolipoproteins also play roles in immune and vascular functions (Stoll and Bendszus, 2006).

There is evidence that apolipoprotein metabolism changes with age. For example, apolipoprotein J mRNA and protein (ApoJ) were found to be upregulated in cellular senescence (Petropoulou et al., 2001, Trougakos et al., 2006), and the apolipoprotein D gene (APOD) is the most significantly upregulated gene as a function of age in mice, apes, and humans (de Magalhaes et al., 2009, Loerch et al., 2008, Zahn and Kim, 2007). APOD also contributes to an extended life span in the fruit fly (Muffat et al., 2008, Sanchez et al., 2006). The homozygote CC genotype in the promoter region of the apolipoprotein C-III gene (APOC3) is significantly more prevalent among centenarians (Bergman et al., 2007) and is associated with significantly lower serum levels of ApoC3 (Atzmon et al., 2006). Besides their influence on Alzheimer's disease (AD) risk, the ε2 and ε4 alleles of the apolipoprotein E gene (APOE) might also be associated with longevity but in opposing ways. Whereas ε2 has been associated with an increase in life span, ε4 has an adverse effect on life span in multiple studies (Shadyab and LaCroix, 2015).

Apolipoproteins have also been implicated in cognitive decline in the elderly and in AD. We have previously shown that individuals aged 70–90 years with mild cognitive impairment, a potential prodrome of AD, have abnormal plasma levels of apolipoproteins, in particular apolipoprotein H (ApoH) and ApoJ (also known as clusterin with CLU denoting the gene for the ApoJ protein), which were also associated with cognitive decline (Song et al., 2012). Plasma and cerebrospinal fluid levels of ApoJ are emerging as meaningful biomarkers for AD and carriers of CLU risk alleles show faster rates of cognitive decline (Thambisetty et al., 2010, Thambisetty et al., 2013, Yu and Tan, 2012). The APOE ε4 allele is the most significant genetic risk factor for the late onset AD and may be a greater risk factor in females than males (Altmann et al., 2014). This APOE polymorphism may also affect plasma levels of apolipoprotein E (ApoE; Gupta et al., 2011, Slooter et al., 1998); however reports of its effects on levels of other apolipoproteins are limited (Henriques et al., 2014, Song et al., 2012). Furthermore, ApoJ, ApoE as well as apolipoprotein A-I (ApoA1) might interact with amyloid-β (Aβ) peptide to influence its neurotoxicity, aggregation, or clearance from the brain (Narayan et al., 2012, Paula-Lima et al., 2009, Verghese et al., 2013). Methylation of a specific CpG in the APOA1 gene was also associated with memory performance in a cohort of elderly community-dwelling individuals from the Sydney Memory and Ageing Study (MAS; Lazarus et al., 2015).

In this cross-sectional study, we set out to define age-related differences in plasma levels of these proteins and their potential contribution to physical and cognitive health, especially in the oldest old (≥95 years). Specifically, we measured 7 plasma apolipoproteins (ApoA1, ApoA2, ApoB, ApoC3, ApoE, ApoH, and ApoJ) in over 1000 individuals aged from 56 to 105 years to determine age-related differences in apolipoprotein levels. All participants were genotyped for APOE ε4 and ε2 carrier status to investigate the association of APOE polymorphism with plasma apolipoprotein levels. We have used a data-driven (inductive) approach to investigate the relationship of apolipoprotein levels with sex, blood lipids, vascular health, frailty, and cognition in individuals aged from 56 to 105 years with a particular focus on the oldest age group of ≥95 years.