This study examines the association of plasma oxidized low-density lipoprotein (OxLDL) levels with all-cause dementia, including Alzheimer's disease (AD) and vascular dementia. Data are taken from the Canadian Study of Health and Aging, a population-based study of a representative sample of persons aged more than 65 years conducted from 1991 to 2002. The present study sample included 670 subjects of which, 155 developed all-cause dementia with 109 cases of AD and 32 of vascular dementia. In Cox regression models, no association between OxLDL and risks of dementia or subtypes was found. A triple interaction between OxLDL, sex, and history of cardiovascular disease on the risk of AD (p = 0.0077) was found. Increased levels of OxLDL were significantly associated with an increased risk of AD in men with a history of cardiovascular disease (hazard ratio = 1.11; 95% confidence interval 1.04–1.19); no association in women was found. These findings suggest that increased levels of OxLDL are not associated with the risk of dementia, AD, and vascular dementia. The association of OxLDL with AD in men with a history of cardiovascular disease merits further investigation.
The definite causes of Alzheimer's disease (AD) are not well established yet. The 2 main hallmark pathologic features of AD are the abnormal accumulation of amyloid-beta (Aβ) peptides leading to senile plaques (Selkoe, 1993) and the hyperphosphorylation of the protein tau forming intracellular neurofibrillary tangles (Selkoe, 2004 and Sobów et al., 2004). Aβ deposits and neurofibrillary tangles are important stimuli for the inflammatory mechanisms observed in the brains of AD patients. Cumulated over many years, the inflammatory mechanism is likely to exacerbate the pathogenic processes that gave rise to it (Akiyama et al., 2000).
In parallel to these processes, increased regional levels of oxidative stress (Markesbery, 1997 and Zhu et al., 2005) and evidence of oxidative damage, mainly oxidized lipids, proteins (Smith et al., 1995), and nucleic acids (Mecocci et al., 1993), can be found in neurodegenerative disorders. Whether oxidative stress plays a key role in the pathogenesis of AD or is just its pathologic manifestation is still controversial (Markesbery, 1997), but some studies indicate that the increase in oxidative stress is one of the earliest changes occurring several years before the disease (Nunomura et al., 2001). Similar signs like an increase in antioxidant levels in the cerebrospinal fluid (CSF) (Kankaanpää et al., 2009) and elevated indices of protein oxidation and lipid peroxidation (Picklo et al., 2002, Sayre et al., 2001 and Subbarao et al., 1990) are detectable in AD patients and in cases of mild cognitive impairment (MCI) (Keller et al., 2005).
Low-density lipoproteins (LDL) are key molecules in the cholesterol transport mechanisms and are susceptible to oxidation into oxidized LDL (OxLDL). OxLDL are immunogenic and also cytotoxic to endothelial cells. Beside their highly atherogenic characteristics (Bhakdi et al., 1995, Steinberg, 1995 and Young and McEneny, 2001), OxLDL are also associated with the development of coronary and vascular diseases (Holvoet et al., 2003, Toshima et al., 2000, Tsimikas et al., 2003 and Zhu et al., 2007). The presence of atherosclerosis has been related to AD in postmortem studies (Jellinger, 2010 and Jellinger and Mitter-Ferstl, 2003). It has been suggested that atherosclerosis, coronary heart disease, and AD may have certain risk factors in common including dyslipidemia, hypertension, oxidative stress, and elevated oxidation levels of LDL (Kivipelto et al., 2001, Pappolla et al., 2003, Sparks, 1997 and Steinberg, 1997).
Unlike its links with coronary heart disease and atherosclerosis, the association between OxLDL levels and AD is still relatively novel and has been less often investigated in the literature. Koyama et al. (2013) evaluated the association between serum OxLDL levels and cognitive impairment in older women and found negative results. The aim of the present study was to evaluate the association between plasma levels of OxLDL and the incidence of all-cause dementia including AD and vascular dementia (VaD) in both sexes. The modification effect of sex, history of cardiovascular disease, and apolipoprotein E e4 allele (apoE4) on the association was also tested.
